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Data from A Self-Assembling and Disassembling (SADA) Bispecific Antibody (BsAb) Platform for Curative Two-step Pretargeted Radioimmunotherapy

Authors :
Nai K. Cheung
Steven M. Larson
Charles M. Rudin
Adam O. Michel
Sebastien Monette
Pat B. Zanzonico
Hong-Fen Guo
Aiza A. Malik
Daniela Burnes Vargas
Mitesh Patel
Edward K. Fung
Darren R. Veach
Guangbin Yang
Ouathek Ouerfelli
Michael R. McDevitt
Mahiuddin Ahmed
Sarah M. Cheal
Brian H. Santich
Publication Year :
2023
Publisher :
American Association for Cancer Research (AACR), 2023.

Abstract

Purpose:Many cancer treatments suffer from dose-limiting toxicities to vital organs due to poor therapeutic indices. To overcome these challenges we developed a novel multimerization platform that rapidly removes tumor-targeting proteins from the blood to substantially improve therapeutic index.Experimental Design:The platform was designed as a fusion of a self-assembling and disassembling (SADA) domain to a tandem single-chain bispecific antibody (BsAb, anti-ganglioside GD2 × anti-DOTA). SADA–BsAbs were assessed with multiple in vivo tumor models using two-step pretargeted radioimmunotherapy (PRIT) to evaluate tumor uptake, dosimetry, and antitumor responses.Results:SADA–BsAbs self-assembled into stable tetramers (220 kDa), but could also disassemble into dimers or monomers (55 kDa) that rapidly cleared via renal filtration and substantially reduced immunogenicity in mice. When used with rapidly clearing DOTA-caged PET isotopes, SADA–BsAbs demonstrated accurate tumor localization, dosimetry, and improved imaging contrast by PET/CT. When combined with therapeutic isotopes, two-step SADA-PRIT safely delivered massive doses of alpha-emitting (225Ac, 1.48 MBq/kg) or beta-emitting (177Lu, 6,660 MBq/kg) S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA) payloads to tumors, ablating them without any short-term or long-term toxicities to the bone marrow, kidneys, or liver.Conclusions:The SADA–BsAb platform safely delivered large doses of radioisotopes to tumors and demonstrated no toxicities to the bone marrow, kidneys, or liver. Because of its modularity, SADA–BsAbs can be easily adapted to most tumor antigens, tumor types, or drug delivery approaches to improve therapeutic index and maximize the delivered dose.See related commentary by Capala and Kunos, p. 377

Details

Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....1838f2e8a38e3fb56d3903450d9ed6e6
Full Text :
https://doi.org/10.1158/1078-0432.c.6530228