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Published on: June 19, 2015
Ligand-Blocking and Membrane-Proximal Domain Targeting Anti-OX40 Antibodies Mediate Potent T Cell-Stimulatory and
Pamela Zhang1, Guang Huan Tu1, Jie Wei1
1Cancer Immunology Discovery, Oncology Research and Development, Pfizer, Inc., 230 E. Grand Ave., South San Francisco, CA 94080, USA.
Abstract:
Agonistic antibodies targeting the tumor necrosis factor (TNF) superfamily of co-stimulatory receptors (TNFRSF) are progressing through various stages of clinical development for cancer treatment, but the desired and defining features of these agents for optimal biological activity remain controversial. One idea, based on recent studies with CD40, is that non-ligand-blocking antibodies targeting membrane-distal cysteine-rich domain 1 (CRD1) have superior agonistic activities compared with ligand-blocking antibodies targeting more membrane-proximal CRDs. Here, we determined the binding and functional characteristics of a panel of antibodies targeting CRDs 1-4 of OX40 (also known as TNFRSF4 or CD134). In striking contrast to CD40, we found that ligand-blocking CRD2-binding and membrane-proximal CRD4-binding anti-OX40 antibodies have the strongest agonistic and anti-tumor activities. These findings have important translational implications and further highlight that the relationship between epitope specificity and agonistic activity will be an important issue to resolve on a case-by-case basis when optimizing antibodies targeting different co-stimulatory tumor necrosis factor receptors (TNFRs).
Insights
Antibodies targeting OX40 (TNFRSF4) for cancer therapy show that blocking antibodies binding to CRD2 or CRD4 are most effective, unlike CD40 antibodies. This finding impacts the design of future cancer treatments.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Agonistic antibodies targeting tumor necrosis factor superfamily receptors (TNFRSF) are investigated for cancer therapy.
- Optimal antibody features for co-stimulatory receptors like OX40 (TNFRSF4) are debated, with some suggesting distal epitope binding is superior.
Purpose of the Study:
- To investigate the binding and functional characteristics of antibodies targeting different cysteine-rich domains (CRDs) of OX40.
- To compare the agonistic activity and anti-tumor effects of anti-OX40 antibodies with varying epitope specificities.
Main Methods:
- Generated and characterized a panel of antibodies targeting CRDs 1-4 of OX40.
- Assessed antibody binding, agonistic activity, and in vivo anti-tumor efficacy.
Main Results:
- Contrary to findings with CD40, ligand-blocking antibodies targeting OX40 CRD2 and membrane-proximal CRD4 demonstrated the strongest agonistic and anti-tumor activities.
- Epitope specificity significantly influences the biological activity of anti-OX40 agonistic antibodies.
Conclusions:
- The optimal epitope for agonistic anti-OX40 antibodies differs from that of anti-CD40 antibodies.
- These findings emphasize the need for case-by-case optimization of antibodies targeting co-stimulatory TNFRs for cancer immunotherapy.
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