Tumor associated monoclonal antibodies (mAbs) are therapeutic agents when used as selective vectors of cytotoxic agents towards malignant tissues. This hypothesis is tested in animal model systems with mAbs directed toward antigens associated with human disease. The cytocidal agents employed are particle emitting radionuclides. The relative efficacy is evaluated in validated murine tumor xenograft models. The radionuclides chosen focus on appropriate alpha emitters and beta emitters. The research has focused on Pb-212, a beta-emitter and subsequent alpha particle source, in parallel with alpha emitters, At-211 and Th-227 for true comparative efficacy studies of Bi-213, Pb-212, At-211, and Th-227. However, effectively at this time there are 5-6 completed pre-clinical studies remaining to published before this project closes with the retirement of Dr. Brechbiel. These studies investigate the use of mAb fragments of panitumumab as a targeting delivery vector along with investigations into the impact on efficacy on choice of administration route. A significant hi-lite from the studies performed by the Chemistry Section is within a recent publication in Trans. Oncol. That demonstrates what may be the strongest survival and curative results to date using 212Pb targeted to the EGFR by panitumumab to treat a highly aggressive disseminated ip disease model of colorectal or ovarian cancer. The publication reports a median survival of greater than 280 days, but that is because there was an 80% survival of the treated animals vs. the controls surviving no more than 21 days. In fact, this group of animals survived in block over 300 days. The combination therapy that was investigated that generate this result was with topotecan. The key point here was the dosing schedule; the topotecan was given 24 hours prior to and then again 24 hours post-administration of the 212Pb-panitumumab. Use of just a single dose of topotecan either prior to or post failed to provide meaningful therapeutic efficacy. The significance of these studies, beyond just the creation of a curative therapy in this animal tumor model is quite simple - this also demonstrates the need for the execution of rather complex animal tumor model based studies top define the proper integration of the components of combination therapies. This requirement has been demonstrated repeatedly; in vitro experiments cannot predict these results and this must be performed empirically. The use of topotecan had been largely abandoned by the Chemistry Section as component of combination therapy due to the unimpressive results that were generated using single doses of the drug combined with 212Pb targeted by an antibody. However, the adoption of a dual dose regimen, completely unpredicted, demonstrated far superior efficacy. To this end, the Chemistry Section has again performed one of the very few new targeted radiation therapy chemotherapy combination studies to demonstrate the potential of a very potent therapy that would also have very real clinical and translational therapeutic potential.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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Milenic, Diane E; Baidoo, Kwamena E; Kim, Young-Seung et al. (2017) Targeted ?-Particle Radiation Therapy of HER1-Positive Disseminated Intraperitoneal Disease: An Investigation of the Human Anti-EGFR Monoclonal Antibody, Panitumumab. Transl Oncol 10:535-545
Milenic, Diane E; Baidoo, Kwamena E; Kim, Young-Seung et al. (2017) Comparative studies on the therapeutic benefit of targeted ?-particle radiation therapy for the treatment of disseminated intraperitoneal disease. Dalton Trans 46:14591-14601
Guérard, F; Beyler, M; Lee, Y-S et al. (2017) Investigation of the complexation of natZr(iv) and 89Zr(iv) by hydroxypyridinones for the development of chelators for PET imaging applications. Dalton Trans 46:4749-4758
Yong, Kwon Joong; Milenic, Diane E; Baidoo, Kwamena E et al. (2016) Cell Killing Mechanisms and Impact on Gene Expression by Gemcitabine and 212Pb-Trastuzumab Treatment in a Disseminated i.p. Tumor Model. PLoS One 11:e0159904
Guérard, François; Lee, Yong-Sok; Baidoo, Kwamena et al. (2016) Unexpected Behavior of the Heaviest Halogen Astatine in the Nucleophilic Substitution of Aryliodonium Salts. Chemistry 22:12332-9
Burvenich, Ingrid J G; Lee, Fook-Thean; O'Keefe, Graeme J et al. (2016) Engineering anti-Lewis-Y hu3S193 antibodies with improved therapeutic ratio for radioimmunotherapy of epithelial cancers. EJNMMI Res 6:26
Yong, Kwon Joong; Milenic, Diane E; Baidoo, Kwamena E et al. (2016) Mechanisms of Cell Killing Response from Low Linear Energy Transfer (LET) Radiation Originating from (177)Lu Radioimmunotherapy Targeting Disseminated Intraperitoneal Tumor Xenografts. Int J Mol Sci 17:
Burvenich, Ingrid J G; Farrugia, William; Lee, Fook T et al. (2016) Cross-species analysis of Fc engineered anti-Lewis-Y human IgG1 variants in human neonatal receptor transgenic mice reveal importance of S254 and Y436 in binding human neonatal Fc receptor. MAbs 8:775-86
Kiess, Ana P; Minn, Il; Vaidyanathan, Ganesan et al. (2016) (2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted ?-Particle Radiopharmaceutical Therapy. J Nucl Med 57:1569-1575
Milenic, Diane E; Molinolo, Alfredo A; Solivella, María S et al. (2015) Toxicological Studies of 212Pb Intravenously or Intraperitoneally Injected into Mice for a Phase 1 Trial. Pharmaceuticals (Basel) 8:416-34

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