In a study published in PNAS, Dr. WANG Feng's group from Institute of Biophysics of the Chinese Academy of Sciences, collaborating with researchers from Scripps Research Institute and Peking University Shenzhen Graduate School, developed a new approach to use bispecific antibodies for tumor-targeted delivery of immune checkpoint blockers.

Treatment by immunotherapy has shown clinical benefit either as a monotherapy or as part of a combination therapy. While highly effective, immunotherapies are limited for low response rate and primary or acquired resistance. Combining two different immune checkpoint blocking antibodies or combining immunotherapy with chemotherapy or radiotherapy could increase response rates and enhance clinical efficacy.

However, current immune checkpoint inhibitors are not tumor-specific, and induce systemic immune activation in other tissues and organs. Combination of immunotherapies further amplify these toxicities, e.g., in melanoma patients, treatment with a combination of Ipilimumab and Nivolumab increased the occurrence of severe side effects by 2-4 fold compared to the monotherapies alone.

By using peptide-antibody conjugation technology, researchers developed a bispecific antibody NDP-MSH-αPD-L1 to target melanoma. This molecule showed high affinity to melanocortin-1 receptor (MC1R) and PD-L1 expressed on melanoma cells, and demonstrated enhanced specific antitumor efficacy in a syngeneic melanoma mouse model as compared to anti-PD-L1 antibody.

Besides, they found that the tumor growth inhibition results are correlated with the number of infiltrated CD3+ cells in tumors, indicating that the efficacy is mediated by activated T cells through PD-L1 blockade.

The therapeutic advantage of tumor targeted immune checkpoint inhibitor is not limited to melanoma. This strategy could be applied to various types of solid tumors. Dr. WANG’s team is currently working on developing bispecific immune checkpoint inhibitor constructs to target multiple tumors and maximize their therapeutic benefits.

Tumor-targeted immune checkpoint blocker NDP-MSH-αPD-L1 showed its anti-tumor efficacy in melanoma tumor-bearing mice. (Image by Dr. WANG Feng's group)