12
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Facilitating high throughput bispecific antibody production and potential applications within biopharmaceutical discovery workflows

      review-article
      a , b , a , a
      mAbs
      Taylor & Francis
      Antibody engineering, biopharmaceutical drug discovery, Bispecific antibody, chemical conjugation, mass spectrometry

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          ABSTRACT

          A major driver for the recent investment surge in bispecific antibody (bsAb) platforms and products is the multitude of distinct mechanisms of action that bsAbs offer compared to a combination of two monoclonal antibodies. Four bsAb products were granted first regulatory approvals in the US or EU during 2023 and the biopharmaceutical industry pipeline is brimming with bsAb candidates across a broad range of therapeutic applications. In previously reported bsAb discovery campaigns, following a hypothesis-based choice of two specific target proteins, selections and screening activities have often been performed in mono-specific formats. The conversion to bispecific modalities has usually been positioned toward the end of the discovery process and has involved small numbers of lead molecules, largely due to challenges in expressing, purifying, and analyzing large numbers of bsAbs. In this review, we discuss emerging strategies to facilitate the production of expanded bsAb panels, focusing particularly upon combinatorial methods to generate bsAb matrices. Such technologies will enable screening in. bispecific formats at earlier stages of discovery campaigns, not only widening the accessible protein space to maximize chances of success, but also advancing empirical bi-target validation activities to assess initial target selection hypotheses.

          Related collections

          Most cited references154

          • Record: found
          • Abstract: found
          • Article: not found

          Bispecific antibodies: a mechanistic review of the pipeline

          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.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            A strain-promoted [3 + 2] azide-alkyne cycloaddition for covalent modification of biomolecules in living systems.

            Selective chemical reactions that are orthogonal to the diverse functionality of biological systems have become important tools in the field of chemical biology. Two notable examples are the Staudinger ligation of azides and phosphines and the Cu(I)-catalyzed [3 + 2] cycloaddition of azides and alkynes ("click chemistry"). The Staudinger ligation has sufficient biocompatibility for performance in living animals but suffers from phosphine oxidation and synthetic challenges. Click chemistry obviates the requirement of phosphines, but the Cu(I) catalyst is toxic to cells, thereby precluding in vivo applications. Here we present a strain-promoted [3 + 2] cycloaddition between cyclooctynes and azides that proceeds under physiological conditions without the need for a catalyst. The utility of the reaction was demonstrated by selective modification of biomolecules in vitro and on living cells, with no apparent toxicity.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              The making of bispecific antibodies

              ABSTRACT During the past two decades we have seen a phenomenal evolution of bispecific antibodies for therapeutic applications. The ‘zoo’ of bispecific antibodies is populated by many different species, comprising around 100 different formats, including small molecules composed solely of the antigen-binding sites of two antibodies, molecules with an IgG structure, and large complex molecules composed of different antigen-binding moieties often combined with dimerization modules. The application of sophisticated molecular design and genetic engineering has solved many of the technical problems associated with the formation of bispecific antibodies such as stability, solubility and other parameters that confer drug properties. These parameters may be summarized under the term ‘developability’. In addition, different ‘target product profiles’, i.e., desired features of the bispecific antibody to be generated, mandates the need for access to a diverse panel of formats. These may vary in size, arrangement, valencies, flexibility and geometry of their binding modules, as well as in their distribution and pharmacokinetic properties. There is not ‘one best format’ for generating bispecific antibodies, and no single format is suitable for all, or even most of, the desired applications. Instead, the bispecific formats collectively serve as a valuable source of diversity that can be applied to the development of therapeutics for various indications. Here, a comprehensive overview of the different bispecific antibody formats is provided.
                Bookmark

                Author and article information

                Journal
                MAbs
                MAbs
                mAbs
                Taylor & Francis
                1942-0862
                1942-0870
                21 February 2024
                2024
                21 February 2024
                : 16
                : 1
                : 2311992
                Affiliations
                [a ]Large Molecule Discovery, GSK, GSK Medicines Research Centre; , Stevenage, UK
                [b ]Department of Pure and Applied Chemistry, University of Strathclyde; , Glasgow, UK
                Author notes
                CONTACT Charlotte. H. Coles charlotte.h.coles@ 123456gsk.com Large Molecule Discovery, GSK, GSK Medicines Research Centre; , Gunnels Wood Road, Stevenage SG1 2NY, UK
                [#]

                C.F. and J.R.T. have contributed equally to this work.

                Author information
                https://orcid.org/0009-0001-0275-141X
                https://orcid.org/0000-0003-2089-274X
                https://orcid.org/0000-0003-4525-7144
                Article
                2311992
                10.1080/19420862.2024.2311992
                10883111
                d7f07552-9300-4aa8-94ed-667ef6a2ea83
                © 2024 GSK plc. Published with license by Taylor & Francis Group, LLC.

                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. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

                History
                Page count
                Figures: 2, Tables: 1, References: 157, Pages: 1
                Categories
                Review Article
                Review

                Immunology
                antibody engineering,biopharmaceutical drug discovery,bispecific antibody,chemical conjugation,mass spectrometry

                Comments

                Comment on this article