Ligand-Blocking and Membrane-Proximal Domain Targeting Anti-OX40 Antibodies Mediate Potent T Cell-Stimulatory and Anti-Tumor Activity

Zhang, Pamela; Tu, Guang Huan; Wei, Jie; Santiago, Pamela; Larrabee, Lance R.; Liao-Chan, Sindy; Mistry, Tına; Chu, Matthew L. H.; Sai, Tao; Lindquist, Kevin C.; Liu, Hua; Chaparro‐Riggers, Javier; Salek-Ardakani, Shahram; Yeung, Yik Andy

doi:10.1016/j.celrep.2019.05.027

Cited by 20 publications

(21 citation statements)

References 31 publications

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“…who also demonstrated strong agonistic function with a CRD4 binding anti-mOX40 mAb. However, those authors also documented equivalent agonistic activity with a CRD2-binding, ligand blocking anti-mOX40 mAb [23], indicating the fine epitope is also important, as we reported previously for anti-CD40 [22].…”

Section: Discussionsupporting

confidence: 82%

“…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%

“…We also demonstrated a domain binding association with differential effector mechanisms for anti-4-1BB mAb [20], showing mAb which bound membrane proximal domains engaged in more effective CDC and ADCC killing mechanisms with ADCP less affected [20] . Recently, Zhang et al reported that mAb binding to mouse (m)OX40 which blocked ligand binding and bound CRD2, or bound at the membrane proximal domain (CRD4), provide stronger agonistic and anti-tumour activity than mAb binding CRD1 and 3 [23]. These results differed from those seen for hCD40, highlighting that the functional effects of mAb domain binding are likely to require assessment for each of the TNFR family members and validation for each species.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Griffiths

Hussain

Smith

et al. 2020

Preprint

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“…This heterogeneity has often frustrated efforts to develop ligand mimics that can selectively activate one signaling pathway, as the molecular requirements for binding different complexes are often highly overlapping. Antibodies have been developed that can induce receptor dimerization, but the location of the epitope that the antibodies target generally does not lead to cross-linking of receptors in their native "activated" arrangement (1). Because the geometry of the dimerized receptor pair greatly influences their activity, a better strategy is needed to obtain functional antibodies.…”

mentioning

confidence: 99%

“…The author declares that he has no conflicts of interest with the contents of this article. 1 To whom correspondence should be addressed: Cancer Immunology Discovery Oncology R&D Group, Pfizer Inc., 10777 Science Center Dr., San Diego, CA 92121. E-mail: Dirk.Zajonc@pfizer.com.…”

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confidence: 99%

Catching a complex for optimal signaling

Zajonc

2019

Journal of Biological Chemistry

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Agonistic antibodies are powerful tools to dimerize receptors in the absence of ligand binding, but high-fidelity receptor activation requires that these antibodies accurately recapitulate the native dimeric state. Spangler et al. employ a clever approach to select for antibodies that bind a specific IL-4R␣/␥ c heterodimeric complex in its native signaling conformation, leading to a monovalent "stapler," a single-chain variable fragment (scFv) that binds at the dimerization interface. This powerful approach can be further exploited for a variety of homo-or heterodimeric receptors to achieve signaling, especially in the absence of endogenous ligand.

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A Dual‐domain Engineered Antibody for Efficient HBV Suppression and Immune Responses Restoration

Jiang,

Chen,

et al. 2024

Advanced Science

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Chronic hepatitis B (CHB) remains a major public health concern because of the inefficiency of currently approved therapies in clearing the hepatitis B surface antigen (HBsAg). Antibody‐based regimens have demonstrated potency regarding virus neutralization and HBsAg clearance. However, high dosages or frequent dosing are required for virologic control. In this study, a dual‐domain‐engineered anti‐hepatitis B virus (HBV) therapeutic antibody 73‐DY is developed that exhibits significantly improved efficacy regarding both serum and intrahepatic viral clearance. In HBV‐tolerant mice, administration of a single dose of 73‐DY at 2 mg kg−1 is sufficient to reduce serum HBsAg by over 3 log10 IU mL−1 and suppress HBsAg to < 100 IU mL−1 for two weeks, demonstrating a dose‐lowering advantage of at least tenfold. Furthermore, 10 mg kg−1 of 73‐DY sustainably suppressed serum viral levels to undetectable levels for ≈ 2 weeks. Molecular analyses indicate that the improved efficacy exhibited by 73‐DY is attributable to the synergy between fragment antigen binding (Fab) and fragment crystallizable (Fc) engineering, which conferred sustained viral suppression and robust viral eradication, respectively. Long‐term immunotherapy with reverse chimeric 73‐DY facilitated the restoration of anti‐HBV immune responses. This study provides a foundation for the development of next‐generation antibody‐based CHB therapies.

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Ligand-Blocking and Membrane-Proximal Domain Targeting Anti-OX40 Antibodies Mediate Potent T Cell-Stimulatory and Anti-Tumor Activity

Cited by 20 publications

References 31 publications

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

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

Catching a complex for optimal signaling

A Dual‐domain Engineered Antibody for Efficient HBV Suppression and Immune Responses Restoration

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