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      Ten years in the making: application of CrossMab technology for the development of therapeutic bispecific antibodies and antibody fusion proteins

      review-article
      Author(s): a , b , a
      Publication date (Electronic, pub):
      Publication date (Electronic, collection):
      Journal: mAbs
      Publisher: Taylor & Francis
      Keywords: Bispecific, CrossMab, Immunotherapy, Oncology, Ophthalmology, TCB, T cell engager

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          ABSTRACT

          Bispecific antibodies have recently attracted intense interest. CrossMab technology was described in 2011 as novel approach enabling correct antibody light-chain association with their respective heavy chain in bispecific antibodies, together with methods enabling correct heavy-chain association using existing pairs of antibodies. Since the original description, CrossMab technology has evolved in the past decade into one of the most mature, versatile, and broadly applied technologies in the field, and nearly 20 bispecific antibodies based on CrossMab technology developed by Roche and others have entered clinical trials. The most advanced of these are the Ang-2/VEGF bispecific antibody faricimab, currently undergoing regulatory review, and the CD20/CD3 T cell bispecific antibody glofitamab, currently in pivotal Phase 3 trials. In this review, we introduce the principles of CrossMab technology, including its application for the generation of bi-/multispecific antibodies with different geometries and mechanisms of action, and provide an overview of CrossMab-based therapeutics in clinical trials.

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          Targeting apoptosis in cancer therapy

          Benedito A Carneiro, Wafik S El-Deiry (2020)
          For over three decades, a mainstay and goal of clinical oncology has been the development of therapies promoting the effective elimination of cancer cells by apoptosis. This programmed cell death process is mediated by several signalling pathways (referred to as intrinsic and extrinsic) triggered by multiple factors, including cellular stress, DNA damage and immune surveillance. The interaction of apoptosis pathways with other signalling mechanisms can also affect cell death. The clinical translation of effective pro-apoptotic agents involves drug discovery studies (addressing the bioavailability, stability, tumour penetration, toxicity profile in non-malignant tissues, drug interactions and off-target effects) as well as an understanding of tumour biology (including heterogeneity and evolution of resistant clones). While tumour cell death can result in response to therapy, the selection, growth and dissemination of resistant cells can ultimately be fatal. In this Review, we present the main apoptosis pathways and other signalling pathways that interact with them, and discuss actionable molecular targets, therapeutic agents in clinical translation and known mechanisms of resistance to these agents.
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            Bispecific antibodies: a mechanistic review of the pipeline

            Aran F Labrijn, Maarten Janmaat, Janice M. Reichert … (2019)
            The term bispecific antibody (bsAb) is used to describe a large family of molecules designed to recognize two different epitopes or antigens. BsAbs come in many formats, ranging from relatively small proteins, merely consisting of two linked antigen-binding fragments, to large immunoglobulin G (IgG)-like molecules with additional domains attached. An attractive bsAb feature is their potential for novel functionalities - that is, activities that do not exist in mixtures of the parental or reference antibodies. In these so-called obligate bsAbs, the physical linkage of the two binding specificities creates a dependency that can be temporal, with binding events occurring sequentially, or spatial, with binding events occurring simultaneously, such as in linking an effector to a target cell. To date, more than 20 different commercialized technology platforms are available for bsAb creation and development, 2 bsAbs are marketed and over 85 are in clinical development. Here, we review the current bsAb landscape from a mechanistic perspective, including a comprehensive overview of the pipeline.
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              68Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer

              Clemens Kratochwil, Paul Flechsig, Thomas Lindner … (2019)
              The recent development of quinoline-based PET tracers that act as fibroblast-activation-protein inhibitors (FAPIs) demonstrated promising preclinical and clinical results. FAP is overexpressed by cancer-associated fibroblasts of several tumor entities. Here, we quantify the tumor uptake on 68Ga-FAPI PET/CT of various primary and metastatic tumors to identify the most promising indications for future application. Methods:68Ga-FAPI PET/CT scans were requested by various referring physicians according to individual clinical indications that were considered insufficiently covered by 18F-FDG PET/CT or other imaging modalities. All PET/CT was performed 1 h after injection of 122-312 MBq of 68Ga-FAPI-04. We retrospectively identified 80 patients with histopathologically proven primary tumors or metastases or radiologically unequivocal metastatic lesions of histologically proven primary tumors. Tumor uptake was quantified by SUVmax and SUVmean (60% isocontour). Results: Eighty patients with 28 different tumor entities (54 primary tumors and 229 metastases) were evaluated. The highest average SUVmax (>12) was found in sarcoma, esophageal, breast, cholangiocarcinoma, and lung cancer. The lowest 68Ga-FAPI uptake (average SUVmax < 6) was observed in pheochromocytoma, renal cell, differentiated thyroid, adenoid cystic, and gastric cancer. The average SUVmax of hepatocellular, colorectal, head-neck, ovarian, pancreatic, and prostate cancer was intermediate (SUV 6-12). SUV varied across and within all tumor entities. Because of low background in muscle and blood pool (SUVmax < 2), the tumor-to-background contrast ratios were more than 3-fold in the intermediate and more than 6-fold in the high-intensity uptake group. Conclusion: Several highly prevalent cancers presented with remarkably high uptake and image contrast on 68Ga-FAPI PET/CT. The high and rather selective tumor uptake may open up new applications for noninvasive tumor characterization, staging examinations, or radioligand therapy.
              Article 0 comments Cited 433 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): MAbs
                Journal ID (iso-abbrev): MAbs
                Title: mAbs
                Publisher: Taylor & Francis
                ISSN (Print): 1942-0862
                ISSN (Electronic): 1942-0870
                Publication date (Electronic, pub): 7 September 2021
                Publication date (Electronic, collection): 2021
                Publication date PMC-release: 7 September 2021
                Volume: 13
                Issue: 1
                Electronic Location Identifier: 1967714
                Affiliations
                [a ]Roche Innovation Center Zurich; , Schlieren, Switzerland
                [b ]Roche Innovation Center Munich; , Penzberg, Germany
                Author notes
                CONTACT Christian Klein christian.klein.ck1@ 123456roche.com Roche Innovation Center Zurich, Roche Pharma Research & Early Development, Roche Glycart AG, Wagistrasse 10, 8952, Schlieren, Switzerland
                Author information
                https://orcid.org/0000-0001-7594-7280
                Article
                Publisher ID: 1967714
                DOI: 10.1080/19420862.2021.1967714
                PMC ID: 8425689
                PubMed ID: 34491877
                SO-VID: 3d390bcd-db59-4404-a31c-ac1a1f291fcf
                Copyright © © 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Page count
                Figures: 2, Tables: 1, References: 215, Pages: 1
                Categories
                Subject: Review
                Subject: Review

                ScienceOpen disciplines: Immunology
                Keywords: bispecific,crossmab,immunotherapy,oncology,ophthalmology,tcb,t cell engager
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: bispecific, crossmab, immunotherapy, oncology, ophthalmology, tcb, t cell engager

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