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

  • Bioorg Chem. 2021 Nov:116:105366. doi: 10.1016/j.bioorg.2021.105366.
Dian Xiao  1 ,  Longlong Luo  2 ,  Jiaguo Li  3 ,  Zhihong Wang  2 ,  Lianqi Liu  1 ,  Fei Xie  1 ,  Jiannan Feng  4 ,  Xinbo Zhou  5
Affiliations
  • 1. National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
  • 2. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
  • 3. School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China.
  • 4. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: [email protected].
  • 5. National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: [email protected].
PMID: 34560561 DOI: 10.1016/j.bioorg.2021.105366
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.

Keywords
Antibody drug conjugate; Cytotoxicity; Immunostimulation; PD-L1.
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