|
1
|
Syed YY. Catumaxomab: First Approval. Drugs 2025:10.1007/s40265-025-02187-9. [PMID: 40304879 DOI: 10.1007/s40265-025-02187-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2025] [Indexed: 05/02/2025]
Abstract
Catumaxomab (Korjuny®) is a first-in-class bispecific trifunctional rat-mouse hybrid monoclonal antibody currently under development with Lindis Biotech for malignant ascites, and bladder, gastric and ovarian cancers. It binds epithelial cell adhesion molecule (EpCAM) on tumour cells and CD3 on T cells, while its Fc domain engages Fcγ receptor-positive accessory cells, bringing immune and tumour cells into close proximity to enhance tumour cell killing through multiple immunological mechanisms. Initially approved in the EU on 20 April 2009 for malignant ascites in adults with EpCAM+ carcinomas when standard therapy was unavailable or no longer feasible, catumaxomab was marketed by Fresenius Biotech GmbH (later Neovii Biotech GmbH) before being withdrawn on 2 June 2017 for commercial reasons. Lindis Biotech later acquired the rights and pursued reapproval. On 11 February 2025, catumaxomab was approved in the EU for the intraperitoneal treatment of malignant ascites in adults with EpCAM+ carcinomas who are not eligible for further systemic anticancer therapy. This article summarizes the milestones in the development of catumaxomab leading to this new approval.
Collapse
Affiliation(s)
- Yahiya Y Syed
- Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New Zealand.
| |
Collapse
|
|
2
|
Gu Y, Zhao Q. Clinical Progresses and Challenges of Bispecific Antibodies for the Treatment of Solid Tumors. Mol Diagn Ther 2024; 28:669-702. [PMID: 39172329 PMCID: PMC11512917 DOI: 10.1007/s40291-024-00734-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2024] [Indexed: 08/23/2024]
Abstract
In recent years, bispecific antibodies (BsAbs) have emerged as a promising therapeutic strategy against tumors. BsAbs can recruit and activate immune cells, block multiple signaling pathways, and deliver therapeutic payloads directly to tumor sites. This review provides a comprehensive overview of the recent advances in the development and clinical application of BsAbs for the treatment of solid tumors. We discuss the different formats, the unique mechanisms of action, and the clinical outcomes of the most advanced BsAbs in solid tumor therapy. Several studies have also analyzed the clinical progress of bispecific antibodies. However, this review distinguishes itself by exploring the challenges associated with bispecific antibodies and proposing potential solutions. As the field progresses, BsAbs hold promise to redefine cancer treatment paradigms and offer new hope to patients with solid tumors.
Collapse
Affiliation(s)
- Yuheng Gu
- Cancer Centre, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China
| | - Qi Zhao
- Cancer Centre, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China.
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR, 999078, China.
| |
Collapse
|
|
3
|
Saini S, Gulati N, Awasthi R, Arora V, Singh SK, Kumar S, Gupta G, Dua K, Pahwa R, Dureja H. Monoclonal Antibodies and Antibody-drug Conjugates as Emerging Therapeutics for Breast Cancer Treatment. Curr Drug Deliv 2024; 21:993-1009. [PMID: 37519200 DOI: 10.2174/1567201820666230731094258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 06/01/2023] [Accepted: 06/26/2023] [Indexed: 08/01/2023]
Abstract
When breast cells divide and multiply out of control, it is called breast cancer. Symptoms include lump formation in the breast, a change in the texture or color of the breast, or a discharge from the nipple. Local or systemic therapy is frequently used to treat breast cancer. Surgical and radiation procedures limited to the affected area are examples of local management. There has been significant worldwide progress in the development of monoclonal antibodies (mAbs) since 1986, when the first therapeutic mAb, Orthoclone OKT3, became commercially available. mAbs can resist the expansion of cancer cells by inducing the destruction of cellular membranes, blocking immune system inhibitors, and preventing the formation of new blood vessels. mAbs can also target growth factor receptors. Understanding the molecular pathways involved in tumor growth and its microenvironment is crucial for developing effective targeted cancer therapeutics. Due to their unique properties, mAbs have a wide range of clinical applications. Antibody-drug conjugates (ADCs) are drugs that improve the therapeutic index by combining an antigen-specific antibody with a payload. This review focuses on the therapeutic applications, mechanistic insights, characteristics, safety aspects, and adverse events of mAbs like trastuzumab, bevacizumab, pertuzumab, ertumaxomab, and atezolizumab in breast cancer treatment. The creation of novel technologies utilizing modified antibodies, such as fragments, conjugates, and multi-specific antibodies, must be a central focus of future studies. This review will help scientists working on developing mAbs to treat cancers more effectively.
Collapse
Affiliation(s)
- Swati Saini
- Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, Haryana, 136119, India
| | - Nisha Gulati
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana, 124001, India
| | - Rajendra Awasthi
- Department of Pharmaceutical Sciences, School of Health Sciences & Technology, University of Petroleum and Energy Studies (UPES), Bidholi, Dehradun 248 007, Uttarakhand, India
| | - Vimal Arora
- University Institute of Pharma Sciences, Chandigarh University, Gharuan, Mohali, Punjab, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, 144411, Punjab, India
| | - Shobhit Kumar
- Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology (MIET), Meerut, Uttar Pradesh, 250005, India
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jaipur, India
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW, 2007, Australia
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia
| | - Rakesh Pahwa
- Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, Haryana, 136119, India
| | - Harish Dureja
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana, 124001, India
| |
Collapse
|
|
4
|
Lan HR, Chen M, Yao SY, Chen JX, Jin KT. Bispecific antibodies revolutionizing breast cancer treatment: a comprehensive overview. Front Immunol 2023; 14:1266450. [PMID: 38111570 PMCID: PMC10725925 DOI: 10.3389/fimmu.2023.1266450] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 11/16/2023] [Indexed: 12/20/2023] Open
Abstract
Breast cancer (BCa) is known as a complex and prevalent disease requiring the development of novel anticancer therapeutic approaches. Bispecific antibodies (BsAbs) have emerged as a favorable strategy for BCa treatment due to their unique ability to target two different antigens simultaneously. By targeting tumor-associated antigens (TAAs) on cancer cells, engaging immune effector cells, or blocking critical signaling pathways, BsAbs offer enhanced tumor specificity and immune system involvement, improving anti-cancer activity. Preclinical and clinical studies have demonstrated the potential of BsAbs in BCa. For example, BsAbs targeting human epidermal growth factor receptor 2 (HER2) have shown the ability to redirect immune cells to HER2-positive BCa cells, resulting in effective tumor cell killing. Moreover, targeting the PD-1/PD-L1 pathway by BsAbs has demonstrated promising outcomes in overcoming immunosuppression and enhancing immune-mediated tumor clearance. Combining BsAbs with existing therapeutic approaches, such as chemotherapy, targeted therapies, or immune checkpoint inhibitors (ICIs), has also revealed synergistic effects in preclinical models and early clinical trials, emphasizing the usefulness and potential of BsAbs in BCa treatment. This review summarizes the latest evidence about BsAbs in treating BCa and the challenges and opportunities of their use in BCa.
Collapse
Affiliation(s)
- Huan-Rong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China
| | - Min Chen
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Shi-Ya Yao
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Jun-Xia Chen
- Department of Gynecology, Shaoxing People’s Hospital, Shaoxing, Zhejiang, China
| | - Ke-Tao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| |
Collapse
|
|
5
|
Singh S, Tian W, Severance ZC, Chaudhary SK, Anokhina V, Mondal B, Pergu R, Singh P, Dhawa U, Singha S, Choudhary A. Proximity-inducing modalities: the past, present, and future. Chem Soc Rev 2023; 52:5485-5515. [PMID: 37477631 DOI: 10.1039/d2cs00943a] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/22/2023]
Abstract
Living systems use proximity to regulate biochemical processes. Inspired by this phenomenon, bifunctional modalities that induce proximity have been developed to redirect cellular processes. An emerging example of this class is molecules that induce ubiquitin-dependent proteasomal degradation of a protein of interest, and their initial development sparked a flurry of discovery for other bifunctional modalities. Recent advances in this area include modalities that can change protein phosphorylation, glycosylation, and acetylation states, modulate gene expression, and recruit components of the immune system. In this review, we highlight bifunctional modalities that perform functions other than degradation and have great potential to revolutionize disease treatment, while also serving as important tools in basic research to explore new aspects of biology.
Collapse
Affiliation(s)
- Sameek Singh
- Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
| | - Wenzhi Tian
- Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
| | - Zachary C Severance
- Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
| | - Santosh K Chaudhary
- Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
| | - Viktoriya Anokhina
- Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
| | - Basudeb Mondal
- Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
| | - Rajaiah Pergu
- Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
| | - Prashant Singh
- Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
| | - Uttam Dhawa
- Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
| | - Santanu Singha
- Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
| | - Amit Choudhary
- Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Divisions of Renal Medicine and Engineering, Brigham and Women's Hospital, Boston, MA 02115, USA
| |
Collapse
|
|
6
|
Han MY, Borazanci EH. Malignant ascites in pancreatic cancer: Pathophysiology, diagnosis, molecular characterization, and therapeutic strategies. Front Oncol 2023; 13:1138759. [PMID: 37007072 PMCID: PMC10060830 DOI: 10.3389/fonc.2023.1138759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Malignant ascites is the accumulation of fluid in the peritoneum as a result of advanced cancer and often signifies the terminal phase of the disease. Management of malignant ascites remains a clinical challenge as symptom palliation is the current standard of cure. Previously, studies examining malignant ascites largely focused on ovarian and gastric cancer. In recent years, there has been a significant increase in research on malignant ascites in pancreatic cancer. Malignant ascites is usually diagnosed based on positive cytology, but cytology is not always diagnostic, indicating the need for novel diagnostic tools and biomarkers. This review aims to summarize the current understanding of malignant ascites in pancreatic cancer and the recent advances in the molecular characterization of malignant ascites fluid from patients with pancreatic cancer including analysis of soluble molecules and extracellular vesicles. Current standard of care treatment options such as paracenteses and diuretics are outlined along with new emerging treatment strategies such as immunotherapy and small-molecule based therapies. New potential investigative directions resulting from these studies are also highlighted.
Collapse
Affiliation(s)
- Margaret Y. Han
- Department of Biosciences, Rice University, Houston, TX, United States
| | - Erkut H. Borazanci
- Department of Oncology, HonorHealth Research Institute, Scottsdale, AZ, United States
- *Correspondence: Erkut H. Borazanci,
| |
Collapse
|
|
7
|
Ivasko SM, Anders K, Grunewald L, Launspach M, Klaus A, Schwiebert S, Ruf P, Lindhofer H, Lode HN, Andersch L, Schulte JH, Eggert A, Hundsdoerfer P, Künkele A, Zirngibl F. Combination of GD2-directed bispecific trifunctional antibody therapy with Pd-1 immune checkpoint blockade induces anti-neuroblastoma immunity in a syngeneic mouse model. Front Immunol 2023; 13:1023206. [PMID: 36700232 PMCID: PMC9869131 DOI: 10.3389/fimmu.2022.1023206] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 11/22/2022] [Indexed: 01/11/2023] Open
Abstract
Introduction Despite advances in treating high-risk neuroblastoma, 50-60% of patients still suffer relapse, necessitating new treatment options. Bispecific trifunctional antibodies (trAbs) are a promising new class of immunotherapy. TrAbs are heterodimeric IgG-like molecules that bind CD3 and a tumor-associated antigen simultaneously, whereby inducing a TCR-independent anti-cancer T cell response. Moreover, via their functional Fc region they recruit and activate cells of the innate immune system like antigen-presenting cells potentially enhancing induction of adaptive tumor-specific immune responses. Methods We used the SUREK trAb, which is bispecific for GD2 and murine Cd3. Tumor-blind trAb and the monoclonal ch14.18 antibody were used as controls. A co-culture model of murine dendritic cells (DCs), T cells and a neuroblastoma cell line was established to evaluate the cytotoxic effect and the T cell effector function in vitro. Expression of immune checkpoint molecules on tumor-infiltrating T cells and the induction of an anti-neuroblastoma immune response using a combination of whole cell vaccination and trAb therapy was investigated in a syngeneic immunocompetent neuroblastoma mouse model (NXS2 in A/J background). Finally, vaccinated mice were assessed for the presence of neuroblastoma-directed antibodies. We show that SUREK trAb-mediated effective killing of NXS2 cells in vitro was strictly dependent on the combined presence of DCs and T cells. Results Using a syngeneic neuroblastoma mouse model, we showed that vaccination with irradiated tumor cells combined with SUREK trAb treatment significantly prolonged survival of tumor challenged mice and partially prevent tumor outgrowth compared to tumor vaccination alone. Treatment led to upregulation of programmed cell death protein 1 (Pd-1) on tumor infiltrating T cells and combination with anti-Pd-1 checkpoint inhibition enhanced the NXS2-directed humoral immune response. Conclusion Here, we provide first preclinical evidence that a tumor vaccination combined with SUREK trAb therapy induces an endogenous anti-neuroblastoma immune response reducing tumor recurrence. Furthermore, a combination with anti-Pd-1 immune checkpoint blockade might even further improve this promising immunotherapeutic concept in order to prevent relapse in high-risk neuroblastoma patients.
