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
Altmetric
Citation Impact
MSK Authors
  1. Nai-Kong Cheung
    627 Cheung
  2. Michael R Mcdevitt
    143 Mcdevitt
  3. Darren Veach
    87 Veach
  4. Pat B Zanzonico
    342 Zanzonico
  5. Sebastien Monette
    138 Monette
  6. Mahiuddin Ahmed
    14 Ahmed
  7. Guangbin Yang
    24 Yang
  8. Steven M Larson
    941 Larson
  9. Sarah Marie Cheal
    46 Cheal
  10. Hong-Fen Guo
    67 Guo
  11. Charles Rudin
    432 Rudin
  12. Brian Horacio Santich
    17 Santich
  13. Miteshkumar V Patel
    10 Patel
  14. Adam Oliver Michel
    18 Michel
  15. Aiza Amjad Malik
    2 Malik