Development of bifunctional anti-PD-L1 antibody MMAE conjugate with cytotoxicity and immunostimulation.

Abstract

In recent years, tumor immunotherapy, especially the combination of PD1/PD-L1 inhibitors and chemotherapy, has developed rapidly. However, the systemic side effects induced by chemotherapy remain a crucial problem that needs to be addressed. Antibody drug conjugates (ADCs) are exceptional target-specific prodrugs that greatly improve the therapeutic window of chemotherapy drugs. Therefore, designing PD-L1-targeting ADCs is an interesting research project. In this study, we confirmed for the first time that the commercial anti-PD-L1 antibody Atezolizumab has better endocytosis efficiencies than Avelumab, and was more suitable for ADC design. Then, the most popular cytotoxic payload MMAE was conjugated to Atezolizumab via a classical dipeptide (valine-alanine) linker to generate a bifunctional PD-L1 ADC (ADC 3). An in vitro cytotoxicity test indicated the potent tumor cell inhibitory activity of ADC 3, with EC50 values of 9.75 nM to 11.94 nM. In addition, a co-culture of PBMCs in vitro proved that ADC 3 retained the immune activation effect of the Atezolizumab antibody. Moreover, ADC 3 exhibited a higher tumor inhibition rate and tumor regression rate in humanized immune system mice. To the best of our knowledge, this is the most active PD-L1-ADC reported thus far, which may promote the development of immunotherapy and novel ADCs.

• Authors: Dian Xiao, Longlong Luo, Jiaguo Li, Zhihong Wang, Lianqi Liu, Fei Xie, Jiannan Feng, Xinbo Zhou
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 116 Pg. 105366 (11 2021) ISSN: 1090-2120 [Electronic] United States
• PMID: 34560561 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• B7-H1 Antigen
• CD274 protein, human
• Immunoconjugates
• Oligopeptides
• atezolizumab
• monomethyl auristatin E

Topics

• Antibodies, Monoclonal, Humanized (chemistry, pharmacology)
• Antineoplastic Agents (chemistry, pharmacology)
• B7-H1 Antigen (antagonists & inhibitors, immunology)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Development
• Humans
• Immunoconjugates (chemistry, pharmacology)
• Immunotherapy
• Molecular Structure
• Oligopeptides (chemistry, pharmacology)
• Structure-Activity Relationship
• Tumor Cells, Cultured