Collapse
Affiliation(s)
- Sara Marie Ivasko
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany,Berlin Institute of Health (BIH), Berlin, Germany
| | - Kathleen Anders
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany,German Cancer Consortium (DKTK), Berlin, Germany
| | - Laura Grunewald
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Michael Launspach
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany,Berlin Institute of Health (BIH), Berlin, Germany
| | - Anika Klaus
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Silke Schwiebert
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Peter Ruf
- Trion Research, Martinsried, Germany
| | | | - Holger N. Lode
- Pediatric Hematology and Oncology, University Medicine Greifswald, Greifswald, Germany
| | - Lena Andersch
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Johannes H. Schulte
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany,German Cancer Consortium (DKTK), Berlin, Germany,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Angelika Eggert
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany,German Cancer Consortium (DKTK), Berlin, Germany,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Patrick Hundsdoerfer
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany,Department of Pediatrics, HELIOS Klinikum Berlin Buch, Berlin, Germany
| | - Annette Künkele
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany,Berlin Institute of Health (BIH), Berlin, Germany,German Cancer Consortium (DKTK), Berlin, Germany,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Felix Zirngibl
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany,Berlin Institute of Health (BIH), Berlin, Germany,*Correspondence: Felix Zirngibl,
| |
Collapse
|
|
8
|
Wei GX, Du Y, Zhou YW, Li LJ, Qiu M. Peritoneal carcinomatosis with intraperitoneal immunotherapy: current treatment options and perspectives. Expert Rev Gastroenterol Hepatol 2022; 16:851-861. [PMID: 36107723 DOI: 10.1080/17474124.2022.2125866] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Peritoneal carcinomatosis (PC) is an advanced malignancy that is not sensitive to systemic conventional chemotherapy. Treatment options for PC are usually palliative rather than curative. Cytoreductive surgery and hyperthermic intraperitoneal (IP) chemotherapy are associated with limited efficacy in patients with PC. However, the peritoneum can produce effective immunity by inducing T-lymphocyte recruitment and proliferation, and the unique immune environment of the peritoneum provides the rationale for IP immunotherapy in PC. AREAS COVERED The authors retrieved relevant documents of IP immunotherapy for PC from PubMed and Medline. This review elaborates on the knowledge of the peritoneal immune microenvironment and IP immunotherapy for PC covering immune stimulators, radioimmunotherapy, catumaxomab, cancer vaccines, chimeric antigen receptor (CAR)-T cells, and immune checkpoint inhibitors. EXPERT OPINION The prognosis of PC is poor. However, the peritoneal cavity is a unique immune compartment with abundant immune cells which can produce effective immunity. IP immunotherapy may be a promising strategy in patients with PC.
Collapse
Affiliation(s)
- Gui-Xia Wei
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yang Du
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yu-Wen Zhou
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Lin-Juan Li
- Thoracic Oncology Ward, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Meng Qiu
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| |
Collapse
|
|
9
|
Underwood DJ, Bettencourt J, Jawad Z. The manufacturing considerations of bispecific antibodies. Expert Opin Biol Ther 2022; 22:1043-1065. [PMID: 35771976 DOI: 10.1080/14712598.2022.2095900] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Antibody therapies have made huge strides in providing safe and efficacious drugs for autoimmune, cancer and infectious disease. These bispecific antibodies can be assembled from the basic building blocks of IgGs, resulting in dozens of formats. AREAS COVERED It is important to consider the manufacturability of these formats early in the antibody discovery phases. Broadly categorizing bispecific antibodies into IgG-like, fragment-based, appended and hybrid formats can help in looking at early manufacturability considerations. EXPERT OPINION Ideally, bispecific antibody manufacturing should contain a minimal number of steps, with processes that give high yields of protein with no contaminants. Many of these have been determined for the fragment-based bispecific blinatumomab and the IgG-like bispecifics from hybridomas. However, for new formats, these need to be considered early in the research and development pipeline. The hybrid formats offer an unusual alternative in generating high pure yields of bispecific molecules if the engineering challenges can be deciphered.
Collapse
Affiliation(s)
| | | | - Zahra Jawad
- Agenus inc., 3 Forbes Road, Lexington, MA, 02421-7305, United States.,Creasallis ltd, Babraham Research Campus, Babraham, Cambridgeshire, CB22 3AT, United Kingdom
| |
Collapse
|
|
10
|
Jin S, Sun Y, Liang X, Gu X, Ning J, Xu Y, Chen S, Pan L. Emerging new therapeutic antibody derivatives for cancer treatment. Signal Transduct Target Ther 2022; 7:39. [PMID: 35132063 PMCID: PMC8821599 DOI: 10.1038/s41392-021-00868-x] [Citation(s) in RCA: 240] [Impact Index Per Article: 80.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 12/14/2021] [Accepted: 12/16/2021] [Indexed: 12/18/2022] Open
Abstract
Monoclonal antibodies constitute a promising class of targeted anticancer agents that enhance natural immune system functions to suppress cancer cell activity and eliminate cancer cells. The successful application of IgG monoclonal antibodies has inspired the development of various types of therapeutic antibodies, such as antibody fragments, bispecific antibodies, and antibody derivatives (e.g., antibody-drug conjugates and immunocytokines). The miniaturization and multifunctionalization of antibodies are flexible and viable strategies for diagnosing or treating malignant tumors in a complex tumor environment. In this review, we summarize antibodies of various molecular types, antibody applications in cancer therapy, and details of clinical study advances. We also discuss the rationale and mechanism of action of various antibody formats, including antibody-drug conjugates, antibody-oligonucleotide conjugates, bispecific/multispecific antibodies, immunocytokines, antibody fragments, and scaffold proteins. With advances in modern biotechnology, well-designed novel antibodies are finally paving the way for successful treatments of various cancers, including precise tumor immunotherapy, in the clinic.
Collapse
Affiliation(s)
- Shijie Jin
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Yanping Sun
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Xiao Liang
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Xinyu Gu
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Jiangtao Ning
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Yingchun Xu
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Shuqing Chen
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China.
- Department of Precision Medicine on Tumor Therapeutics, ZJU-Hangzhou Global Scientific and Technological Innovation Center, 311200, Hangzhou, China.
| | - Liqiang Pan
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China.
- The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China.
- Key Laboratory of Pancreatic Disease of Zhejiang Province, 310003, Hangzhou, China.
| |
Collapse
|
|
11
|
García-Fernández C, Saz A, Fornaguera C, Borrós S. Cancer immunotherapies revisited: state of the art of conventional treatments and next-generation nanomedicines. Cancer Gene Ther 2021; 28:935-946. [PMID: 33837365 DOI: 10.1038/s41417-021-00333-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/24/2021] [Accepted: 03/24/2021] [Indexed: 02/02/2023]
Abstract
Nowadays, the landscape of cancer treatments has broadened thanks to the clinical application of immunotherapeutics. After decades of failures, cancer immunotherapy represents an exciting alternative for those patients suffering from a wide variety of cancers, especially for those skin cancers, such as the early stages of melanoma. However, those cancers affecting internal organs still face a long way to success, because of the poor biodistribution of immunotherapies. Here, nanomedicine appears as a hopeful strategy to modulate the biodistribution aiming at target organ accumulation. In this way, efficacy will be improved, while reducing the side effects at the same time. In this review, we aim to highlight the most promising cancer immunotherapeutic strategies. From monoclonal antibodies and their traditional use as targeted therapies to their current use as immune checkpoint inhibitors; as well as adoptive cell transfer therapies; oncolytic viruses, and therapeutic cancer vaccination. Then, we aim to discuss the important role of nanomedicine to improve the performance of these immunotherapeutic tools to finally review the already marketed nanomedicine-based cancer immunotherapies.
Collapse
Affiliation(s)
- Coral García-Fernández
- Grup d'Enginyeria de Materials (Gemat), Institut Químic de Sarrià (IQS), Univeritat Ramon Llull (URL), Barcelona, Spain
| | - Anna Saz
- Grup d'Enginyeria de Materials (Gemat), Institut Químic de Sarrià (IQS), Univeritat Ramon Llull (URL), Barcelona, Spain
| | - Cristina Fornaguera
- Grup d'Enginyeria de Materials (Gemat), Institut Químic de Sarrià (IQS), Univeritat Ramon Llull (URL), Barcelona, Spain.
| | - Salvador Borrós
- Grup d'Enginyeria de Materials (Gemat), Institut Químic de Sarrià (IQS), Univeritat Ramon Llull (URL), Barcelona, Spain
| |
Collapse
|
|
12
|
Zirngibl F, Ivasko SM, Grunewald L, Klaus A, Schwiebert S, Ruf P, Lindhofer H, Astrahantseff K, Andersch L, Schulte JH, Lode HN, Eggert A, Anders K, Hundsdoerfer P, Künkele A. GD2-directed bispecific trifunctional antibody outperforms dinutuximab beta in a murine model for aggressive metastasized neuroblastoma. J Immunother Cancer 2021; 9:jitc-2021-002923. [PMID: 34285106 PMCID: PMC8292814 DOI: 10.1136/jitc-2021-002923] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/18/2021] [Indexed: 11/13/2022] Open
Abstract
Background Neuroblastoma is the most common extracranial solid tumor of childhood. Patients with high-risk disease undergo extremely aggressive therapy and nonetheless have cure rates below 50%. Treatment with the ch14.18 monoclonal antibody (dinutuximab beta), directed against the GD2 disialoganglioside, improved 5-year event-free survival in high-risk patients when administered in postconsolidation therapy and was recently implemented in standard therapy. Relapse still occurred in 57% of these patients, necessitating new therapeutic options. Bispecific trifunctional antibodies (trAbs) are IgG-like molecules directed against T cells and cancer surface antigens, redirecting T cells (via their CD3 specificity) and accessory immune cells (via their functioning Fc-fragment) toward tumor cells. We sought proof-of-concept for GD2/CD3-directed trAb efficacy against neuroblastoma. Methods We used two GD2-specific trAbs differing only in their CD3-binding specificity: EKTOMUN (GD2/human CD3) and SUREK (GD2/mouse Cd3). This allowed trAb evaluation in human and murine experimental settings. Tumor-blind trAb and the ch14.18 antibody were used as controls. A coculture model of human peripheral blood mononuclear cells (PBMCs) and neuroblastoma cell lines was established to evaluate trAb antitumor efficacy by assessing expression of T-cell surface markers for activation, proinflammatory cytokine release and cytotoxicity assays. Characteristics of tumor-infiltrating T cells and response of neuroblastoma metastases to SUREK treatment were investigated in a syngeneic immunocompetent neuroblastoma mouse model mimicking minimal residual disease. Results We show that EKTOMUN treatment caused effector cell activation and release of proinflammatory cytokines in coculture with neuroblastoma cell lines. Furthermore, EKTOMUN mediated GD2-dependent cytotoxic effects in human neuroblastoma cell lines in coculture with PBMCs, irrespective of the level of target antigen expression. This effect was dependent on the presence of accessory immune cells. Treatment with SUREK reduced the intratumor Cd4/Cd8 ratio and activated tumor infiltrating T cells in vivo. In a minimal residual disease model for neuroblastoma, we demonstrated that single-agent treatment with SUREK strongly reduced or eliminated neuroblastoma metastases in vivo. SUREK as well as EKTOMUN demonstrated superior tumor control compared with the anti-GD2 antibody, ch14.18. Conclusions Here we provide proof-of-concept for EKTOMUN preclinical efficacy against neuroblastoma, presenting this bispecific trAb as a promising new agent to fight neuroblastoma.
