Polymeric PD1/PDL1 bispecific antibody enhances immune checkpoint blockade therapy

Immune checkpoint blockade (ICB) therapy, particularly PD1/PDL1 inhibition, has demonstrated success in bolstering durable responses in patients. However, the response rate remains below 30 %. In this study, we developed a polymeric bispecific antibody (BsAb) targeting PD1/PDL1 to enhance ICB therapy. Specifically, poly((L)-glutamic acid) (PGLU) was conjugated with a double cyclic Fc binding peptide, Fc-III-4C, through condensation reactions between the -COOH group of PGLU and the -NH2 group of Fc-III-4C. This conjugate was then mixed with alpha PD1 and alpha PDL1 monoclonal antibodies (mAbs) in an aqueous solution. Mechanistically, the PD1/PDL1 BsAb (BsAb(alpha PD1+alpha PDL1)) acts as a bridge between tumor cells and CD8(+) T cells, continuously activating CD8(+) T cells to a greater extent. This leads to significantly suppressed tumor growth and prolonged survival in a mouse model of colon cancer compared to treatment with either a single mAb or a mixture of free mAbs. The tumor suppression rate achieved by the BsAb(alpha PD1+alpha PDL1) was 90.1 %, with a corresponding survival rate of 83.3 % after 48 days. Thus, this study underscores the effectiveness of the BsAb(alpha PD1+alpha PDL1) as a synchronizing T cell engager and dual ICBs, offering theoretical guidance for clinical ICB therapy.