A self-assembling and disassembling (SADA) bispecific antibody (BsAb) platform for curative two-step pretargeted radioimmunotherapy Journal Article


Authors: Santich, B. H.; Cheal, S. M.; Ahmed, M.; McDevitt, M. R.; Ouerfelli, O.; Yang, G.; Veach, D. R.; Fung, E. K.; Patel, M.; Burnes Vargas, D.; Malik, A. A.; Guo, H. F.; Zanzonico, P. B.; Monette, S.; Michel, A. O.; Rudin, C. M.; Larson, S. M.; Cheung, N. K.
Article Title: A self-assembling and disassembling (SADA) bispecific antibody (BsAb) platform for curative two-step pretargeted radioimmunotherapy
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. 2020 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 27
Issue: 2
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2021-01-15
Start Page: 532
End Page: 541
Language: English
DOI: 10.1158/1078-0432.Ccr-20-2150
PROVIDER: scopus
PMCID: PMC7855367
PUBMED: 32958698
DOI/URL:
Notes: Article -- Export Date: 1 March 2021 -- Source: Scopus
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MSK Authors
  1. Nai-Kong Cheung
    652 Cheung
  2. Michael R Mcdevitt
    144 Mcdevitt
  3. Darren Veach
    98 Veach
  4. Ouathek Ouerfelli
    102 Ouerfelli
  5. Pat B Zanzonico
    359 Zanzonico
  6. Sebastien Monette
    151 Monette
  7. Mahiuddin Ahmed
    14 Ahmed
  8. Guangbin Yang
    28 Yang
  9. Steven M Larson
    959 Larson
  10. Sarah Marie Cheal
    49 Cheal
  11. Hong-Fen Guo
    76 Guo
  12. Charles Rudin
    495 Rudin
  13. Brian Horacio Santich
    18 Santich
  14. Miteshkumar V Patel
    16 Patel
  15. Adam Oliver Michel
    19 Michel
  16. Aiza Amjad Malik
    2 Malik