Collapse
Affiliation(s)
- Felix Zirngibl
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany .,Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Sara M Ivasko
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Laura Grunewald
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Anika Klaus
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Silke Schwiebert
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Peter Ruf
- Trion Research, Martinsried, Germany
| | | | - Kathy Astrahantseff
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Lena Andersch
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Johannes H Schulte
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Partner Site Berlin CCCC, German Cancer Consortium, Berlin, Berlin, Germany
| | - Holger N Lode
- Pediatric Hematology and Oncology, University Medicine Greifswald, Greifswald, Germany
| | - Angelika Eggert
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Partner Site Berlin CCCC, German Cancer Consortium, Berlin, Berlin, Germany
| | - Kathleen Anders
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Partner Site Berlin CCCC, German Cancer Consortium, Berlin, Berlin, Germany
| | - Patrick Hundsdoerfer
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Department of Pediatrics, HELIOS Klinikum Berlin-Buch, Berlin, Germany
| | - Annette Künkele
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Partner Site Berlin CCCC, German Cancer Consortium, Berlin, Berlin, Germany
| |
Collapse
|
|
13
|
First time intravesically administered trifunctional antibody catumaxomab in patients with recurrent non-muscle invasive bladder cancer indicates high tolerability and local immunological activity. Cancer Immunol Immunother 2021; 70:2727-2735. [PMID: 33837852 PMCID: PMC8360869 DOI: 10.1007/s00262-021-02930-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 03/26/2021] [Indexed: 11/30/2022]
Abstract
Transurethral resection of the tumor (TUR-B) followed by adjuvant intravesical treatment with cytostatic drugs or Bacillus Calmette–Guérin (BCG) as standard therapy of non-muscle-invasive bladder cancer (NMIBC) is associated with a high recurrence rate of about 60–70%, considerable side effects and requires close monitoring. Alternative treatment options are warranted. Two patients with epithelial cell adhesion molecule (EpCAM)-positive recurrent non-muscle invasive bladder cancer were treated the first time by an intravesical administration of the trifunctional bispecific EpCAM targeting antibody catumaxomab (total dosage of 470 and 1120 µg, respectively). The binding and killing activity of catumaxomab in urine milieu was evaluated in vitro. In contrast to its previous systemic application catumaxomab was well tolerated without any obvious signs of toxicity. Relevant cytokine plasma levels were not detected and no significant systemic drug release was observed. The induction of a human anti-mouse-antibody (HAMA) reaction was either absent or untypically weak contrary to the high immunogenicity of intraperitoneal applied catumaxomab. Tumor cells that were detectable in urine patient samples disappeared after catumaxomab therapy. Endoscopically confirmed recurrence-free intervals were 32 and 25 months. Our data suggest that intravesical administration of catumaxomab in NMIBC is feasible, safe and efficacious, thus arguing for further clinical development of catumaxomab in this indication.
Collapse
|
|
14
|
Nordmaj MA, Roberts ME, Sachse ES, Dagil R, Andersen AP, Skeltved N, Grunddal KV, Erdoğan SM, Choudhary S, Gustsavsson T, Ørum-Madsen MS, Moskalev I, Tian W, Yang Z, Clausen TM, Theander TG, Daugaard M, Nielsen MA, Salanti A. Development of a bispecific immune engager using a recombinant malaria protein. Cell Death Dis 2021; 12:353. [PMID: 33824272 PMCID: PMC8024270 DOI: 10.1038/s41419-021-03611-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 03/01/2021] [Accepted: 03/11/2021] [Indexed: 11/20/2022]
Abstract
As an immune evasion and survival strategy, the Plasmodium falciparum malaria parasite has evolved a protein named VAR2CSA. This protein mediates sequestration of infected red blood cells in the placenta through the interaction with a unique carbohydrate abundantly and exclusively present in the placenta. Cancer cells were found to share the same expression of this distinct carbohydrate, termed oncofetal chondroitin sulfate on their surface. In this study we have used a protein conjugation system to produce a bispecific immune engager, V-aCD3, based on recombinant VAR2CSA as the cancer targeting moiety and an anti-CD3 single-chain variable fragment linked to a single-chain Fc as the immune engager. Conjugation of these two proteins resulted in a single functional moiety that induced immune mediated killing of a broad range of cancer cells in vitro and facilitated tumor arrest in an orthotopic bladder cancer xenograft model.
Collapse
Affiliation(s)
- Mie A Nordmaj
- Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.,Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Morgan E Roberts
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Emilie S Sachse
- Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.,Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Robert Dagil
- Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.,Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Anne Poder Andersen
- Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.,Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Nanna Skeltved
- Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.,Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Kaare V Grunddal
- Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.,Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Sayit Mahmut Erdoğan
- Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.,Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Swati Choudhary
- Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.,Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Tobias Gustsavsson
- Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.,Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Maj Sofie Ørum-Madsen
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Igor Moskalev
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Weihua Tian
- Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Zhang Yang
- Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Thomas M Clausen
- Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.,Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.,Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, 92093, United States
| | - Thor G Theander
- Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.,Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Mads Daugaard
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Morten A Nielsen
- Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.,Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Ali Salanti
- Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. .,Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
| |
Collapse
|
|
15
|
Hosseini SS, Khalili S, Baradaran B, Bidar N, Shahbazi MA, Mosafer J, Hashemzaei M, Mokhtarzadeh A, Hamblin MR. Bispecific monoclonal antibodies for targeted immunotherapy of solid tumors: Recent advances and clinical trials. Int J Biol Macromol 2020; 167:1030-1047. [PMID: 33197478 DOI: 10.1016/j.ijbiomac.2020.11.058] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/04/2020] [Accepted: 11/09/2020] [Indexed: 02/07/2023]
Abstract
Bispecific antibodie (BsAbs) combine two or more epitope-recognizing sequences into a single protein molecule. The first therapeutic applications of BsAbs were focused on cancer therapy. However, these antibodies have grown to cover a wider disease spectrum, including imaging, diagnosis, prophylaxis, and therapy of inflammatory and autoimmune diseases. BsAbs can be categorized into IgG-like formats and non-IgG-like formats. Different technologies have been used for the construction of BsAbs including "CrossMAb", "Quadroma", "knobs-into-holes" and molecular cloning. The mechanism of action for BsAbs includes the induction of CDC, ADCC, ADCP, apoptosis, and recruitment of cell surface receptors, as well as activation or inhibition of signaling pathways. The first clinical trials included mainly leukemia and lymphoma, but solid tumors are now being investigated. The BsAbs bind to a tumor-specific antigen using one epitope, while the second epitope binds to immune cell receptors such as CD3, CD16, CD64, and CD89, with the goal of stimulating the immune response against cancer cells. Currently, over 20 different commercial methods have been developed for the construction of BsAbs. Three BsAbs are currently clinically approved and marketed, and more than 85 clinical trials are in progress. In the present review, we discuss recent trends in the design, engineering, clinical applications, and clinical trials of BsAbs in solid tumors.
Collapse
Affiliation(s)
- Seyed Samad Hosseini
- Department of Biotechnology, Higher Education Institute of Rab-Rashid, Tabriz, Iran
| | - Saeed Khalili
- Department of Biology Sciences, Faculty of Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Negar Bidar
- Department of Biotechnology, Higher Education Institute of Rab-Rashid, Tabriz, Iran
| | - Mohammad-Ali Shahbazi
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki FI-00014, Finland; Department of Pharmaceutical Nanotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Jafar Mosafer
- Nanotechnology Research center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biotechnology, School of Paramedical Science, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Mahmoud Hashemzaei
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Zabol University of Medical Sciences, Zabol, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, 02114, USA; Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA; Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa.
| |
Collapse
|
|
16
|
Developing Trojan horses to induce, diagnose and suppress Alzheimer’s pathology. Pharmacol Res 2019; 149:104471. [DOI: 10.1016/j.phrs.2019.104471] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 09/17/2019] [Accepted: 09/30/2019] [Indexed: 01/05/2023]
|
|
17
|
Parakh S, King D, Gan HK, Scott AM. Current Development of Monoclonal Antibodies in Cancer Therapy. Recent Results Cancer Res 2019; 214:1-70. [PMID: 31473848 DOI: 10.1007/978-3-030-23765-3_1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Exploiting the unique specificity of monoclonal antibodies has revolutionized the treatment and diagnosis of haematological and solid organ malignancies; bringing benefit to millions of patients over the past decades. Recent achievements include conjugating antibodies with toxic payloads resulting in superior efficacy and/or reduced toxicity, development of molecular imaging techniques targeting specific antigens for use as predictive and prognostic biomarkers, the development of novel bi- and tri-specific antibodies to enhance therapeutic benefit and abrogate resistance and the success of immunotherapy agents. In this chapter, we review an overview of antibody structure and function relevant to cancer therapy and provide an overview of pivotal clinical trials which have led to regulatory approval of monoclonal antibodies in cancer treatment. We further discuss resistance mechanisms and the unique side effects of each class of antibody and provide an overview of emerging therapeutic agents.
Collapse
Affiliation(s)
- Sagun Parakh
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Heidelberg, Melbourne, VIC, 3084, Australia.,Department of Medical Oncology, Olivia Newton-John Cancer and Wellness Centre, Austin Health, Heidelberg, Melbourne, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Australia
| | - Dylan King
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Heidelberg, Melbourne, VIC, 3084, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Australia
| | - Hui K Gan
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Heidelberg, Melbourne, VIC, 3084, Australia.,Department of Medical Oncology, Olivia Newton-John Cancer and Wellness Centre, Austin Health, Heidelberg, Melbourne, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Australia
| | - Andrew M Scott
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Heidelberg, Melbourne, VIC, 3084, Australia. .,School of Cancer Medicine, La Trobe University, Melbourne, Australia. .,Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia. .,Department of Medicine, University of Melbourne, Melbourne, Australia.
| |
Collapse
|
|
18
|
Kholodenko RV, Kalinovsky DV, Doronin II, Ponomarev ED, Kholodenko IV. Antibody Fragments as Potential Biopharmaceuticals for Cancer Therapy: Success and Limitations. Curr Med Chem 2019; 26:396-426. [DOI: 10.2174/0929867324666170817152554] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 07/17/2017] [Accepted: 07/24/2017] [Indexed: 12/23/2022]
Abstract
Monoclonal antibodies (mAbs) are an important class of therapeutic agents approved for the therapy of many types of malignancies. However, in certain cases applications of conventional mAbs have several limitations in anticancer immunotherapy. These limitations include insufficient efficacy and adverse effects. The antigen-binding fragments of antibodies have a considerable potential to overcome the disadvantages of conventional mAbs, such as poor penetration into solid tumors and Fc-mediated bystander activation of the immune system. Fragments of antibodies retain antigen specificity and part of functional properties of conventional mAbs and at the same time have much better penetration into the tumors and a greatly reduced level of adverse effects. Recent advantages in antibody engineering allowed to produce different types of antibody fragments with improved structure and properties for efficient elimination of tumor cells. These molecules opened up new perspectives for anticancer therapy. Here, we will overview the structural features of the various types of antibody fragments and their applications for anticancer therapy as separate molecules and as part of complex conjugates or structures. Mechanisms of antitumor action of antibody fragments as well as their advantages and disadvantages for clinical application will be discussed in this review.
