Etiological and genetic drivers of osteosarcoma (OS) are not well studied and vary from one tumor to another; making it challenging to pursue conventional targeted therapy. Recent studies have shown that cation independent mannose-6-phosphate/insulin-like growth factor-2 receptor (IGF2R) is consistently overexpressed in almost all of standard and patient-derived OS cell lines, making it an ideal therapeutic target for development of antibody-based drugs. Monoclonal antibodies, targeting IGF2R, can be conjugated with alpha- or beta-emitter radionuclides to deliver cytocidal doses of radiation to target IGF2R expression in OS. This approach known as radioimmunotherapy (RIT) can therefore be developed as a novel treatment for OS. In addition, OS is one of the common cancers in companion dogs and very closely resembles human OS in clinical presentation and molecular aberrations. In this study, we have developed human antibodies that cross-react with similar affinities to IGF2R proteins of human, canine and murine origin. We used naïve and synthetic antibody Fab-format phage display libraries to develop antibodies to a conserved region on IGF2R. The generated antibodies were radiolabeled and characterized in vitro and in vivo using human and canine OS patient-derived tumors in SCID mouse models. We demonstrate specific binding to IGF2R and tumor uptake in these models, as well as binding to tumor tissue of canine OS patients, making these antibodies suitable for further development of RIT for OS
Background: Osteosarcoma (OS) has an overall patient survival rate of ~70% with no significant improvements in the last two decades, and novel effective treatments are needed. OS in companion dogs is phenotypically close to human OS, which makes a comparative oncology approach to developing new treatments for OS very attractive. We have recently created a novel human antibody, IF3 to IGF2R, which binds to this receptor on both human and canine OS tumors. Here, we evaluated the efficacy and safety of radioimmunotherapy with 177Lu-labeled IF3 of mice bearing canine-patient-derived tumors and performed canine and human dosimetry calculations. Methods: Biodistribution and microSPECT/CT imaging with 111In-IF3 was performed in mice bearing canine OS Gracie tumors, and canine and human dosimetry calculations were performed based on these results. RIT of Gracie-tumor-bearing mice was completed with 177Lu-IF3. Results: Biodistribution and imaging showed a high uptake of 111In-IF3 in the tumor and spleen. Dosimetry identified the tumor, spleen and pancreas as the organs with the highest uptake. RIT was very effective in abrogating tumor growth in mice with some spleen-associated toxicity. Conclusions: These results demonstrate that RIT with 177Lu-IF3 targeting IGF2R on experimental canine OS tumors effectively decreases tumor growth. However, because of the limitations of murine models, careful evaluation of the possible toxicity of this treatment should be performed via nuclear imaging and image-based dosimetry in healthy dogs before clinical trials in companion dogs with OS can be attempted.
Background: Neurotensin receptor 1 (NTSR1) is overexpressed in multiple cancer indications that include pancreatic, colorectal and prostate cancers, all of which have limited therapeutic treatment options and unmet medical need. Fusion is developing novel targeted alpha therapeutics (TATs) that enable the specific delivery of high energy alpha particles (actinium-225; [225Ac]) to tumor cells while sparing surrounding normal tissues. The alpha radiation released by TATs causes cell damage through the induction of multiple double-stranded DNA breaks leading to tumor cell death. Here, we describe the therapeutic efficacy of an [225Ac]-conjugated, NTSR1 targeting small molecule in a colorectal cancer tumor model. Materials and Methods: CT26 colorectal cancer cells overexpressing murine NTSR1 (mNTSR1) were generated by lentiviral transduction. Selected cells were evaluated for stable mNTSR1 expression by an in vitro radioligand binding assay and subsequently implanted subcutaneously into Balb/c mice for in vivo evaluations. FPI-2056 (parent compound) was radiolabeled with either lutetium-177 ([177Lu]-FPI-2057) or actinium-225 ([225Ac]-FPI-2059). Biodistribution assessment studies were conducted in mice bearing CT26-mNTSR1 tumors dosed intravenously with [177Lu]-FPI-2057. Therapeutic efficacy studies were conducted by intravenous administration of single doses of 0.185 - 5.55 MBq/kg of [225Ac]-FPI-2059 (0.1-3 µCi) to animals bearing CT26-mNTSR1 tumors, followed by tumor growth monitoring for 50 days. Study endpoints included tumor volume measurements and impact on animal health status. Results: Evaluation of [177Lu]-FPI-2057 biodistribution and excretion revealed rapid renal clearance via urine with a clearance from the blood by 24 h. Uptake of [177Lu]-FPI-2057 was detected in the CT26-mNTSR1 tumors with a maximum concentration of 7.0 %ID/g at 6 h post-injection, dropping to 4.6 and 2.8 %ID/g at 24 and 48 h post-injection, with 20-fold higher uptake in the tumor vs. blood levels at both 24 and 48h time points. Therapeutic administration of a single dose of [225Ac]-FPI-2059 resulted in dose-dependent tumor growth inhibition at doses above 1.85 MBq/kg of [225Ac]-FPI-2059 (1 μCi), which translated into increased survival compared to control animals. Conclusion: These results demonstrate that targeted delivery of [225Ac]-FPI-2059 to NTSR1 expressing tumors results in significant growth inhibition and enhanced survival, thereby providing promising preclinical evidence to support the clinical development of [225Ac]-FPI-2059. Citation Format: Saleemulla Mahammad, Jaline Broqueza, Brigitte L. Theriault, John Forbes, Christopher P. Leamon, John Valliant. NTSR1-targeted alpha therapeutic [Ac-225]-FPI-2059 induces growth inhibition in a preclinical colorectal tumor model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5045.
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