Electrostatic properties of human germlines and biodistribution of small biologics.

ABSTRACT: Off-target biodistribution of biologics bears important toxicological consequences. Antibody fragments intended for use as vectors of cytotoxic payloads (e.g. antibody-drug conjugates, radiotherapy) can accumulate at clearance organs like kidneys and liver, where they can cause dose-limiting toxicities. Renal and hepatic uptakes are known to be affected by protein electrostatics, which promote protein internalization through pinocytosis. Using minibodies as a model of an antibody fragment lacking FcRn recycling, we compared the biodistributions of leads with different degrees of accumulation at the kidney and liver. We identified a positive electrostatic patch highly conserved in a germline family very commonly used in the humanization of approved biologics. Neutralization of this patch le

SUBMITTER: De Souza Cordeiro LM 

PROVIDER: S-EPMC10860348 | biostudies-literature | 2024 Jan-Dec

REPOSITORIES: biostudies-literature