Collapse
Affiliation(s)
- Roman V. Kholodenko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho- Maklaya St., 16/10, Moscow 117997, Russian Federation
| | - Daniel V. Kalinovsky
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho- Maklaya St., 16/10, Moscow 117997, Russian Federation
| | - Igor I. Doronin
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho- Maklaya St., 16/10, Moscow 117997, Russian Federation
| | - Eugene D. Ponomarev
- School of Biomedical Sciences, Faculty of Medicine and Brain, The Chinese University of Hong Kong, Shatin NT, Hong Kong
| | - Irina V. Kholodenko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho- Maklaya St., 16/10, Moscow 117997, Russian Federation
| |
Collapse
|
|
19
|
Abstract
Bispecific antibodies have moved from being an academic curiosity with therapeutic promise to reality, with two molecules being currently commercialized (Hemlibra® and Blincyto®) and many more in clinical trials. The success of bispecific antibodies is mainly due to the continuously growing number of mechanisms of actions (MOA) they enable that are not accessible to monoclonal antibodies. One of the earliest MOA of bispecific antibodies and currently the one with the largest number of clinical trials is the redirecting of the cytotoxic activity of T-cells for oncology applications, now extending its use in infective diseases. The use of bispecific antibodies for crossing the blood-brain barrier is another important application because of its potential to advance the therapeutic options for neurological diseases. Another noteworthy application due to its growing trend is enabling a more tissue-specific delivery or activity of antibodies. The different molecular solutions to the initial hurdles that limited the development of bispecific antibodies have led to the current diverse set of bispecific or multispecific antibody formats that can be grouped into three main categories: IgG-like formats, antibody fragment-based formats, or appended IgG formats. The expanded applications of bispecific antibodies come at the price of additional challenges for clinical development. The rising complexity in their structure may increase the risk of immunogenicity and the multiple antigen specificity complicates the selection of relevant species for safety assessment.
Collapse
Affiliation(s)
- Bushra Husain
- Protein Chemistry Department, Genentech Inc., South San Francisco, CA, 94080, USA
| | - Diego Ellerman
- Protein Chemistry Department, Genentech Inc., South San Francisco, CA, 94080, USA.
| |
Collapse
|
|
20
|
Knödler M, Körfer J, Kunzmann V, Trojan J, Daum S, Schenk M, Kullmann F, Schroll S, Behringer D, Stahl M, Al-Batran SE, Hacker U, Ibach S, Lindhofer H, Lordick F. Randomised phase II trial to investigate catumaxomab (anti-EpCAM × anti-CD3) for treatment of peritoneal carcinomatosis in patients with gastric cancer. Br J Cancer 2018; 119:296-302. [PMID: 29988111 PMCID: PMC6070920 DOI: 10.1038/s41416-018-0150-6] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 05/12/2018] [Accepted: 05/21/2018] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Peritoneal carcinomatosis (PC) represents an unfavourable prognostic factor for patients with gastric cancer (GC). Intraperitoneal treatment with the bispecific and trifunctional antibody catumaxomab (EpCAM, CD3), in addition to systemic chemotherapy, could improve elimination of PC. METHODS This prospective, randomised, phase II study investigated the efficacy of catumaxomab followed by chemotherapy (arm A, 5-fluorouracil, leucovorin, oxaliplatin, docetaxel, FLOT) or FLOT alone (arm B) in patients with GC and PC. Primary endpoint was the rate of macroscopic complete remission (mCR) of PC at the time of second diagnostic laparoscopy/laparotomy prior to optional surgery. RESULTS Median follow-up was 52 months. Out of 35 patients screened, 15 were allocated to arm A and 16 to arm B. mCR rate was 27% in arm A and 19% in arm B (p = 0.69). Severe side effects associated with catumaxomab were nausea, infection, abdominal pain, and elevated liver enzymes. Median progression-free (6.7 vs. 5.4 months, p = 0.71) and overall survival (13.2 vs. 13.0 months, p = 0.97) were not significantly different in both treatment arms. CONCLUSIONS Addition of catumaxomab to systemic chemotherapy was feasible and tolerable in advanced GC. Although the primary endpoint could not be demonstrated, results are promising for future investigations integrating intraperitoneal immunotherapy into a multimodal treatment strategy.
Collapse
Affiliation(s)
- Maren Knödler
- University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Leipzig, Germany.
| | - Justus Körfer
- University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Leipzig, Germany
| | - Volker Kunzmann
- Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - Jörg Trojan
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Severin Daum
- Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, University Hospital Berlin (Charite), Campus Benjamin Franklin, Berlin, Germany
| | - Michael Schenk
- Department of Clinical Oncology and Hematology, Hospital Barmherzige Brüder Regensburg, Regensburg, Germany
| | - Frank Kullmann
- Department of Internal Medicine I, Hospital Weiden, Weiden, Germany
| | - Sebastian Schroll
- Department of Internal Medicine III, Hospital Braunschweig, Braunschweig, Germany
| | - Dirk Behringer
- Department of Hematology, Oncology and Palliative Medicine, Augusta-Kranken-Anstalt, Bochum, Germany
| | - Michael Stahl
- Department of Clinical Oncology and Hematology, Hospital Essen-Mitte Essen, Essen, Germany
| | - Salah-Eddin Al-Batran
- Department of Clinical Oncology and Hematology, Hospital Nordwest GmbH, Frankfurt, Germany
| | - Ulrich Hacker
- University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Leipzig, Germany
| | - Stefan Ibach
- WiSP Scientific Service Pharma GmbH, Langenfeld, Germany
| | | | - Florian Lordick
- University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Leipzig, Germany
| |
Collapse
|
|
21
|
Deppisch N, Ruf P, Eißler N, Lindhofer H, Mocikat R. Potent CD4+ T cell-associated antitumor memory responses induced by trifunctional bispecific antibodies in combination with immune checkpoint inhibition. Oncotarget 2018; 8:4520-4529. [PMID: 27966460 PMCID: PMC5354850 DOI: 10.18632/oncotarget.13888] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 12/05/2016] [Indexed: 12/13/2022] Open
Abstract
Combinatorial approaches of immunotherapy hold great promise for the treatment of malignant disease. Here, we examined the potential of combining an immune checkpoint inhibitor and trifunctional bispecific antibodies (trAbs) in a preclinical melanoma mouse model using surrogate antibodies of Ipilimumab and Catumaxomab, both of which have already been approved for clinical use. The specific binding arms of trAbs redirect T cells to tumor cells and trigger direct cytotoxicity, while the Fc region activates accessory cells eventually giving rise to a long-lasting immunologic memory. We show here that T cells redirected to tumor cells by trAbs strongly upregulate CTLA-4 expression in vitro and in vivo. This suggested that blocking of CTLA-4 in combination with trAb treatment enhances T-cell activation in a tumor-selective manner. However, when mice were challenged with melanoma cells and subsequently treated with antibodies, there was only a moderate beneficial effect of the combinatorial approach in vivo with regard to direct tumor destruction in comparison to trAb therapy alone. By contrast, a significantly improved vaccination effect was obtained by CTLA-4 blocking during trAb-dependent immunization. This resulted in enhanced rejection of melanoma cells given after pre-immunization. The improved immunologic memory induced by the combinatorial approach correlated with an increased humoral antitumor response as measured in the sera and an expansion of CD4+ memory T cells found in the spleens.
Collapse
Affiliation(s)
- Nina Deppisch
- Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Germany
| | - Peter Ruf
- Trion Research GmbH, Martinsried, Germany
| | - Nina Eißler
- Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Germany
| | | | - Ralph Mocikat
- Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Germany.,AG Translationale Molekulare Immunologie, Helmholtz-Zentrum München, Germany
| |
Collapse
|
|
22
|
The state-of-play and future of antibody therapeutics. Adv Drug Deliv Rev 2017; 122:2-19. [PMID: 27916504 DOI: 10.1016/j.addr.2016.11.004] [Citation(s) in RCA: 215] [Impact Index Per Article: 26.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 11/26/2016] [Accepted: 11/28/2016] [Indexed: 12/22/2022]
Abstract
It has been over four decades since the development of monoclonal antibodies (mAbs) using a hybridoma cell line was first reported. Since then more than thirty therapeutic antibodies have been marketed, mostly as oncology, autoimmune and inflammatory therapeutics. While antibodies are very efficient, their cost-effectiveness has always been discussed owing to their high costs, accumulating to more than one billion dollars from preclinical development through to market approval. Because of this, therapeutic antibodies are inaccessible to some patients in both developed and developing countries. The growing interest in biosimilar antibodies as affordable versions of therapeutic antibodies may provide alternative treatment options as well potentially decreasing costs. As certain markets begin to capitalize on this opportunity, regulatory authorities continue to refine the requirements for demonstrating quality, efficacy and safety of biosimilar compared to originator products. In addition to biosimilars, innovations in antibody engineering are providing the opportunity to design biobetter antibodies with improved properties to maximize efficacy. Enhancing effector function, antibody drug conjugates (ADC) or targeting multiple disease pathways via multi-specific antibodies are being explored. The manufacturing process of antibodies is also moving forward with advancements relating to host cell production and purification processes. Studies into the physical and chemical degradation pathways of antibodies are contributing to the design of more stable proteins guided by computational tools. Moreover, the delivery and pharmacokinetics of antibody-based therapeutics are improving as optimized formulations are pursued through the implementation of recent innovations in the field.
Collapse
|
|
23
|
Liu H, Pan Y, Meng S, Zhang W, Zhou F. Current treatment options of T cell-associated immunotherapy in multiple myeloma. Clin Exp Med 2017; 17:431-439. [PMID: 28120217 DOI: 10.1007/s10238-017-0450-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 12/15/2016] [Indexed: 11/29/2022]
Abstract
Multiple myeloma (MM) is a complex disease and is presently an incurable malignant plasma cell tumor. Although the introduction of proteasome inhibitor and the immunomodulators markedly improved the effect of myeloma therapy, most patients still suffer from relapse even with an initially effective therapy. Accumulating evidence suggests that immunotherapy is a promising option in treating MM. And T cell plays crucial role through inducing sustained immune response in vivo in the immunotherapy of tumors. In this article, we will discuss progress of several T cell-based immunotherapies with insight into how they eradicate myeloma cells and their disadvantages.
Collapse
Affiliation(s)
- Hailing Liu
- Department of Clinical Hematology, Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Yunbao Pan
- Department of Pathology, Affiliated Hospital, Wuxi Medical School, Jiangnan University, Wuxi, 214062, Jiangsu, China
| | - Shan Meng
- Department of Clinical Hematology, Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Wanggang Zhang
- Department of Clinical Hematology, Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Fuling Zhou
- Department of Clinical Hematology, Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, 710004, China.
- Department of Clinical Hematology, Zhongnan Hospital, Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan, 430071, Hubei, China.
| |
Collapse
|
|
24
|
Zhang X, Yang Y, Fan D, Xiong D. The development of bispecific antibodies and their applications in tumor immune escape. Exp Hematol Oncol 2017; 6:12. [PMID: 28469973 PMCID: PMC5414286 DOI: 10.1186/s40164-017-0072-7] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 04/27/2017] [Indexed: 12/13/2022] Open
Abstract
During the past two decades, a great evolution of bispecific antibodies (BsAbs) for therapeutic applications has been made. BsAbs can bind simultaneously two different antigens or epitopes, which leads to a wide range of applications including redirecting T cells or NK cells to tumor cells, blocking two different signaling pathways, dual targeting of different disease mediators, and delivering payloads to targeted sites. Aside from approved catumaxomab (anti-CD3 and anti-EpCAM) and blinatumomab (anti-CD3 and anti-CD19), many more BsAbs are now in various phases of clinical development. Here, this review focus on the development of bispecific antibodies and their applications in tumor immune escape.
