Targeting two distinct epitopes on human CD73 with a bispecific antibody improves anticancer activity

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• CD73 enzymatic activity generates immunosuppressive extracellular adenosine.
• Antibodies targeting CD73 have shown preclinical anticancer effects via various mechanisms.
• These mechanisms include enzyme inhibition, Fc receptor engagement, and CD73 redistribution.

Purpose of the Study:

• To generate and evaluate biparatopic bispecific antibodies (bsAbs) combining distinct anti-CD73 antibody activities.
• To assess the enhanced anticancer efficacy of these bsAbs in preclinical models.

Main Methods:

• Generation of biparatopic bsAbs using controlled Fab arm exchange from parental anti-CD73 antibodies.
• In vitro and in vivo evaluation of the anticancer activity of the generated bsAbs.

Main Results:

• The biparatopic bsAb demonstrated improved enzyme inhibitory activity compared to parental antibodies.
• Adenosine-mediated T-cell suppression was neutralized, evidenced by increased T-cell proliferation and interferon-gamma production.
• Enhanced internalization of cell surface CD73 and potent Fc-mediated immune cell engagement were observed.
• Tumor-bearing mice treated with the bsAb showed prolonged survival.

Conclusions:

• Complementary anticancer mechanisms of distinct anti-CD73 antibodies can be effectively combined and enhanced in biparatopic bsAbs.
• The superior and multi-mechanistic activity of these bsAbs positions them as promising therapeutic candidates for CD73-targeted cancer therapy.
• This strategy offers a potential paradigm shift for future antibody design in cancer treatment.