Complex Interplay between Epitope Specificity and Isotype Dictates the Biological Activity of Anti-human CD40 Antibodies

Yu, Xiaojie; Chan, H T Claude; Orr, Christian M.; Dadas, Osman; Booth, Steven G; Dahal, Lekh N.; Penfold, Christine A.; O’Brien, Lyn M.; Mockridge, C. Ian; French, Ruth R.; Duriez, Patrick J.; Douglas, Leon; Pearson, Arwen R.; Cragg, Mark S.; Tews, Ivo; Glennie, Martin J.; White, Ann L.

doi:10.1016/j.ccell.2018.02.009

Cited by 91 publications

(182 citation statements)

References 50 publications

(104 reference statements)

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“…However, it appears that 2 distinct epitopes defined by CD40L/CD154 competitivity lead to an agonistic or antagonistic response at physiological concentrations of FcgR. 52 Thus, mapping the precise site of antibody-antigen binding can help to define the elicited response.…”

Section: Epitopementioning

confidence: 99%

Considerations for the Design of Antibody-Based Therapeutics

Goulet

Atkins

2020

Journal of Pharmaceutical Sciences

199

154

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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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Section: Epitopementioning

confidence: 99%

Considerations for the Design of Antibody-Based Therapeutics

Goulet

Atkins

2020

Journal of Pharmaceutical Sciences

199

154

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“…In support of this, the agonistic LILRB3 mAb did not suppress T cell proliferation in the absence of monocytes. Binding epitopes influence the ability of mAb to modulate receptor function in many systems (35,45) and so it was unsurprising to see LILRB3 mAb capable of differing functions. However, the D4-binding A1 mAb was a strong inhibitor of proliferation; whereas, other D4-binding mAb (e.g., A28) had no significant effect.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, domain-specific epitopes did not seem to correlate directly with LILRB3 mAb-mediated effector cell functions and may not be predictive of LILRB3 mAb function per se. Further detailed analyses, e.g., surface alanine scanning mutagenesis (45) and/or structural studies, are required to define the specific extracellular epitopes engaged by the selected LILRB3 mAb and to investigate their influence on receptor activity.…”

Section: Discussionmentioning

confidence: 99%

LILRB3 (ILT5) is a myeloid checkpoint on myeloid cells that elicits profound immununomodulation

Yeboah

Papagregoriou

Jones

et al. 2020

Preprint

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Despite advances in identifying the key immunoregulatory roles of the human leukocyte immunoglobulin (Ig)-like receptor (LILR) family members, the function of the inhibitory receptor LILRB3 (ILT5, CD85a, LIR3) remains unclear. Studies indicate a predominant myeloid expression; however, high homology within the LILR family and a relative paucity of reagents have hindered progress. To investigate its function and potential immunomodulatory capacity, a panel of LILRB3-specific monoclonal antibodies (mAb) was generated. LILBR3-specific mAb bound to discrete epitopes in either Ig-like domain two or four. LILRB3 ligation on primary human monocytes by agonistic mAb resulted in phenotypic and functional changes, leading to potent inhibition of immune responses in vitro, including significant reduction in T cell proliferation. Importantly, agonizing LILRB3 in humanized mice induced tolerance and permitted efficient engraftment of allogeneic cells. Our findings reveal powerful immunoregulatory functions of LILRB3 and identify it as an important myeloid immune checkpoint receptor.

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“…Previous work studying the mechanisms of action of therapeutic antibodies has shown that the region of the molecule targeted is also an important consideration, with even subtle shifts in binding epitope resulting in large impacts on effector function and efficacy [19,20]. Recent work on several TNFRs has further highlighted the importance of these aspects in influencing the type and strength of effector function [20][21][22][23]. For example, we demonstrated the importance of domain binding on the biological activity of anti-CD40 mAb, showing that membrane distal CRD1binding mAb were strong agonists of CD40 with membrane proximal mAb less potent [22].…”

Section: Introductionmentioning

confidence: 99%

Domain Binding and Isotype Dictate the Activity of Anti-human OX40 Antibodies

Griffiths

Hussain

Smith

et al. 2020

Preprint

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AbstractPrevious data suggests that anti-OX40 mAb can elicit anti-tumour effects in mice through deletion of Tregs. However, OX40 also has powerful costimulatory effects on T cells which could evoke therapeutic responses. The contributions of these different effector mechanisms has not previously been systematically evaluated, particularly for mAb directed to human OX40. Therefore, we generated a novel human OX40 knock-in (KI) mouse to evaluate a panel of anti-hOX40 mAb and show that their activities relate directly to two key properties: 1) isotype – with mIgG1 mAb evoking receptor agonism and CD8+ T cell expansion and mIgG2a mAb evoking deletion of Treg and; 2) epitope - with membrane-proximal mAb delivering more powerful agonism. Intriguingly, both isotypes acted therapeutically in tumour models by engaging these different mechanisms. These findings highlight the significant impact of isotype and epitope on the modulation of anti-hOX40 mAb therapy, and indicate that CD8+ T cell expansion or Treg depletion might be preferable according to the composition of different tumours.SummaryHuman trials with anti-OX40 antibodies have been disappointing indicating that optimal reagents have not yet been developed. Here, using a new panel of antibodies, we show that isotype and epitope combine to determine agonistic and therapeutic activity.

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Complex Interplay between Epitope Specificity and Isotype Dictates the Biological Activity of Anti-human CD40 Antibodies

Cited by 91 publications

References 50 publications

Considerations for the Design of Antibody-Based Therapeutics

Considerations for the Design of Antibody-Based Therapeutics

LILRB3 (ILT5) is a myeloid checkpoint on myeloid cells that elicits profound immununomodulation

Domain Binding and Isotype Dictate the Activity of Anti-human OX40 Antibodies

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