Collapse
Affiliation(s)
- Xiaolong Zhang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, 300020 People's Republic of China
| | - Yuanyuan Yang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, 300020 People's Republic of China
| | - Dongmei Fan
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, 300020 People's Republic of China
| | - Dongsheng Xiong
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, 300020 People's Republic of China
| |
Collapse
|
|
25
|
Kintzing JR, Filsinger Interrante MV, Cochran JR. Emerging Strategies for Developing Next-Generation Protein Therapeutics for Cancer Treatment. Trends Pharmacol Sci 2016; 37:993-1008. [PMID: 27836202 PMCID: PMC6238641 DOI: 10.1016/j.tips.2016.10.005] [Citation(s) in RCA: 144] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 10/11/2016] [Accepted: 10/11/2016] [Indexed: 12/12/2022]
Abstract
Protein-based therapeutics have been revolutionizing the oncology space since they first appeared in the clinic two decades ago. Unlike traditional small-molecule chemotherapeutics, protein biologics promote active targeting of cancer cells by binding to cell-surface receptors and other markers specifically associated with or overexpressed on tumors versus healthy tissue. While the first approved cancer biologics were monoclonal antibodies, the burgeoning field of protein engineering is spawning research on an expanded range of protein formats and modifications that allow tuning of properties such as target-binding affinity, serum half-life, stability, and immunogenicity. In this review we highlight some of these strategies and provide examples of modified and engineered proteins under development as preclinical and clinical-stage drug candidates for the treatment of cancer.
Collapse
Affiliation(s)
- James R Kintzing
- Department of Bioengineering, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford, CA, USA
| | - Maria V Filsinger Interrante
- Department of Bioengineering, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford, CA, USA
| | - Jennifer R Cochran
- Department of Bioengineering, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford, CA, USA; Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
| |
Collapse
|
|
26
|
Ströhlein MA, Heiss MM, Jauch KW. The current status of immunotherapy in peritoneal carcinomatosis. Expert Rev Anticancer Ther 2016; 16:1019-27. [PMID: 27530056 DOI: 10.1080/14737140.2016.1224666] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Peritoneal carcinomatosis (PC) is a cancer disease with an urgent need for effective treatment. Conventional chemotherapy failed to show acceptable results. Cytoreductive surgery and hyperthermic chemoperfusion (HIPEC) are only beneficial in few patients with resectable peritoneal metastasis. Immunotherapy could be attractive against PC, as all requirements for immunotherapy are available in the peritoneal cavity. AREAS COVERED This review analyzes the present literature for immunotherapy of PC. Advances from immune stimulators, radionucleotide-conjugated- and bispecific antibodies to future developments like adoptive engineered T-cells with chimeric receptors are discussed. The clinical development of catumaxomab, which was the first intraperitoneal immunotherapy to be approved for clinical treatment, is discussed. The requirements for future developments are illustrated. Expert commentary: Immunotherapy of peritoneal carcinomatosis is manageable, showing striking cancer cell killing. Improved profiles of adverse events by therapy-induced cytokine release, enhanced specific killing and optimal treatment schedules within multimodal treatment will be key factors.
Collapse
Affiliation(s)
- Michael Alfred Ströhlein
- a Department of Abdominal, Vascular and Transplant Surgery, Cologne Merheim Medical Center , Witten/Herdecke University , Cologne , Germany
| | - Markus Maria Heiss
- a Department of Abdominal, Vascular and Transplant Surgery, Cologne Merheim Medical Center , Witten/Herdecke University , Cologne , Germany
| | - Karl-Walter Jauch
- b Medical Center of the Ludwig Maximilian University Munich , Munich , Germany
| |
Collapse
|
|
27
|
Liu M, Li Z, Yang J, Jiang Y, Chen Z, Ali Z, He N, Wang Z. Cell-specific biomarkers and targeted biopharmaceuticals for breast cancer treatment. Cell Prolif 2016; 49:409-20. [PMID: 27312135 PMCID: PMC6496337 DOI: 10.1111/cpr.12266] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Accepted: 05/04/2016] [Indexed: 12/13/2022] Open
Abstract
Breast cancer is the second leading cause of cancer death among women, and its related treatment has been attracting significant attention over the past decades. Among the various treatments, targeted therapy has shown great promise as a precision treatment, by binding to cancer cell-specific biomarkers. So far, great achievements have been made in targeted therapy of breast cancer. In this review, we first discuss cell-specific biomarkers, which are not only useful for classification of breast cancer subtyping but also can be utilized as goals for targeted therapy. Then, the innovative and generic-targeted biopharmaceuticals for breast cancer, including monoclonal antibodies, non-antibody proteins and small molecule drugs, are reviewed. Finally, we provide our outlook on future developments of biopharmaceuticals, and provide solutions to problems in this field.
Collapse
Affiliation(s)
- Mei Liu
- School of Biological Science and Medical EngineeringSoutheast UniversityNanjingChina
| | - Zhiyang Li
- School of Biological Science and Medical EngineeringSoutheast UniversityNanjingChina
- Department of Laboratory MedicineNanjing Drum Tower Hospital Clinical CollegeNanjing UniversityNanjingChina
| | - Jingjing Yang
- School of Chemistry and Chemical EngineeringSoutheast UniversityNanjingChina
| | - Yanyun Jiang
- School of Chemistry and Chemical EngineeringSoutheast UniversityNanjingChina
| | - Zhongsi Chen
- School of Biological Science and Medical EngineeringSoutheast UniversityNanjingChina
| | - Zeeshan Ali
- School of Chemistry and Chemical EngineeringSoutheast UniversityNanjingChina
| | - Nongyue He
- School of Biological Science and Medical EngineeringSoutheast UniversityNanjingChina
| | - Zhifei Wang
- School of Chemistry and Chemical EngineeringSoutheast UniversityNanjingChina
| |
Collapse
|
|
28
|
Haense N, Atmaca A, Pauligk C, Steinmetz K, Marmé F, Haag GM, Rieger M, Ottmann OG, Ruf P, Lindhofer H, Al-Batran SE. A phase I trial of the trifunctional anti Her2 × anti CD3 antibody ertumaxomab in patients with advanced solid tumors. BMC Cancer 2016; 16:420. [PMID: 27387446 PMCID: PMC4937525 DOI: 10.1186/s12885-016-2449-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Accepted: 06/27/2016] [Indexed: 11/10/2022] Open
Abstract
Background Ertumaxomab (ertu) is a bispecific, trifunctional antibody targeting Her2/neu, CD3 and the Fcγ-receptors I, IIa, and III forming a tri-cell complex between tumor cell, T cell and accessory cells. Methods Patients (pts) with Her2/neu (1+/SISH positive, 2+ and 3+) expressing tumors progressing after standard therapy were treated to investigate safety, tolerability and preliminary efficacy. In this study, ertu was applied i.v. in 2 cycles following a predefined dose escalating scheme. Each cycle consisted of five ascending doses (10–500 μg) applied weekly within 28 days with a 21 day treatment-free interval. If 2 pts experienced a dose limiting toxicity (DLT) at a given dose level, the maximum tolerated dose (MTD) had been exceeded. Results Fourteen heavily pretreated pts (e.g. breast, rectal, gastric cancer) were enrolled in the four main cohorts. Three (21 %) pts had to be replaced. Two serious adverse events (SAE) with possible relation to the investigational drug were seen, both fully reversible. A DLT was not detected. Consequently, the MTD could not be determined. All adverse events (AE) were transient and completely reversible. Most frequent AEs were fatigue (14/14), pain (13/14), cephalgia (12/14), chills (11/14), nausea (8/14), fever (7/14), emesis (7/14) and diarrhea (5/14). Single doses up to 300 μg were well tolerated (total dose up to 800 μg per cycle). We observed one partial remission and two disease stabilizations after first treatment cycle. Conclusions Single doses up to 300 μg could be safely administered in an escalating dose scheme. Immunological responses and clinical activity warrant further evaluation in patients with Her2 over expressing tumors. Trial registration EudraCT number: 2011-003201-14; ClinicalTrials.gov identifier: NCT01569412
Collapse
Affiliation(s)
- N Haense
- Institute of clinical research (IKF) at Krankenhaus Nordwest, UCT-University Cancer Center, Steinbacher Hohl 2-26, 60488, Frankfurt am Main, Germany
| | - A Atmaca
- Department of Hematology and Oncology, Krankenhaus Nordwest, UCT-University Cancer Center, Steinbacher Hohl 2-26, 60488, Frankfurt am Main, Germany
| | - C Pauligk
- Institute of clinical research (IKF) at Krankenhaus Nordwest, UCT-University Cancer Center, Steinbacher Hohl 2-26, 60488, Frankfurt am Main, Germany
| | - K Steinmetz
- Institute of clinical research (IKF) at Krankenhaus Nordwest, UCT-University Cancer Center, Steinbacher Hohl 2-26, 60488, Frankfurt am Main, Germany
| | - F Marmé
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany
| | - G M Haag
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany
| | - M Rieger
- Onkologische Schwerpunktpraxis, Eschollbrücker Str. 26, 64295, Darmstadt, Germany
| | - O G Ottmann
- Department of Medicine, Hematology and Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany
| | - P Ruf
- TRION Research GmbH, Am Klopferspitz 19, 82152, Martinsried, Germany
| | - H Lindhofer
- TRION Research GmbH, Am Klopferspitz 19, 82152, Martinsried, Germany
| | - S-E Al-Batran
- Institute of clinical research (IKF) at Krankenhaus Nordwest, UCT-University Cancer Center, Steinbacher Hohl 2-26, 60488, Frankfurt am Main, Germany.
| |
Collapse
|
|
29
|
Pilanc KN, Ordu Ç, Akpnar H, Balc C, Başsülü N, Köksal Üİ, Elbüken F, Okutur K, Bülbül G, Sağlam S, Demir G. Dramatic Response to Catumaxomab Treatment for Malign Ascites Related to Renal Cell Carcinoma With Sarcomotoid Differentiation. Am J Ther 2016; 23:e1078-e1081. [PMID: 24732906 DOI: 10.1097/mjt.0000000000000064] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Refractory malignant ascites (MA) is a common complication in cancer patients. Renal cell carcinoma (RCC) is rarely present with peritoneal ascites, which is commonly associated with carcinomas of the gastrointestinal and female reproductive tracts; including especially ovarian high-grade serous carcinoma. Currently, chemotherapy and paracentesis represent the most widely used methods to relieve the symptoms. Recently, intraperitoneal therapy with catumaxomab-a trifunctional hybrid antibody-has been introduced for the treatment of MA. The benefit of this treatment has been demonstrated in patients with distinct abdominal malignancies. In this case report, we present the first case of successful catumaxomab treatment against MA in a patient with advanced RCC with sarcomatoid differentiation. After the second administration of catumaxomab, paracentesis became no longer necessary. Catumaxomab might represent a safe treatment option for MA in the course of metastatic RCC with sarcomatoid differentiation.
Collapse
Affiliation(s)
- Kezban Nur Pilanc
- Departments of 1Medical Oncology, 2Urology, 3Radiology, and 4Pathology, Faculty of Medicine, Bilim University; and 5Department of Radiology, Gayrettepe Florence Nightingale Hospital, Instanbul, Turkey
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Abstract
Cancer immunotherapy has recently generated much excitement after the continuing success of the immunomodulating anti-CTLA-4 and anti-PD-1 antibodies against various types of cancers. Aside from these immunomodulating antibodies, bispecific antibodies, chimeric antigen receptor T cells, and other technologies are being actively studied. Among the various approaches to cancer immunotherapy, 2 bispecific antibodies are currently approved for patient care. Many more bispecific antibodies are now in various phases of clinical development and will become the next generation of antibody-based therapies. Further understanding of immunology and advances in protein engineering will help to generate a greater variety of bispecific antibodies to fight cancer. Here, we focus on bispecific antibodies that recruit immune cells to engage and kill tumor cells.
