Advancing Targeted Radionuclide Therapy Through the National Cancer Institute’s Small Business Innovation Research Pathway

Glioblastoma

Glioblastomas are among the most aggressive cancers and are sorely in need of new treatment strategies. Molecular Targeting Technologies, Inc., received phase I funding to develop radioiodinated saposin C–dioleoylphosphatidylserine nanovesicles for the treatment of glioblastoma. Saposin C–dioleoylphosphatidylserine has been shown to cross the blood–brain barrier and bind extracellular phosphatidylserine. Because radiation therapy causes phosphatidylserine to be upregulated on tumor cells, saposin C–dioleoylphosphatidylserine has enhanced anticancer potential in combination with radiation. This treatment strategy is of interest to clinicians because these agents cross the blood–brain barrier and the chemistry is well understood. Unlike chemotherapy, saposin C–dioleoylphosphatidylserine has sensitized hypoxic cells that, many believe, are responsible for failure of chemotherapy in glioblastoma (14).

Melanoma

Metastatic melanomas have a poor prognosis, but the unique proteins expressed by melanoma cells offer an opportunity for selective tumor targeting to improve treatment outcomes. The overexpression of the melanocortin 1 receptor (MCR1) on melanoma cells is an attractive target for melanoma-targeted therapy (15) and is sought after by SBIR contract recipients. The advantage of targeting melanoma-specific molecules is that this approach does not rely on specific-tumor genotypes or variability of a patient’s immune response.

Modulation Therapeutics, Inc., is developing a ²²⁵Ac-based therapy for the treatment of ocular and advanced cutaneous melanoma. The company has developed a targeting molecule that binds MCR1 expressed on melanoma cells. The company attached DOTA to a MCR1 ligand and chelated the compound to ²²⁵Ac to create ²²⁵Ac-DOTA-MCR1 ligand. After demonstrating that the compound has no overt toxicity and is efficacious in animal models of uveal and cutaneous melanoma, the company was awarded phase II funding.

Viewpoint Molecular Targeting, LLC, received phase I and II funding to determine the feasibility of a novel ^203/212Pb-labeled therapy for metastatic melanoma. The investigators attached ^203/212Pb to DOTA-VMT-MCR1 and DOTA-RMX-glucosamine conjugate, which target melanoma-specific molecules. The objectives of the phase I SBIR were to determine the feasibility of radiosynthesis of ²¹²Pb-DOTA-RMX-glucosamine conjugate and ²¹²Pb-DOTA-VMT-MCR1, evaluate the feasibility of ²¹²Pb-DOTA-RMX-glucosamine conjugate and ²¹²Pb-DOTA-VMT-MCR1 therapy in melanoma-tumor–bearing mice, and determine the feasibility of a dual-targeted (glucose transporter 1/MCR1) bioconjugate for radionuclide imaging and therapy for metastatic melanoma. These studies would lay the necessary groundwork before IND-enabling studies and initiation of clinical trials.

RadImmune, Inc., received phase I funding to develop a radioimmunotherapy for metastatic melanoma based on a novel IgG to melanin. RadImmune previously completed a phase I clinical trial of an IgM antibody to melanin labeled with ¹⁸⁸Re. However, the IgM isotype of the antibody was a barrier to clinical development. The aims of the phase I proposal were to conjugate 8C3 IgG with chelating agents to enable radiolabeling with α- and β-emitting radionuclides, perform pharmacokinetics/pharmacodynamics studies and radiation dosimetry calculations in murine and human melanoma models, and perform proof-of-concept experiments in murine and human melanoma models, including efficacy and short-term toxicity of the treatment. On the basis of these experiments, the most suitable radiolabeled form of IgG to melanin will be selected for future IND-enabling studies.

Breast Cancer

Triple-negative breast cancers do not express the targetable estrogen receptor or the human epidermal growth factor receptor 2 (HER2) that is expressed by other types of breast cancer. Consequently, triple-negative breast cancers have a worse prognosis, and therefore, it is necessary to identify novel targets. Cellectar Biosciences, Inc., obtained fast-track funding to develop CLR1404 (18-(p-iodophenyl)octadecyl phosphocholine) for patients with triple-negative breast cancer. CLR1404 is an alkyl phosphocholine that accumulates in lipid rafts, and since cancer cells have more lipid rafts than do normal cells, there is a selective mechanism for CLR1404 uptake (16). The aims of the proposal were to conjugate ¹²⁵I to the tumor-targeting agent CLR1404 and define the physical and chemical properties of the compound to enable reliable drug synthesis; assess pharmacokinetics, radiation dosimetry, and normal-tissue toxicities in murine triple-negative breast cancer models; and conduct efficacy studies in mouse models.

OncoTAb, Inc., is also developing a radioimmunotherapy for triple-negative breast cancer. TAB004 is an antibody to the tumor form of the glycoprotein mucin 1 with high uptake in breast cancer tissues (17). The aims of the phase I proposal were to determine the feasibility of labeling the tumor-specific TAB004 antibody with ¹³¹I, evaluate the ability of the TRT to reduce tumors in mouse models of triple-negative breast cancer, and initiate preliminary toxicity studies.

SibTech, Inc., is collaborating with Johns Hopkins University to investigate a ¹⁷⁷Lu radiopharmaceutical for vascular endothelial growth factor receptor–mediated targeting of tumor vasculature. The company’s data on mouse models of breast cancer demonstrate that the compound induces vascular regression, inhibits tumor growth, improves survival, and can be combined with chemotherapy. SibTech received fast-track funding to support the phase I goal of determining whether selective targeting of vascular endothelial growth factor receptor 1 or 2 is more advantageous in mouse models of orthotopic breast cancer. After the lead drug candidate is selected, the phase II aims are to achieve good-manufacturing-practice production, conduct dosimetry and toxicology studies, and undertake a phase I clinical trial.

