A Self-Assembling and Disassembling (SADA) Bispecific Antibody (BsAb) Platform for Curative Two-step Pretargeted Radioimmunotherapy
- 21 September 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 27 (2), 532-541
- https://doi.org/10.1158/1078-0432.ccr-20-2150
Abstract
Purpose: Many cancer treatments suffer from dose-limiting toxicities to vital organs due to poor therapeutic indices (TI). To overcome these challenges we developed a novel multimerization platform that rapidly removed tumor targeting proteins from the blood to substantially improve TI.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 x anti-DOTA). SADA-BsAbs were assessed with multiple in vivo tumor models using 2-step pretargeted radioimmunotherapy (PRIT) to evaluate tumor uptake, dosimetry and anti-tumor 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, 2-step SADA-PRIT safely delivered massive doses of alpha-emitting (225Ac, 1.48 MBq/kg) or beta-emitting (177Lu, 6,660 MBq/kg) 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. Due to its modularity, SADA-BsAbs can be easily adapted to most tumor antigens, tumor types, or drug delivery approaches to improve TI and maximize the delivered dose.Keywords
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Funding Information
- MSKCC (R01 CA233896)
- MSKCC (P30 CA008748)
This publication has 35 references indexed in Scilit:
- A Perspective on Cancer Cell MetastasisScience, 2011
- Engineering an antibody with picomolar affinity to DOTA chelates of multiple radionuclides for pretargeted radioimmunotherapy and imagingNuclear Medicine and Biology, 2011
- Biodistribution and Clearance of Small Molecule Hapten Chelates for Pretargeted RadioimmunotherapyMolecular Imaging & Biology, 2010
- A modeling analysis of the effects of molecular size and binding affinity on tumor targetingMolecular Cancer Therapeutics, 2009
- A Primary Xenograft Model of Small-Cell Lung Cancer Reveals Irreversible Changes in Gene Expression Imposed by CultureIn vitroCancer Research, 2009
- Disruption of GM2/GD2 synthase gene resulted in overt expression of 9‐O‐acetyl GD3 irrespective of Tis211Journal of Neurochemistry, 2008
- Multifunctional Antibodies by the Dock-and-Lock Method for Improved Cancer Imaging and Therapy by PretargetingJournal of Nuclear Medicine, 2007
- Enhanced Circulating Half-Life and Antitumor Activity of a Site-Specific Pegylated Interferon-α Protein TherapeuticBioconjugate Chemistry, 2007
- PEGylation and Multimerization of the Anti-p185HER-2 Single Chain Fv Fragment 4D5Online Journal of Public Health Informatics, 2006
- Renal Tubulointerstitial Changes after Internal Irradiation with α-Particle–Emitting Actinium DaughtersJournal of the American Society of Nephrology, 2005