Collapse
Affiliation(s)
- Siqi Chen
- a School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou , China.,b Center for Cellular & Structural Biology, Sun Yat-Sen University , Guangzhou , China
| | - Jing Li
- a School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou , China.,b Center for Cellular & Structural Biology, Sun Yat-Sen University , Guangzhou , China
| | - Qing Li
- a School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou , China.,b Center for Cellular & Structural Biology, Sun Yat-Sen University , Guangzhou , China
| | - Zhong Wang
- a School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou , China.,b Center for Cellular & Structural Biology, Sun Yat-Sen University , Guangzhou , China
| |
Collapse
|
|
31
|
Abstract
PURPOSE OF REVIEW Adoptive T-cell therapy has become one of the most exciting fields of cancer therapy in the past few years. In this article, we describe a method which combines adoptive T-cell therapy with antibody therapy by arming T cells from cord blood, normal patients, and cancer patients with bispecific antibodies capable of binding to tumor-associated antigens on one side of the bispecific antibody construct and T cells on another side of the construct. This approach redirects T cells against tumor cells in a non-MHC-restricted manner. RECENT FINDINGS Various methods for manipulating the immune system including check-point inhibitors, chimeric antigen receptor T cells, and bispecific antibodies have shown promising activity in treating both hematological malignancies and solid tumors with excellent success. In recent studies, activated T cells armed with bispecific antibodies have shown good preclinical activity, safety, and promising efficacy in the clinical trials. SUMMARY Activated T cells armed with bispecific antibodies represent a promising treatment for cancer immunotherapy.
Collapse
|
|
32
|
Carvalho S, Levi‐Schaffer F, Sela M, Yarden Y. Immunotherapy of cancer: from monoclonal to oligoclonal cocktails of anti-cancer antibodies: IUPHAR Review 18. Br J Pharmacol 2016; 173:1407-24. [PMID: 26833433 PMCID: PMC4831314 DOI: 10.1111/bph.13450] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Revised: 01/14/2016] [Accepted: 01/20/2016] [Indexed: 12/11/2022] Open
Abstract
Antibody-based therapy of cancer employs monoclonal antibodies (mAbs) specific to soluble ligands, membrane antigens of T-lymphocytes or proteins located at the surface of cancer cells. The latter mAbs are often combined with cytotoxic regimens, because they block survival of residual fractions of tumours that evade therapy-induced cell death. Antibodies, along with kinase inhibitors, have become in the last decade the mainstay of oncological pharmacology. However, partial and transient responses, as well as emergence of tumour resistance, currently limit clinical application of mAbs. To overcome these hurdles, oligoclonal antibody mixtures are being tested in animal models and in clinical trials. The first homo-combination of two mAbs, each engaging a distinct site of HER2, an oncogenic receptor tyrosine kinase (RTK), has been approved for treatment of breast cancer. Likewise, a hetero-combination of antibodies to two distinct T-cell antigens, PD1 and CTLA4, has been approved for treatment of melanoma. In a similar vein, additive or synergistic anti-tumour effects observed in animal models have prompted clinical testing of hetero-combinations of antibodies simultaneously engaging distinct RTKs. We discuss the promise of antibody cocktails reminiscent of currently used mixtures of chemotherapeutics and highlight mechanisms potentially underlying their enhanced clinical efficacy.
Collapse
Affiliation(s)
- Silvia Carvalho
- Department of Biological RegulationWeizmann Institute of ScienceRehovotIsrael
| | - Francesca Levi‐Schaffer
- Pharmacology and Experimental Therapeutics Unit, Institute for Drug Research, School of Pharmacy, Faculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael
| | - Michael Sela
- Department of ImmunologyWeizmann Institute of ScienceRehovotIsrael
| | - Yosef Yarden
- Department of Biological RegulationWeizmann Institute of ScienceRehovotIsrael
| |
Collapse
|
|
33
|
Kiefer JD, Neri D. Immunocytokines and bispecific antibodies: two complementary strategies for the selective activation of immune cells at the tumor site. Immunol Rev 2016; 270:178-92. [PMID: 26864112 PMCID: PMC5154379 DOI: 10.1111/imr.12391] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The activation of the immune system for a selective removal of tumor cells represents an attractive strategy for the treatment of metastatic malignancies, which cannot be cured by existing methodologies. In this review, we examine the design and therapeutic potential of immunocytokines and bispecific antibodies, two classes of bifunctional products which can selectively activate the immune system at the tumor site. Certain protein engineering aspects, such as the choice of the antibody format, are common to both classes of therapeutic agents and can have a profound impact on tumor homing performance in vivo of individual products. However, immunocytokines and bispecific antibodies display different mechanisms of action. Future research activities will reveal whether an additive of even synergistic benefit can be obtained from the judicious combination of these two types of biopharmaceutical agents.
Collapse
Affiliation(s)
- Jonathan D Kiefer
- Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland
| | - Dario Neri
- Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland
| |
Collapse
|
|
34
|
Menderes G, Schwab CL, Black J, Santin AD. The Role of the Immune System in Ovarian Cancer and Implications on Therapy. Expert Rev Clin Immunol 2016; 12:681-95. [PMID: 26821930 DOI: 10.1586/1744666x.2016.1147957] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States. While the treatment options have improved with conventional cytotoxic chemotherapy and advanced surgical techniques, disease recurrence is common and fatal in nearly all cases. Current evidence suggests that the immune system and its ability to recognize and eliminate microscopic disease is paramount in preventing recurrence. The goal of immunotherapy is to balance the activation of the immune system against cancer while preventing the potential for tremendous toxicity elicited by immune modulation. In this paper we will review the role of immune system in disease pathogenesis and different immunotherapies available for the treatment of ovarian cancer as well as current ongoing studies and potential future directions.
Collapse
Affiliation(s)
- Gulden Menderes
- a Department of Obstetrics, Gynecology & Reproductive Sciences , Yale University School of Medicine , New Haven , CT , USA
| | - Carlton L Schwab
- a Department of Obstetrics, Gynecology & Reproductive Sciences , Yale University School of Medicine , New Haven , CT , USA
| | - Jonathan Black
- a Department of Obstetrics, Gynecology & Reproductive Sciences , Yale University School of Medicine , New Haven , CT , USA
| | - Alessandro D Santin
- a Department of Obstetrics, Gynecology & Reproductive Sciences , Yale University School of Medicine , New Haven , CT , USA
| |
Collapse
|
|
35
|
Taking up Cancer Immunotherapy Challenges: Bispecific Antibodies, the Path Forward? Antibodies (Basel) 2015; 5:antib5010001. [PMID: 31557983 PMCID: PMC6698871 DOI: 10.3390/antib5010001] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 12/15/2015] [Accepted: 12/18/2015] [Indexed: 02/07/2023] Open
Abstract
As evidenced by the recent approvals of Removab (EU, Trion Pharma) in 2009 and of Blincyto (US, Amgen) in 2014, the high potential of bispecific antibodies in the field of immuno-oncology is eliciting a renewed interest from pharmaceutical companies. Supported by rapid advances in antibody engineering and the development of several technological platforms such as Triomab or bispecific T cell engagers (BiTEs), the “bispecifics” market has increased significantly over the past decade and may occupy a pivotal space in the future. Over 30 bispecific molecules are currently in different stages of clinical trials and more than 70 in preclinical phase. This review focuses on the clinical potential of bispecific antibodies as immune effector cell engagers in the onco-immunotherapy field. We summarize current strategies targeting various immune cells and their clinical interests. Furthermore, perspectives of bispecific antibodies in future clinical developments are addressed.
Collapse
|
|
36
|
|
|
37
|
Kurbacher CM, Horn O, Kurbacher JA, Herz S, Kurbacher AT, Hildenbrand R, Bollmann R. Outpatient Intraperitoneal Catumaxomab Therapy for Malignant Ascites Related to Advanced Gynecologic Neoplasms. Oncologist 2015; 20:1333-41. [PMID: 26417039 DOI: 10.1634/theoncologist.2015-0076] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2015] [Accepted: 07/14/2015] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Catumaxomab (CATU) is a trifunctional antibody approved for intraperitoneal (i.p.) treatment of malignant ascites (MA) related to carcinomas expressing the epithelial cell-adhesion molecule (EpCAM). CATU is mostly given to hospitalized patients, although outpatient treatment seems appropriate in selected individuals. This observational trial sought to obtain more detailed information regarding the feasibility of CATU in outpatients with MA related to various gynecologic tumors, including epithelial ovarian (EOC) and metastatic breast cancer (MBC). MATERIALS AND METHODS A total of 30 patients were included, 17 with EOC, 7 with MBC, and 6 with other malignancies. The patients had failed a median of 5 (range 1-12) previous systemic treatments. CATU was administered via an indwelling i.p. catheter at four increasing doses (i.e., 10, 20, 50, and 150 µg) given at 4-day intervals over 2 weeks. Toxicities were scored according to the Common Terminology Criteria for Adverse Events, version 4.03. Puncture-free survival (PuFS) was calculated from the start of CATU until the next puncture for MA, death, or loss to follow-up. Overall survival (OS) was calculated from the start of CATU to death from any reason or loss to follow-up. We also investigated various clinical parameters to predict PuFS and OS. These included age, tumor type, performance status, intensity of pretreatment, presence of extraperitoneal metastases, relative lymphocyte count at baseline, patient adherence to therapy, and the patients' ability to undergo systemic treatment after CATU. RESULTS CATU was exclusively given on an outpatient basis, and 19 patients (63.3%) received all four planned i.p. instillations. Toxicity was the reason for discontinuation in only 2 patients. Toxicity was generally manageable, with abdominal pain, nausea/vomiting, fatigue, and fever the predominant adverse effects. Secondary hospitalization was necessary for 7 patients (23.3%), with a general deteriorated condition in 5 and fever/infection or abdominal pain in 1 patient each. Subsequent systemic treatment was possible in 11 patients (36.7%). Only 5 patients (16.7%) required a second puncture after i.p. CATU. The median PuFS was 56 days, and the median OS was 79.5 days. Positive predictors of both PuFS and OS were performance status, absence of extraperitoneal tumor, the capability to receive all four CATU infusions, and the ability to undergo subsequent systemic treatment. CONCLUSION Outpatient i.p. CATU therapy for MA related to various gynecologic carcinomas is safe and effective in producing good ascites control in most individuals, allowing for subsequent systemic therapy in a substantial proportion of patients. IMPLICATIONS FOR PRACTICE Intraperitoneal treatment with the trifunctional antibody catumaxomab (CATU) was possible in a selected population of 30 outpatients with malignant ascites due to epithelial female genital tract or breast carcinoma. Toxicity was largely manageable. Patients in good condition at baseline, without extraperitoneal tumor and/or liver metastases, and with the ability to complete all four planned CATU instillations and the capability of undergoing subsequent systemic therapy benefited the most in terms of both puncture-free and overall survival. Outpatient i.p. CATU is safe and effective in a selected group of patients with malignant ascites due to various gynecologic malignancies and could be cost-saving compared with an inpatient approach.