HER2-Positive Cancers

Activating HER2 mutations have been identified in numerous solid cancers and represent an attractive target for TRT (18). For patients with HER2-positive breast and gastroesophageal cancers, HER2-directed therapy has become incorporated into standard-of-care practice based on improved overall survival or disease-free survival (19–22). The benefit of HER2 therapy in other malignancies has yet to be firmly established, though active research is currently under way (18).

EvoRx Technologies, Inc., received phase I funding to use scanning unnatural-protease-resistant (SUPR) peptides as molecularly targeted agents for HER2-positive cancer. The advantage of SUPR peptides is that they bind targets with high specificity, leading to high tumor uptake, and the small size of SUPR peptides leads to high rates of clearance from the body as compared with antibodies and a consequent decrease in normal-tissue toxicity. The goals of the proposal were to use anti-HER2 SUPR peptides to deliver radionuclides to HER2-positive tumors in mouse breast cancer models and establish the efficacy of the anti-HER2 SUPR peptides.

Rockland Immunochemicals, Inc., is working in collaboration with Abzyme Therapeutics, LLC, and the University of Pittsburgh’s Department of Radiology to develop a pretargeted radioimmunotherapy for HER2-positive cancers. Pretargeted radioimmunotherapy involves the administration of a cancer cell–targeting bispecific antibody followed, after the antibody binds to the tumor and clears from the blood, by a radiolabeled small-molecule ligand that binds to the antibody but is cleared rapidly from the rest of the body, reducing the exposure of normal tissues to radiation (23). The phase I aims are to develop bispecific recombinant single-domain antibodies with one arm targeting HER2 on cancer cells and the other arm targeting digoxigenin and to investigate in vivo clearance, tumor accumulation, stability, bioavailability, and the ability to capture digoxigenylated fluorescence dyes and radionuclides.

Prostate Cancer

Prostate cancer is one of the most common cancer diagnoses in men and a leading cause of cancer mortality. Traditional external-beam radiotherapy and brachytherapy are effective for localized disease, but these modalities are less effective for patients with regional and distant disease. TRT has the potential to improve outcomes for these patients with disseminated prostate cancer. Oncotherapeutica, Inc., received phase I funding to develop a prodrug with ¹³¹I attached for the treatment of prostate cancer. The prodrug is designed to be specifically activated within prostate cancer tumors. The specific aims were to synthesize the ¹²⁷I-prodrug/¹²⁵I-prodrug derivative and corresponding 127IDS/125IDS, inject ¹²⁵I-prodrug into mice with prostate cancer to determine tumor and normal-tissue uptake, and identify the maximum tolerated dose in mice and confirm therapeutic efficacy in mice with prostate cancer.

Cancer Targeted Technology, LLC, obtained fast-track funding to develop a ¹⁷⁷Lu-based targeted radiotherapy for prostate cancer. The radionuclide is targeted to prostate-specific membrane antigen, which is a transmembrane protein expressed on prostate cells. The aims of phase I included identifying the lead ¹⁷⁷Lu-labeled prostate-specific membrane antigen–targeting agent, conducting biodistribution and pharmacokinetic studies, and performing a preliminary assessment of efficacy. Phase II objectives include scale-up manufacturing and IND-enabling studies. Several of the phase II objectives will be conducted by subcontractors at the University of Pittsburgh.

Pancreatic Cancer

Houston Pharmaceuticals, Inc., received phase I funding to develop a radiolabeled ligand that binds the IL-13RA2 receptor in pancreatic cancer cells. IL-13RA2 is highly expressed by pancreatic cancer cells but not in normal tissue and thus is an attractive molecular target (24). The phase I objectives were to develop a radiolabeled ligand that selectively binds IL-13RA2 receptor; determine its binding affinity, specificity, and stability; and determine its pharmacokinetics and biodistribution in a model of pancreatic cancer.

Neuroendocrine Tumors

RadioMedix, Inc., received phase I funding to develop an α-emitter–based TRT for neuroendocrine tumors. A β-emitter–based ¹⁷⁷Lu-DOTATATE, which is currently used in the clinic, improves the response rate and progression-free survival compared with high-dose octreotide for patients with midgut neuroendocrine tumors (9). The investigators propose that an α-emitter could overcome resistance developed to β-emitter radionuclide therapy. The goal of the phase I research proposal was to develop ²¹²Pb-octreotate. Specific aims included determining the feasibility of radiosynthesis and evaluating the pharmacokinetics, efficacy, and toxicity of ²¹²Pb-octreotate in xenographs.

TRT Dosimetry

Personalized dosimetry for TRT involves assessment of medical images, radionuclide pharmacokinetics, and patient-specific anatomy to determine the optimal therapy for an individual patient (25,26). The lack of individualized dosimetry could be a barrier to the success of TRT, since different patients may have different pharmacokinetics and accumulation of radionuclides in tumor and normal tissues, leading to different biologic responses. Dosimetry measurements have the potential to affect the NCI’s TRT program because the definition of dose can be refined and expanded to include multiple modalities and, ultimately, a biologic response that is individualized. Rapid, LLC, received phase I funding to develop dosimetry software for TRTs that can be used in combination with external-beam radiotherapy. The aims of the proposal were to create and validate the software using existing clinical data and to submit an investigational device exemption with the FDA in preparation for a phase II clinical trial.