Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy

Abstract

Purpose Bispecific antibodies (BsAbs) have emerged as a leading drug class for cancer therapy and are becoming increasingly of interest for therapeutic applications. As of April 2020, over 123 BsAbs are under clinical evaluation for use in oncology (including the two marketed BsAbs Blinatumomab and Catumaxomab). The majority (82 of 123) of BsAbs under clinical evaluation can be categorized as bispecific immune cell engager whereas a second less well-discussed subclass of BsAbs targets two tumor-associated antigens (TAAs). In this review, we summarize the clinical development of dual TAAs targeting BsAbs and provide an overview of critical considerations when designing dual TAA targeting BsAbs. Methods Herein the relevant literature and clinical trials published in English until April 1st 2020 were searched using PubMed and ClinicalTrials.gov database. BsAbs were considered to be active in clinic if their clinical trials were not terminated, withdrawn or completed before 2018 without reporting results. Data missed by searching ClinicalTrials.gov was manually curated. Results Dual TAAs targeting BsAbs offer several advantages including increased tumor selectivity, potential to concurrently modulate two functional pathways in the tumor cell and may yield improved payload delivery. Conclusions Dual TAAs targeting BsAbs represent a valuable class of biologics and early stage clinical studies have demonstrated promising anti-tumor efficacy in both hematologic malignancies and solid tumors.

Amivantamab in EGFR Exon 20 Insertion–Mutated Non–Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study

“…The incidence of severe toxicity and toxicityrelated discontinuations were low despite a lack of selectivity against the wild-type EGFR, suggesting that the bispecific nature of amivantamab may affect the safety profile, potentially through altered target cell selectivity (eg, tumor cells). 21,29,30 Early efficacy in this study identified clinically significant monotherapy activity of amivantamab in EGFR Exon20ins NSCLC in the chemotherapy-naive (n 5 10) and chemotherapy-relapsed setting (n 5 29). This experience led to Breakthrough Therapy Designation in both the United States and China for the latter population on the basis of the investigator-assessed ORR of 41%, the median DOR of 7 months, and the CBR of 72%.…”

Potential Role of CD47-Directed Bispecific Antibodies in Cancer Immunotherapy

“…Recently, we have witnessed much progress with bsAb technologies and therapeutics as reviewed here and elsewhere ( 13 , 71 ), which have found wide applicability to immunotherapy for cancer treatment. And thus, many bsAb constructs with differing mechanisms of action are being investigated, each with their own limitations and advantages.…”

Bispecific Antibodies: From Research to Clinical Application

“…BsAbs can target two specific antigens or different areas of the same antigen at the same time (114) HER2, also known as neu, ErbB-2, CD340, and p185, is a member of the ERBB family of receptor tyrosine kinases. This family also includes ERBB1, ERBB3, and ERBB4.…”

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