Background
Clinical research has demonstrated that combining immunotherapy anti-PD-1/PD-L1 antibodies with anti-angiogenic VEGF/VEGFR blockers improves cancer treatment outcomes. These combined therapies have received approval for several cancer types. A bispecific antibody targeting both PD-L1 and VEGF could enrich the antibody concentration in tumor tissue by specifically binding to PD-L1 expressed in the tumor, thereby increasing VEGF blockade in the local tumor area. Currently, there is no approved monotherapy targeting both PD-L1 and VEGF pathways. IMM2510 and PM8002 are two early-stage drug candidates with dual anti-PD-L1 and anti-VEGF properties. They exhibited promising efficacy against advanced solid tumors and favorable tolerance in clinical trials.
Methods and Results
We developed a novel bispecific anti-PD-L1/anti-VEGF antibody, BB-203. BB-203 was engineered using humanized anti-PD-L1 and anti-VEGF VHH fragments fused with a human IgG1 Fc. BB-203 maintained the high binding affinities and potent biological functions of its parental VHH-Fc antibodies. Results from whole-cell binding assays showed that BB-203 had a higher binding affinity to PD-L1 than Avelumab. BB-203 also exhibited higher potency in blocking human PD-L1 compared to Avelumab, IMM2510, and PM8002 in PD1/PD-L1 blockade assay. The potency of BB-203 in blocking human VEGFA was similar to Avastin, IMM2510, and PM8002 in VEGF bioassay.
BB-203 showed remarkable stability in both accelerated stability tests and serum stability tests. Pharmacokinetic studies revealed that BB-203 had a PK profile similar to Avelumab, a conventional IgG1 antibody.
The in vivo efficacy of BB-203 was evaluated using a MC38-hPD-L1 model with MC38 cancer cells genetically modified to express the human PD-L1 to replace the mouse PD-L1. The study demonstrated that BB-203 had robust anti-tumor activity, achieving an 81% tumor growth inhibition (TGI), significantly higher than that of its parental monospecific VHH-Fc antibodies, which had TGIs of 24% or 30%, respectively. This highlights the synergistic anti-tumor effect of the two arms of BB-203. Additionally, BB-203 exhibited significantly greater tumor suppression compared to an equimolar dose of IMM2510, which achieved a TGI of 56%. The superior efficacy of BB-203 compared to IMM2510 may be attributed to its more potent anti-PD-L1 activity and higher tumor tissue penetration due to its smaller size (105 KDa) compared to IMM2510 (170 KDa). No weight loss or other obvious side effects were observed.
Conclusions
The novel anti-PD-L1/anti-VEGF bispecific VHH antibody BB-203 has potent target-blocking activities in vitro and strong anti-tumor efficacy in vivo. Together with its excellent developability, BB-203 potentially is the best-in-class anti-PD-L1/anti-VEGF bispecific antibody drug candidate.