Nature Communications: LeadArtis outlines a new bispecific antibody that could hold the key to activate cancer killer T-cells to find and destroy highly prevalent tumors


LeadArtis and collaborators have published in the highly regarded scientific journal Nature Communications a new tactic to generate a tumor-targeted bispecific antibody to target a particularly relevant immune receptor, 4-1BB, which can activate cancer killer T-cells to erradicate tumors.

The activation of immune cells using conventional anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials but also significant off-tumor toxicities associated with FcγR interactions. In this article, we describe am epidermal growth factor receptor (EGFR) tumor targeted bispecific 4-1BB agonistic trimerbody (named BHT) with two major advantages compared to conventional mAbs: Lack of the fragment crystallizable (Fc) region involved in 4-1BB IgG-mediated toxicity; and a suitable trimeric structure as its physiological 4-1BB ligand. Compared to conventional 4-1BB mAb agonists, the BHT demonstrated high-avidity binding to 4-1BB and EGFR and a potent in vitro costimulatory capacity. The BHT rapidly accumulates in EGFR-positive tumors and exhibits anti-tumor activity similar to 4-1BB-agonistic mAbs. Importantly, treatment with the BHT does not induce systemic inflammatory cytokine production or hepatotoxicity associated with mAb-based 4-1BB agonists. These results implicate FcγR interactions in the 4-1BB-agonist-associated immune abnormalities, and promote the use of the BHT presented in this work for safe and effective costimulatory strategies in cancer immunotherapy.

The study is the culmination of more than 5 years of research from Leadartis scientists and collaborators. They believe that this finding could lead to a new wave of cancer-fighting antibodies.

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