A series of α-DOTA-PRIT therapy studies were performed in three solid human cancer xenograft models of colorectal cancer (GPA33), breast cancer (HER2), and neuroblastoma (GD2), including evaluation of chronic toxicity at ~20 weeks of select survivors. We call our novel tumor-targeting DOTA-hapten PRIT system “proteus-DOTA” or “Pr.” Herein we report the first results of radiochemistry development, radiopharmacology, and stoichiometry of tumor antigen binding, including the role of specific activity, anti-tumor efficacy, and normal tissue toxicity with the Pr-PRIT approach (as α-DOTA-PRIT). This is the initial report of an α-based pre-targeted radioimmunotherapy (PRIT) using 225Ac and its theranostic pair, 111In. All other authors have no competing interests. MSK has filed for patent protection on behalf of D.A.S for technology discussed in this paper. D.A.S is a consultant to, on the board of, and/or has equity in: PGNX, SLS, KLUS, IOVA, PFE, ATNM, Oncopep and Eureka Therapeutics. B.H.S and N.K.C are inventors on US Patent No. O.O is an unpaid member of the scientific advisory board of Angiogenex and owns shares in Angiogenex. G.Y and O.O are listed as inventors and receive royalties from patents that were filed by MSK. S.M.L serves or has served as a consultant to Cynvec LLC, Eli Lilly & Co., Prescient Therapeutics Limited, Advanced Innovative Partners, LLC, Gerson Lehrman Group, Progenics Pharmaceuticals, Inc., and Janssen Pharmaceuticals, Inc. S.M.L is the inventor and owner of issued patents both currently unlicensed and licensed by MSK to Samus Therapeutics, Inc., Elucida Oncology, Inc., and Y-mAbs Therapeutics, Inc.

and Y-mAbs Therapeutics, and holding stock in ImaginAb, Inc.

holding ownership interest/equity in Elucida Oncology, Inc. S.M.L reports receiving commercial research grants from Genentech, Inc., WILEX AG, Telix Pharmaceuticals Limited, and Regeneron Pharmaceuticals, Inc. N.K.C is a scientific advisory board member of Abpro Labs and Eureka Therapeutics.

N.K.C is the inventor and owner of issued patents licensed by MSK to Y-mAbs Therapeutics, Biotec Pharmacon, and Abpro Labs. in 2017, holding ownership interest/equity in Y-mAbs Therapeutics and in Abpro-Labs, and owning stock options in Eureka Therapeutics, Inc. Competing Interests: N.K.C reports receiving commercial research grants from Y-mAbs Therapeutics, Inc.

Proteus for escalations