Journal
JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 9, Issue 10, Pages -Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2021-003464
Keywords
immunotherapy; antibody affinity; immunity; innate; tumor microenvironment
Categories
Funding
- Pfizer
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The study developed a novel affinity-tuned bispecific antibody targeting CD47 and PD-L1 to antagonize innate and adaptive immune checkpoint pathways. This antibody showed enhanced selectivity in the tumor microenvironment and improved therapeutic window compared to monotherapies or combination therapies with alpha CD47 and alpha PD-L1. The bispecific treatment uniquely modulated myeloid and T cells, providing potential for clinical development to improve patient outcomes over current PD-(L)1 and CD47-targeted therapies.
Background T cell checkpoint immunotherapies have shown promising results in the clinic, but most patients remain non-responsive. CD47-signal regulatory protein alpha (SIRP alpha) myeloid checkpoint blockade has shown early clinical activity in hematologic malignancies. However, CD47 expression on peripheral blood limits alpha CD47 antibody selectivity and thus efficacy in solid tumors. Methods To improve the antibody selectivity and therapeutic window, we developed a novel affinity-tuned bispecific antibody targeting CD47 and programmed death-ligand 1 (PD-L1) to antagonize both innate and adaptive immune checkpoint pathways. This PD-L1-targeted CD47 bispecific antibody was designed with potent affinity for PD-L1 and moderate affinity for CD47 to achieve preferential binding on tumor and myeloid cells expressing PD-L1 in the tumor microenvironment (TME). Results The antibody design reduced binding on red blood cells and enhanced selectivity to the TME, improving the therapeutic window compared with alpha CD47 and its combination with alpha PD-L1 in syngeneic tumor models. Mechanistically, both myeloid and T cells were activated and contributed to antitumor activity of alpha CD47/PD-L1 bispecific antibody. Distinct from alpha CD47 and alpha PD-L1 monotherapies or combination therapies, single-cell RNA sequencing (scRNA-seq) and gene expression analysis revealed that the bispecific treatment resulted in unique innate activation, including pattern recognition receptor-mediated induction of type I interferon pathways and antigen presentation in dendritic cells and macrophage populations. Furthermore, treatment increased the Tcf7(+) stem-like progenitor CD8 T cell population in the TME and promoted its differentiation to an effector-like state. Consistent with mouse data, the compounds were well tolerated and demonstrated robust myeloid and T cell activation in non-human primates (NHPs). Notably, RNA-seq analysis in NHPs provided evidence that the innate activation was mainly contributed by CD47-SIRP alpha but not PD-L1-PD-1 blockade from the bispecific antibody. Conclusion These findings provide novel mechanistic insights into how myeloid and T cells can be uniquely modulated by the dual innate and adaptive checkpoint antibody and demonstrate its potential in clinical development (NCT04881045) to improve patient outcomes over current PD-(L)1 and CD47-targeted therapies.
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