Issue 1, 2021

Finding and characterizing a catalytic antibody light chain, H34, capable of degrading the PD-1 molecule

Abstract

Programmed cell death 1 (PD-1) is an immune checkpoint molecule regulating T-cell function. Preventing PD-1 binding to its ligand PD-L1 has emerged as an important tool in immunotherapy. Here, we describe a unique human catalytic antibody light chain, H34, which mediates enzymatic degradation of human PD-1 peptides and recombinant human PD-1 protein and thus functions to prevent the binding of PD-1 with PD-L1. H34 degraded one half of the PD-1 molecules within about 6 h under the experimental conditions. Investigating the acquisition of the catalytic function by H34, which belongs to subgroup I and lacks a Pro95 residue in CDR-3, revealed the importance of this sequence, as a Pro95-reconstituted mutant (H34-Pro95(+)) exhibited very little catalytic activity to cleave PD-1. Interestingly, EDTA inhibited the catalytic activity of H34, which could work as a metallo-protease. Zn2+ or Co2+ ions may work as a cofactor. It is meaningfull that H34 was obtained from the human antibody gene taken from a healthy volunteer, suggesting that we potentially have such unique molecules in our body.

Graphical abstract: Finding and characterizing a catalytic antibody light chain, H34, capable of degrading the PD-1 molecule

Supplementary files

Article information

Article type
Paper
Submitted
25 Aug 2020
Accepted
11 Nov 2020
First published
10 Dez 2020
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2021,2, 220-229

Finding and characterizing a catalytic antibody light chain, H34, capable of degrading the PD-1 molecule

E. Hifumi, H. Taguchi, T. Nonaka, T. Harada and T. Uda, RSC Chem. Biol., 2021, 2, 220 DOI: 10.1039/D0CB00155D

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