Tumor targeted alpha particle therapy with an actinium-225 labelled antibody for carbonic anhydrase IX

Morgan, Katherine A.; Wichmann, Christian W.; Osellame, Laura D.; Cao, Zhipeng; Guo, Nancy; Scott, Andrew M.; Donnelly, Paul S.

doi:10.1039/d3sc06365h

Tumor targeted alpha particle therapy with an actinium-225 labelled antibody for carbonic anhydrase IX

Journal Article · Fri Jan 26 00:00:00 EST 2024 · Chemical Science

DOI:https://doi.org/10.1039/d3sc06365h· OSTI ID:2470419

^[1]; ^[2]; ^[3]; ^[3]; Guo, Nancy ^[4]; ^[5]; ^[1]

Univ. of Melbourne, VIC (Australia)
Olivia Newton-John Cancer Research Inst., Melbourne (Australia); La Trobe Univ., Melbourne, VIC (Australia); Austin Health, Melbourne (Australia)
Olivia Newton-John Cancer Research Inst., Melbourne (Australia); La Trobe Univ., Melbourne, VIC (Australia)
Olivia Newton-John Cancer Research Institute, Melbourne (Australia)
Olivia Newton-John Cancer Research Inst., Melbourne (Australia); La Trobe Univ., Melbourne, VIC (Australia); Austin Health, Melbourne (Australia); Univ. of Melbourne, VIC (Australia)

Selective antibody targeted delivery of α particle emitting actinium-225 to tumors has significant therapeutic potential. This work highlights the design and synthesis of a new bifunctional macrocyclic diazacrown ether chelator, H₂MacropaSqOEt, that can be conjugated to antibodies and forms stable complexes with actinium-225. The macrocyclic diazacrown ether chelator incorporates a linker comprised of a short polyethylene glycol fragment and a squaramide ester that allows selective reaction with lysine residues on antibodies to form stable vinylogous amide linkages. This new H₂MacropaSqOEt chelator was used to modify a monoclonal antibody, girentuximab (hG250), that binds to carbonic anhydrase IX, an enzyme that is overexpressed on the surface of cancers such as clear cell renal cell carcinoma. This new antibody conjugate (H₂MacropaSq-hG250) had an average chelator to antibody ratio of 4 : 1 and retained high affinity for carbonic anhydrase IX. H₂MacropaSq-hG250 was radiolabeled quantitatively with [²²⁵Ac]Ac^III within one minute at room temperature with micromolar concentrations of antibody and the radioactive complex is stable in human serum for >7 days. Evaluation of [²²⁵Ac]Ac(MacropaSq-hG250) in a mouse xenograft model, that overexpresses carbonic anhydrase IX, demonstrated a highly significant therapeutic response. It is likely that H₂MacropaSqOEt could be used to modify other antibodies providing a readily adaptable platform for other actinium-225 based therapeutics.

View Accepted Manuscript (DOE)

Research Organization:: US Department of Energy (USDOE), Washington, DC (United States). Office of Science, Nuclear Physics (NP), Isotope Program

Sponsoring Organization:: USDOE Office of Science (SC), Office of Isotope R&D and Production (IRP)

OSTI ID:: 2470419

Journal Information:: Chemical Science, Journal Name: Chemical Science Journal Issue: 9 Vol. 15; ISSN 2041-6520

Publisher:: Royal Society of ChemistryCopyright Statement

Country of Publication:: United States

Language:: English

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