A bispecific antibody targeting HER2 and PD-L1 inhibits tumor growth with superior efficacy

Abstract

Activation of the programmed cell death protein 1 and programmed cell death ligand 1 (PD-1/PD-L1) signaling axis plays important roles in intrinsic or acquired resistance to human epidermal growth factor receptor 2 (HER2)-directed therapies in the clinic. Therefore, therapies simultaneously targeting both HER2 and PD-1/PD-L1 signaling pathways are of great significance. Here, aiming to direct the anti-PD-L1 responses toward HER2-expressing tumor cells, we constructed a humanized bispecific IgG1 subclass antibody targeting both HER2 and PD-L1 (HER2/PD-L1; BsAb), which displayed satisfactory purity, thermostability, and serum stability. We found that BsAb showed enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity in vitro . In the late phase of peripheral blood mononuclear cell (PBMC)-humanized HER2 + tumor xenograft models, BsAb showed superior therapeutic efficacies as compared with monoclonal antibodies (mAbs) or combination treatment strategies. In cynomolgus monkeys, BsAb showed favorable pharmacokinetics and toxicity profiles when administered at a 10 mg/kg dosage. Thus, HER2/PD-L1 BsAb was demonstrated as a potentially effective option for managing HER2 + and trastuzumab-resistant tumors in the clinic. We propose that the enhanced antitumor activities of BsAb in vivo may be due to direct inhibition of HER2 signaling or activation of T cells.

Emerging Targeted Therapies for HER2-Positive Breast Cancer

“…Another BsAb is HER2/PD-L1. It consists of whole trastuzumab IgG1, which can trigger ADCC and CDC, and tandem anti-PD-L1 [ 218 ]. In trastuzumab-resistant preclinical models, this BsAb outperformed the two monoclonal antibodies alone, highlighting its potential to overcome trastuzumab resistance [ 218 ].…”

“…It consists of whole trastuzumab IgG1, which can trigger ADCC and CDC, and tandem anti-PD-L1 [ 218 ]. In trastuzumab-resistant preclinical models, this BsAb outperformed the two monoclonal antibodies alone, highlighting its potential to overcome trastuzumab resistance [ 218 ]. In a phase 1 clinical trial in patients with HER2+ solid tumors (NCT04162327), the HER2/PD-1 BsAb IBI315/Fidasimtamab showed no dose-limiting toxicity and a 20% objective response rate [ 219 ].…”

Clinical implication of genetic composition and molecular mechanism on treatment strategies of HER2-positive breast cancers

“…BsAb have been developed to target both HER2 and PD-L1 ( 120 , 121 ). These will direct T cells to engage HER2 cells blocking simultaneously both HER2 downstream signals and PD-1/PD-L1 axis to increase ADCC.…”

“…Besides ADCC, there are other effector functions that include CDC and antibody-dependent cellular phagocytosis (ADCP), which can lead to collateral damage to PD-1-expressing tumor-infiltrating T cells. The other BsAb reported was constructed with the whole trastuzumab IgG and tandem anti-PD-L1 scFVs in the format of IgG-scFV ( 121 ). The BsAb generated was more stable with more enhanced ADCC than trastuzumab, especially in the late phase of the disease model using PMBC humanized tumor xenograft.…”

Engineering of a Bispecific Nanofitin with Immune Checkpoint Inhibitory Activity Conditioned by the Cross-Arm Binding to EGFR and PDL1

“…Another means of improving anti-PD1/PDL1 therapies leans toward preventing their on-target/off-tumor binding and the subsequent occurrence of immune-related adverse events (irAEs). The latter could be achieved by promoting their tumor partitioning-dependent activation by tumor-associated antigen (TAA) targeting [ 20 , 21 , 22 ]. To this end, Koopmans et al described the development of a bispecific antibody targeting both PDL1 and EGFR, hence driving the PDL1 blockade to EGFR-overexpressing cancer cells selectively [ 20 ].…”