Collapse
Affiliation(s)
- Christian Martin Kurbacher
- Department of Gynecology and Obstetrics I (Gynecologic Oncology), Gynecologic Center Bonn-Friedensplatz, Bonn, Germany Faculty of Medicine, University of Cologne, Cologne, Germany
| | - Olympia Horn
- Department of Gynecology and Obstetrics I (Gynecologic Oncology), Gynecologic Center Bonn-Friedensplatz, Bonn, Germany
| | - Jutta Anna Kurbacher
- Department of Gynecology and Obstetrics II (General Gynecology and Obstetrics), Gynecologic Center Bonn-Friedensplatz, Bonn, Germany
| | - Susanne Herz
- Department of Gynecology and Obstetrics I (Gynecologic Oncology), Gynecologic Center Bonn-Friedensplatz, Bonn, Germany
| | - Ann Tabea Kurbacher
- Department of Gynecology and Obstetrics I (Gynecologic Oncology), Gynecologic Center Bonn-Friedensplatz, Bonn, Germany
| | | | | |
Collapse
|
|
38
|
Schwab CL, English DP, Roque DM, Pasternak M, Santin AD. Past, present and future targets for immunotherapy in ovarian cancer. Immunotherapy 2015; 6:1279-93. [PMID: 25524384 DOI: 10.2217/imt.14.90] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Ovarian cancer is the leading cause of death from gynecologic malignancy in the US. Treatments have improved with conventional cytotoxic chemotherapy and advanced surgical techniques but disease recurrence is common and fatal in nearly all cases. Current evidence suggests that the immune system and its ability to recognize and eliminate microscopic disease is paramount in preventing recurrence. Ovarian cancer immunotherapy is targeting tumors through active, passive and adoptive approaches. The goal of immunotherapy is to balance the activation of the immune system against cancer while preventing the potential for tremendous toxicity elicited by immune modulation. In this paper we will review the different immunotherapies available for ovarian cancer as well as current ongoing studies and potential future directions.
Collapse
Affiliation(s)
- Carlton L Schwab
- Department of Obstetrics, Gynecology & Reproductive Sciences, Division of Gynecologic Oncology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
| | | | | | | | | |
Collapse
|
|
39
|
Catumaxomab for the treatment of malignant ascites in patients with chemotherapy-refractory ovarian cancer: a phase II study. Int J Gynecol Cancer 2015; 24:1583-9. [PMID: 25254563 DOI: 10.1097/igc.0000000000000286] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE The aim of this study was to investigate the efficacy and safety of intraperitoneal catumaxomab in heavily pretreated patients with chemotherapy-refractory ovarian cancer and recurrent symptomatic malignant ascites. METHODS The study is a single-arm open-label multicenter US phase II study. Patients received 4 three-hour intraperitoneal catumaxomab infusions (10, 20, 50, and 150 μg within 10 days). The primary end point was the percentage of patients with at least a 4-fold increase in the puncture-free interval (PuFI) relative to the pretreatment interval. The main secondary end points were puncture-free survival, overall survival, ascites symptoms, and safety. Time to first therapeutic puncture (TTPu) was analyzed post hoc. RESULTS Forty patients were screened, and 32 patients (80%) were treated. Seven patients (23%) achieved the primary end point. The median PuFI was prolonged 2-fold from 12 to 27.5 days. The median TTPu was prolonged 4-fold from 12 to 52 days. The median puncture-free survival and overall survival were 29.5 and 111 days, respectively. Nineteen patients (59%) required puncture after catumaxomab treatment. Ascites symptoms improved in most of the 13 predefined categories. At study end, most symptoms were still improved compared with screening. The most frequent treatment-related adverse events were related to cytokine release (vomiting, nausea, pyrexia, fatigue, and chills) or intraperitoneal administration (abdominal pain). Transient increases in liver parameters and transient decreases in blood lymphocytes were regularly observed but were generally without clinical relevance. CONCLUSIONS Catumaxomab prolonged PuFI and TTPu had a beneficial effect on quality of life, as shown by the improvement in ascites symptoms, and had an acceptable safety profile, which is consistent with its mode of action.
Collapse
|
|
40
|
Deppisch N, Ruf P, Eissler N, Neff F, Buhmann R, Lindhofer H, Mocikat R. Efficacy and Tolerability of a GD2-Directed Trifunctional Bispecific Antibody in a Preclinical Model: Subcutaneous Administration Is Superior to Intravenous Delivery. Mol Cancer Ther 2015; 14:1877-83. [PMID: 26063765 DOI: 10.1158/1535-7163.mct-15-0156] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Accepted: 06/03/2015] [Indexed: 11/16/2022]
Abstract
Trifunctional bispecific antibodies (trAb) are novel anticancer drugs that recruit and activate different types of immune effector cells at the targeted tumor. Thus, tumor cells are effectively eliminated and a long-lasting tumor-specific T-cell memory is induced. The trAb Ektomab is directed against human CD3 on T cells and the tumor-associated ganglioside GD2, which is an attractive target for immunotherapy of melanoma in humans. To optimize clinical applicability, we studied different application routes with respect to therapeutic efficacy and tolerability by using the surrogate trAb Surek (anti-GD2 × anti-murine CD3) and a murine melanoma engineered to express GD2. We show that subcutaneous injection of the trAb is superior to the intravenous delivery pathway, which is the standard application route for therapeutic antibodies. Despite lower plasma levels after subcutaneous administration, the same tumor-protective potential was observed in vivo compared with intravenous administration of Surek. However, subcutaneously delivered Surek showed better tolerability. This could be explained by a continuous release of the antibody leading to constant plasma levels and a delayed induction of proinflammatory cytokines. Importantly, the induction of counter-regulatory mechanisms was reduced after subcutaneous application. These findings are relevant for the clinical application of trifunctional bispecific antibodies and, possibly, also other immunoglobulin constructs. Mol Cancer Ther; 14(8); 1877-83. ©2015 AACR.
Collapse
Affiliation(s)
- Nina Deppisch
- Helmholtz-Zentrum München, Institut für Molekulare Immunologie, Munich, Germany
| | - Peter Ruf
- Trion Research GmbH, Martinsried, Germany
| | - Nina Eissler
- Helmholtz-Zentrum München, Institut für Molekulare Immunologie, Munich, Germany
| | - Frauke Neff
- Helmholtz-Zentrum München, Institut für Pathologie, Munich, Germany
| | - Raymund Buhmann
- Ludwig-Maximilians-Universität München, Klinikum Großhadern, Medizinische Klinik III und Abteilung für Transfusionsmedizin, Munich, Germany
| | | | - Ralph Mocikat
- Helmholtz-Zentrum München, Institut für Molekulare Immunologie, Munich, Germany.
| |
Collapse
|
|
41
|
Fossati M, Buzzonetti A, Monego G, Catzola V, Scambia G, Fattorossi A, Battaglia A. Immunological changes in the ascites of cancer patients after intraperitoneal administration of the bispecific antibody catumaxomab (anti-EpCAM×anti-CD3). Gynecol Oncol 2015; 138:343-51. [PMID: 26049121 DOI: 10.1016/j.ygyno.2015.06.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 05/27/2015] [Accepted: 06/01/2015] [Indexed: 01/08/2023]
Abstract
OBJECTIVE To explore the effects of intraperitoneal (i.p.) infusion of catumaxomab, a bispecific monoclonal antibody (anti-EpCAM×anti-CD3), on T cells, NK cells and macrophages in ascites of cancer patients and to understand how ascitic immune cells can be activated despite the pervasive immunosuppressive ability of ascites microenvironment. METHODS Six patients with malignant ascites received i.p. catumaxomab infusion. Ascitic immune cells were profiled by flow cytometry and gene expression at baseline and after i.p. catumaxomab infusion. In vitro experiments enabled investigations on the adverse effect of ascites microenvironment on catumaxomab-stimulated immune cells. RESULTS I.p. catumaxomab infusion enhanced the expression of the CD69 and CD38 activation molecules in CD4(+) and CD8(+) T cells, NK cells and macrophages, and favoured CD8(+) T cell accumulation into the peritoneal cavity. An analogous immune cell activation as well as IFN-γ and IL-2 production were induced by catumaxomab in vitro. In vitro experiments showed that the immunosuppressive milieu of ascites abrogated all the immunostimulatory activities of catumaxomab. Adding EpCAM(+) tumour cells to the culture permitted both catumaxomab Fab regions to engage cognate antigens and restored immunostimulatory catumaxomab activity. CONCLUSIONS This is the first demonstration in a clinical setting that i.p. catumaxomab infusion activates NK cells and macrophages in addition to T cells in ascites and favours CD8(+) T cell accumulation into the peritoneal cavity. Moreover, our findings indicate that the concomitant binding of both catumaxomab Fab regions delivers an activation signal that is strong enough to activate immune cells despite the prevailing immunosuppressive environment of malignant ascites.
Collapse
Affiliation(s)
- Marco Fossati
- Laboratory of Immunology, Department of Gynecology Oncology, Università Cattolica S. Cuore, Rome, Italy
| | - Alexia Buzzonetti
- Laboratory of Immunology, Department of Gynecology Oncology, Università Cattolica S. Cuore, Rome, Italy
| | - Giovanni Monego
- Department of Human Anatomy and Cell Biology, Università Cattolica S. Cuore, Rome, Italy
| | - Valentina Catzola
- Laboratory of Immunology, Department of Gynecology Oncology, Università Cattolica S. Cuore, Rome, Italy
| | - Giovanni Scambia
- Laboratory of Immunology, Department of Gynecology Oncology, Università Cattolica S. Cuore, Rome, Italy
| | - Andrea Fattorossi
- Laboratory of Immunology, Department of Gynecology Oncology, Università Cattolica S. Cuore, Rome, Italy
| | - Alessandra Battaglia
- Laboratory of Immunology, Department of Gynecology Oncology, Università Cattolica S. Cuore, Rome, Italy.
| |
Collapse
|
|
42
|
|
|
43
|
A phase I trial of intravenous catumaxomab: a bispecific monoclonal antibody targeting EpCAM and the T cell coreceptor CD3. Cancer Chemother Pharmacol 2015; 75:1065-73. [PMID: 25814216 DOI: 10.1007/s00280-015-2728-5] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 03/16/2015] [Indexed: 10/23/2022]
Abstract
PURPOSE The aim of the study was to evaluate the safety and determine the maximum tolerated dose (MTD) of intravenous catumaxomab, a trifunctional bispecific antibody that binds to EpCAM on epithelial cancer cells and CD3 on T cells. METHODS The trial was a dose-escalation study with a 3 + 3 design in epithelial cancers with known EpCAM expression. The dose-limiting toxicity (DLT) period consisted of 4 weeks, with weekly intravenous administration of catumaxomab. Key DLTs were ≥grade 3 optimally treated non-hematological toxicity; ≥grade 3 infusion-related reactions refractory to supportive care; ≥grade 3 increase in liver enzymes and/or bilirubin not resolving to grade 2. RESULTS Sixteen patients were enrolled receiving doses of 2 (n = 5), 4 (n = 3), 7 (n = 7) and 10 µg catumaxomab (n = 1). The most common treatment-emergent adverse events (TEAEs) were chills (93.8 %) and pyrexia (87.5 %). The most common TEAE of grade ≥3 was transient dose-dependent increases in aspartate aminotransferase (56.3 %). The intensity of toxicities decreased with the number of infusions. Also, serum IL-6 increased in a dose-dependent manner and reverted to low or undetectable levels after four infusions. A reversible decrease in liver function test (prothrombin time) at the 7-µg dose level was considered a DLT. The first patient at 10 µg experienced a fatal hepatic failure related to catumaxomab that led to the termination of the study. CONCLUSIONS The MTD of weekly intravenous catumaxomab was 7 µg. Major toxicities were cytokine release-related symptoms and hepatotoxicity.
Collapse
|
|
44
|
Bispecific antibodies. Drug Discov Today 2015; 20:838-47. [PMID: 25728220 DOI: 10.1016/j.drudis.2015.02.008] [Citation(s) in RCA: 440] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 01/29/2015] [Accepted: 02/11/2015] [Indexed: 11/23/2022]
Abstract
Bispecific antibodies (bsAbs) combine specificities of two antibodies and simultaneously address different antigens or epitopes. BsAbs with 'two-target' functionality can interfere with multiple surface receptors or ligands associated, for example with cancer, proliferation or inflammatory processes. BsAbs can also place targets into close proximity, either to support protein complex formation on one cell, or to trigger contacts between cells. Examples of 'forced-connection' functionalities are bsAbs that support protein complexation in the clotting cascade, or tumor-targeted immune cell recruiters and/or activators. Following years of research and development (R&D), the first bsAb was approved in 2009. Another bsAb entered the market in December 2014 and several more are in clinical trials. Here, we describe the potentials of bsAbs to become the next wave of antibody-based therapies, focusing on molecules in clinical development.
