Dual targeting of RANKL and PD-1 with a bispecific antibody improves anti-tumor immunity

In summary, the bispecific anti-RANKL/PD-1 antibody demonstrates potent tumor growth inhibition in settings of ICI resistance and represents a novel modality for clinical development in advanced cancer.

Mechanistically, the anti-tumor activity of anti-RANKL/PD-1 BsAb required CD8+T cells, host PD-1 and IFNγ. Targeting RANKL and PD-1 simultaneously within the tumor microenvironment (TME) improved anti-tumor efficacy compared with combination of two separate mAbs. Conclusion: In summary, the bispecific anti-RANKL/PD-1 antibody demonstrates potent tumor growth inhibition in settings of ICI resistance and represents a novel modality for clinical development in advanced cancer.

We characterized target binding and functional activity of the anti-RANKL/PD-1 BsAb in cell-based assays. Anti-tumor activity was confirmed in experimental lung metastasis models and in mice with established subcutaneously transplanted tumors.

The anti-RANKL/PD-1 BsAb retained binding to both RANKL and PD-1 and blocked the interaction with respective counter-structures RANK and PD-L1. The inhibitory effect of anti-RANKL/PD-1 BsAb was confirmed by demonstrating a complete block of RANKL-dependent osteoclast formation. Monotherapy activity of anti-RANKL/PD-1 BsAb was observed in anti-PD-1 resistant tumors and, when combined with anti-CTLA-4 mAb, increased anti-tumor responses. An equivalent or superior anti-tumor response was observed with the anti-RANKL/PD-1 BsAb compared with the combination of parental anti-RANKL plus anti-PD-1 antibodies depending upon the tumor model.