biostudies-literatureUnknown16(1)De Souza Cordeiro LMthere is no fundingOff-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 lemAbs2311991https://www.ebi.ac.uk/biostudies/studies/S-EPMC10860348biostudies-literatureElectrostatic properties of human germlines and biodistribution of small biologics.PMC10860348Aivazian AAtkinson KCDe Souza Cordeiro LMJoyce PFMascioni AJia FfalseElectrostatic properties of human germlines and biodistribution of small biologics.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 le2024-01-01T00:00:00Z2024 Jan-Dec2026-06-01T17:25:56.786Z2024-11-14T12:55:34.392ZS-EPMC108603483833412910.1080/19420862.2024.2311991