Collapse
|
|
45
|
A survey of treatment approaches of malignant ascites in Germany and Austria. Support Care Cancer 2014; 23:2073-8. [PMID: 25528551 DOI: 10.1007/s00520-014-2557-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Accepted: 12/07/2014] [Indexed: 01/26/2023]
Abstract
BACKGROUND Malignant ascites (MA) is a common manifestation of advanced cancer. Currently, there are no evidence-based guidelines for the management of MA. We conducted a survey with physicians throughout Germany and Austria, to get an overview of current approaches and opinions in the treatment of MA. METHODS One hundred and twenty-eight medical oncologists (MO), gastroenterologists (GE), and gynecologists (GYN) completed an electronic questionnaire consisting of 33 questions. RESULTS Ninety percent of the physicians were from Germany and 10% from Austria; 48% of those were MO, 30% were GYN, and 14% were GE. Most physicians treated an average of 34 patients (pts)/year with MA. Twenty-six percent of these pts suffered from ovarian, 20% from pancreatic, 17% from gastric, and 14% from colorectal cancer. The majority of the physicians associated MA with poor prognosis (92%) and significant reduction in quality of life (87%). One third felt that MA was a contraindication for full dosing of systemic chemotherapy. Paracentesis (PC) was performed in 70% of pts with symptom relieve and quality of life being the main reasons. Almost half of the pts required 3-5 PC, 50% even more than 5 PC during the course of their disease. Only 15% of pts needed multiple PC per week; the majority (79%) needed the procedure either once a week or every 14 days. In 61% of pts, 3-5 L of ascites fluid was drained. Only in 8%, 5 L and more were removed. Volume substitution with IV albumin was performed in 40% of pts. Most pts (55%) had to stay 1-3 h in a healthcare facility for the procedure. However, 21% had to stay ≥1 day. While almost all physicians (89%) performed a PC at some point in the treatment of MA, 75% felt that a systemic chemotherapy and 55% thought a concomitant diuretic therapy were a necessary adjunct. Seven percent of the pts received a targeted treatment with catumaxomab. CONCLUSIONS Repeated PC is the main pillar of treatment of MA; its effect is only temporary and requires significant hospital resources. Further treatment strategies of MA have to be evaluated in prospective studies. Targeted therapies like catumaxomab and VEGF inhibitors should be integrated into these.
Collapse
|
|
46
|
Schuster FR, Stanglmaier M, Woessmann W, Winkler B, Siepermann M, Meisel R, Schlegel PG, Hess J, Lindhofer H, Borkhardt A, Buhmann R. Immunotherapy with the trifunctional anti-CD20 x anti-CD3 antibody FBTA05 (Lymphomun) in paediatric high-risk patients with recurrent CD20-positive B cell malignancies. Br J Haematol 2014; 169:90-102. [PMID: 25495919 DOI: 10.1111/bjh.13242] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 11/04/2014] [Indexed: 12/23/2022]
Abstract
Children with B cell malignancies refractory to standard therapy are known to have a poor prognosis and very limited treatment options. Here, we report on the treatment and follow-up of ten patients diagnosed with relapsed or refractory mature B-cell Non Hodgkin Lymphoma (B-NHL), Burkitt leukaemia (B-AL) or pre B-acute lymphoblastic leukaemia (pre B-ALL). All children were treated with FBTA05 (now designated Lymphomun), an anti-CD3 x anti-CD20 trifunctional bispecific antibody (trAb) in compassionate use. Within individual treatment schedules, Lymphomun was applied (a) after allogeneic stem cell transplantation (allo-SCT, n = 6) to induce sustained long-term remission, or (b) stand alone prior to subsequent chemotherapy to eradicate residual disease before allo-SCT (n = 4). Nine of ten children displayed a clinical response: three stable diseases (SD), one partial remission (PR) and five induced or sustained complete remissions (CR). Five of these nine responders died during follow-up. The other patients still maintain CR with a current overall survival of 874-1424 days (median: 1150 days). In conclusion, despite the dismal clinical prognosis of children refractory to standard therapy, immunotherapy with Lymphomun resulted in a favourable clinical outcome in this cohort of refractory paediatric patients.
Collapse
Affiliation(s)
- Friedhelm R Schuster
- Department of Paediatric Oncology, Haematology and Immunology, University of Duesseldorf, Duesseldorf, Germany
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Lameris R, de Bruin RCG, Schneiders FL, van Bergen en Henegouwen PMP, Verheul HMW, de Gruijl TD, van der Vliet HJ. Bispecific antibody platforms for cancer immunotherapy. Crit Rev Oncol Hematol 2014; 92:153-65. [PMID: 25195094 DOI: 10.1016/j.critrevonc.2014.08.003] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2014] [Revised: 06/11/2014] [Accepted: 08/08/2014] [Indexed: 01/10/2023] Open
Abstract
Over the past decades advances in bioengineering and expanded insight in tumor immunology have resulted in the emergence of novel bispecific antibody (bsAb) constructs that are capable of redirecting immune effector cells to the tumor microenvironment. (Pre-) clinical studies of various bsAb constructs have shown impressive results in terms of immune effector cell retargeting, target dependent activation and the induction of anti-tumor responses. This review summarizes recent advances in the field of bsAb-therapy and limitations that were encountered. Furthermore, we will discuss potential future developments that can be expected to take the bsAb approach successfully forward.
Collapse
Affiliation(s)
- Roeland Lameris
- Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Renée C G de Bruin
- Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Famke L Schneiders
- Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Paul M P van Bergen en Henegouwen
- Division of Cell Biology, Department of Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
| | - Henk M W Verheul
- Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Tanja D de Gruijl
- Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Hans J van der Vliet
- Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
| |
Collapse
|
|
48
|
Re-challenge with catumaxomab in patients with malignant ascites: results from the SECIMAS study. Med Oncol 2014; 31:308. [PMID: 25367854 DOI: 10.1007/s12032-014-0308-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Accepted: 10/28/2014] [Indexed: 10/24/2022]
Abstract
Malignant ascites is a common phenomenon in cancer patients. It poses a great challenge to the clinician, because of limited treatment options and strong impairment of the quality of life of the often palliative patients. The SECIMAS study investigated the feasibility of a re-challenge with four catumaxomab intraperitoneal infusions in patients who had already received a first cycle of four infusions in the phase III CASIMAS study, which compared catumaxomab with and without prednisolone premedication. The primary endpoint was the proportion of patients who received at least three catumaxomab infusions. Secondary endpoints included a composite safety score (CSS) summarising the worst grades for the main catumaxomab-related adverse events (pyrexia, nausea, vomiting and abdominal pain), safety, efficacy and the occurrence of anti-drug antibodies (ADAs). Eight of nine screened patients received a second catumaxomab cycle. Compliance with a catumaxomab re-challenge was high: all eight patients (100%) received all four infusions. The median CSS was 3.0 versus 3.4 in CASIMAS. The tolerability profile of the second catumaxomab cycle was comparable to that of the first cycle. Median puncture-free survival (48 days) and overall survival (407 days) were longer than in CASIMAS (35 and 103 days, respectively), although median time to next puncture was shorter (60 vs. 97 days). Of six patients sampled, all were ADA positive at screening and remained ADA positive until the end of the study. The presence of ADAs did not affect catumaxomab's safety or efficacy. The CSS and tolerability profile for catumaxomab in SECIMAS were comparable to those in CASIMAS. The majority of patients benefitted from a second cycle of catumaxomab. A re-challenge seems to be feasible and safe for selected patients with recurrent malignant ascites due to carcinoma after a first cycle of catumaxomab.
Collapse
|
|
49
|
Abstract
Bi- and multispecific antibody derivatives (bsAbs) can be considered as the next generation of targeted biologics for cancer therapy. The general concept of bsAbs is a physical connection of recombinant antibody-derived entities with at least two binding specificities. This generates bsAbs that bind at least two antigens or epitopes, thus altering their binding functionalities and specificities in comparison to "normal" antibodies. Most bsAbs are produced as recombinant proteins, either as large IgG-like proteins that contain Fc regions, or as smaller entities with multiple antigen-binding regions but without Fc. Application of bsAbs in experimental cancer therapy currently includes molecules that bind different cell surface proteins to achieve more complete blockage of proliferative or angiogenesis-associated pathways. This approach of blocking more than one pathway component, or to simultaneously hit complementing pathways, also may limit potential escape mechanisms of cancer cells. BsAbs also are applied in the clinic as vehicles to deliver immune effector cells and/or cytokines to tumors.
Collapse
Affiliation(s)
- Ulrich H Weidle
- Roche Pharmaceuticals Research and Early Development (pRED), Discovery Oncology (UHW) and Large Molecule Research (UB), Roche Innovation Center Penzberg, Germany
| | - Roland E Kontermann
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
| | - Ulrich Brinkmann
- Roche Pharmaceuticals Research and Early Development (pRED), Discovery Oncology (UHW) and Large Molecule Research (UB), Roche Innovation Center Penzberg, Germany.
| |
Collapse
|
|
50
|
Sehouli J, Pietzner K, Wimberger P, Vergote I, Rosenberg P, Schneeweiss A, Bokemeyer C, Salat C, Scambia G, Berton-Rigaud D, Santoro A, Cervantes A, Trédan O, Tournigand C, Colombo N, Dudnichenko AS, Westermann A, Friccius-Quecke H, Lordick F. Catumaxomab with and without prednisolone premedication for the treatment of malignant ascites due to epithelial cancer: results of the randomised phase IIIb CASIMAS study. Med Oncol 2014; 31:76. [PMID: 24965536 DOI: 10.1007/s12032-014-0076-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Accepted: 06/12/2014] [Indexed: 01/27/2023]
Abstract
This two-arm, randomised, multicentre, open-label, phase IIIb study investigated the safety and efficacy of a 3-h catumaxomab infusion with/without prednisolone premedication to reduce catumaxomab-related adverse events. Patients with malignant ascites due to epithelial cancer received four 3-h intraperitoneal catumaxomab infusions with/without intravenous prednisolone (25 mg) premedication before each infusion. The primary safety endpoint was a composite safety score calculated from the incidence and intensity of the most frequent catumaxomab-related adverse events (pyrexia, nausea, vomiting and abdominal pain). Puncture-free survival (PuFS) was a co-primary endpoint. Time to next puncture (TTPu) and overall survival (OS) were secondary endpoints. Prednisolone premedication did not result in a significant reduction in the main catumaxomab-related adverse events. The mean composite safety score was comparable in both arms (catumaxomab plus prednisolone, 4.1; catumaxomab, 3.8; p = 0.383). Median PuFS (30 vs. 37 days) and TTPu (78 vs. 102 days) were shorter in the catumaxomab plus prednisolone arm than in the catumaxomab arm, but the differences were not statistically significant (p = 0.402 and 0.599, respectively). Median OS was longer in the catumaxomab plus prednisolone arm than in the catumaxomab arm (124 vs. 86 days), but the difference was not statistically significant (p = 0.186). The superiority of catumaxomab plus prednisolone versus catumaxomab alone could not be proven for the primary endpoint. Prednisolone did not result in a significant reduction in the main catumaxomab-related adverse events. The study confirms the safety and efficacy of catumaxomab administered as four 3-h intraperitoneal infusions for the treatment of malignant ascites.
Collapse
Affiliation(s)
- Jalid Sehouli
- Department of Gynecology, European Competence Center for Ovarian Cancer, Charité-University Medicine of Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|