Cadonilimab, a tetravalent PD-1/CTLA-4 bispecific antibody with trans-binding and enhanced target binding avidity

Clinical studies have shown that combination therapy of antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) significantly improves clinical benefit over PD-1 antibody alone. However, broad application of this combination has been limited by toxicities. Cadonilimab (AK104) is a symmetric tetravalent bispecific antibody with a crystallizable fragment (Fc)-null design. In addition to demonstrating biological activity similar to that of the combination of CTLA-4 and PD-1 antibodies, cadonilimab possess higher binding avidity in a high-density PD-1 and CTLA-4 setting than in a low-density PD-1 setting, while a mono-specific anti-PD-1 antibody does not demonstrate this differential activity. With no binding to Fc receptors, cadonilimab shows minimal antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and interleukin-6 (IL-6)/IL-8 release. These features all likely contribute to significantly lower toxicities of cadonilimab observed in the clinic. Higher binding avidity of cadonilimab in a tumor-like setting and Fc-null design may lead to better drug retention in tumors and contribute to better safety while achieving anti-tumor efficacy.

Automated summary

Clinical studies have confirmed that the combination therapy of antibodies targeting CTLA-4 and PD-1 significantly enhances clinical benefit compared to the use of PD-1 antibody alone. However, limited application of this combination is due to toxicities. Cadonilimab, a tetravalent bispecific antibody, demonstrates similar biological activity as the combination therapy and exhibits higher binding avidity in high-density PD-1 and CTLA-4 environments. Its Fc-null design reduces toxic side effects. These features make cadonilimab a potential candidate for improving both safety and anti-tumor efficacy.