Enhanced tumor-targeting selectivity by modulating bispecific antibody binding affinity and format valence

Mazor, Yariv; Sachsenmeier, Kris F.; Yang, Chunshu; Hansen, Anna M.; Filderman, J; Mulgrew, Kathy; Wu, Herren; Dall’Acqua, William F.

doi:10.1038/srep40098

Cited by 93 publications

(79 citation statements)

References 49 publications

(70 reference statements)

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“…The therapeutic index in this strategy is based on lack of simultaneous expression of the two tumor targets in normal cells. The two-target approach has been tested preclinically using several target pairs (41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

Slaga¹,

Ellerman²,

Lombana³

et al. 2018

Sci. Transl. Med.

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A primary barrier to the success of T cell–recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, we developed an anti-HER2/CD3 T cell–dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues. Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells. The increased selectivity to HER2-overexpressing cells is expected to mitigate the risk of adverse effects and increase the therapeutic index. Results included in this manuscript not only support the clinical development of anti-HER2/CD3 1Fab–immunoglobulin G TDB but also introduce a potentially widely applicable strategy for other T cell–directed therapies. The potential of this discovery has broad applications to further enable consideration of solid tumor targets that were previously limited by on-target, but off-tumor, autoimmunity.

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Section: Discussionmentioning

confidence: 99%

Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

Slaga¹,

Ellerman²,

Lombana³

et al. 2018

Sci. Transl. Med.

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“…55 Optimization of the affinity and valency of each antibodybinding domain may allow for increased tumor-targeting selectivity. 56 Thus, bsAbs targeting multiple antigens on the same type of target cell may increase the therapeutic window of anticancer drugs by increasing potency and decreasing off-target effects.…”

Section: Advantages Of Multispecificitymentioning

confidence: 99%

Considerations for the Design of Antibody-Based Therapeutics

Goulet

Atkins

2020

Journal of Pharmaceutical Sciences

160

148

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Keywords: antibody(s) antibody drug(s) antibody drug conjugate(s) (ADC) physicochemical properties pharmacokinetics monoclonal antibody(s) immunotherapy IgG antibody(s) drug design developability a b s t r a c t Antibody-based proteins have become an important class of biologic therapeutics, due in large part to the stability, specificity, and adaptability of the antibody framework. Indeed, antibodies not only have the inherent ability to bind both antigens and endogenous immune receptors but also have proven extremely amenable to protein engineering. Thus, several derivatives of the monoclonal antibody format, including bispecific antibodies, antibody-drug conjugates, and antibody fragments, have demonstrated efficacy for treating human disease, particularly in the fields of immunology and oncology. Reviewed here are considerations for the design of antibody-based therapeutics, including immunological context, therapeutic mechanisms, and engineering strategies. First, characteristics of antibodies are introduced, with emphasis on structural domains, functionally important receptors, isotypic and allotypic differences, and modifications such as glycosylation. Then, aspects of therapeutic antibody design are discussed, including identification of antigen-specific variable regions, choice of expression system, use of multispecific formats, and design of antibody derivatives based on fragmentation, oligomerization, or conjugation to other functional moieties. Finally, strategies to enhance antibody function through protein engineering are reviewed while highlighting the impact of fundamental biophysical properties on protein developability.

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“…[47][48][49] These monovalent DuetMab molecules carried the Fab domain of their IgG counterparts paired with a Fab of a non-binding isotype control IgG (NMGC). 39,44,50,51 Thus, these bispecific DuetMab derivatives are functionally monovalent to their target antigens. The corresponding DuetMab antibodies were produced from mammalian cells, and their oligomeric state and purity were determined as previously described.…”

Section: Monovalent Binding To Target Antigen Augments Cdc Activitymentioning

confidence: 99%

“…The corresponding DuetMab antibodies were produced from mammalian cells, and their oligomeric state and purity were determined as previously described. 44,50 The intrinsic binding kinetics of the IgG and DuetMab pairs were determined by Octet analysis. It was found that the monovalent DuetMabs retained the intrinsic binding kinetics of the bivalent IgGs from which they were derived (Table 1).…”

Section: Monovalent Binding To Target Antigen Augments Cdc Activitymentioning

confidence: 99%

Regulation of antibody-mediated complement-dependent cytotoxicity by modulating the intrinsic affinity and binding valency of IgG for target antigen

Wang

Yang

Jin

et al. 2019

mAbs

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Complement-dependent cytotoxicity (CDC) is a potent effector mechanism, engaging both innate and adaptive immunity. Although strategies to improve the CDC activity of antibody therapeutics have primarily focused on enhancing the interaction between the antibody crystallizable fragment (Fc) and the first subcomponent of the C1 complement complex (C1q), the relative importance of intrinsic affinity and binding valency of an antibody to the target antigen is poorly understood. Here we show that antibody binding affinity to a cell surface target antigen evidently affects the extent and efficacy of antibody-mediated complement activation. We further report the fundamental role of antibody binding valency in the capacity to recruit C1q and regulate CDC. More specifically, an array of affinity-modulated variants and functionally monovalent bispecific derivatives of high-affinity anti-epidermal growth factor receptor (EGFR) and anti-human epidermal growth factor receptor 2 (HER2) therapeutic immunoglobulin Gs (IgGs), previously reported to be deficient in mediating complement activation, were tested for their ability to bind C1q by biolayer interferometry using antigen-loaded biosensors and to exert CDC against a panel of EGFR and HER2 tumor cells of various histological origins. Significantly, affinity-reduced variants or monovalent derivatives, but not their high-affinity bivalent IgG counterparts, induced near-complete cell cytotoxicity in tumor cell lines that had formerly been shown to be resistant to complement-mediated attack. Our findings suggest that monovalent target engagement may contribute to an optimal geometrical positioning of the antibody Fc to engage C1q and deploy the complement pathway.

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Enhanced tumor-targeting selectivity by modulating bispecific antibody binding affinity and format valence

Cited by 93 publications

References 49 publications

Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

Considerations for the Design of Antibody-Based Therapeutics

Regulation of antibody-mediated complement-dependent cytotoxicity by modulating the intrinsic affinity and binding valency of IgG for target antigen

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