Electrostatic properties of human germlines and biodistribution of small biologics

Electrostatic 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 toxicit...

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Bibliographic Details
Published in:mAbs Vol. 16; no. 1; p. 2311991
Main Authors: De Souza Cordeiro, Leticia Maria, Atkinson, Kelley Christine, Aivazian, Argin, Joyce, Patrick Frank, Jia, Fang, Mascioni, Alessandro
Format: Journal Article
Language:English
Published: United States Taylor & Francis 2024
Taylor & Francis Group
Subjects:
Antibody
antibody drug conjugate
antibody engineering
biodistribution
Biological Products
biologics
electrostatics
Germ Cells
Humans
Immunoglobulin Fragments
Kidney
Static Electricity
Tissue Distribution
antibody engineering
biodistribution
biologics
electrostatics
Antibody
radiopharmaceutical
antibody drug conjugate
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Summary: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 led to a drastic reduction in the kidney uptake, leading to a biodistribution more favorable to the delivery of highly cytotoxic payloads. Next, we conducted a high throughput study of the electrostatic properties for all combinations of VH and VL germlines. This analysis shows how different VH/VL combinations exhibit varying tendencies to create electrostatic patches, resulting in Fv variants with different isoelectric points. Our work emphasizes the importance of carefully selecting germlines for humanization with optimal electrostatic properties in order to control the unspecific tissue uptake of low molecular weight biologics.
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ISSN:1942-0862
1942-0870
DOI:10.1080/19420862.2024.2311991