Week 1, December 2024: Biparatopic Antibodies

Biparatopic antibodies (bpAbs) are bispecific antibodies which bind distinct, non-overlapping epitopes on an antigen. This unique binding mode allows for superior affinity and specificity, promotes antagonism, locks target conformation, and results in higher-order target clustering. The antibody-target complexes can elicit strong agonism, increase immune effector function, or result in rapid target downregulation and lysosomal trafficking.  

The latest novel antibody drug is Ziihera (zanidatamab-hrii). Approved on November 20, 2024, Ziihera will treat unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer. It is the first FDA-approved biparatopic antibody therapy. Zanidatamab works by binding to two extracellular sites on HER2. This results in internalization leading to a reduction of the receptor on the tumor cell surface, therefore inducing complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). These mechanisms result in tumor growth inhibition and cell death in vitro and in vivo. 

Besides Ziihera, there are several other biparatopic antibodies under investigation. This month for example, Alphamab Oncology announced that JSKN033 presented a favorable safety profile and encouraging anti-cancer activity in heavily treated patients. JSKN033 is an anti-HER2 bispecific ADC, comprising of three components: a bispecific antibody targeting two non-overlapping epitopes of HER2 extracellular domains, a cleavable linker, and a topoisomerase I inhibitor. It has entered phase 3 clinical trials.  

Meanwhile, ISB 1442 is a fully human bispecific, biparatopic antibody targeting CD38 and CD47 which is undergoing a phase 1/2 study. Treatment with ISB 1442 is associated with manageable toxicity and the study continues to enroll in the dose escalation (NCT05427812). The antibody works by harnessing innate immunity and enhancing tumor cell killing through antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).