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NIH/NCI 472 - Antibody-Drug Conjugates as Radiopharmaceutical Theranostics for Cancer

Fast-Track proposals will be accepted.

Direct-to-Phase II proposals will be accepted.

Number of anticipated awards: 3-5

Budget (total costs, per award):

Phase I: up to $400,000 for up to 12 months

Phase II: up to $2,250,000 for up to 2 years

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

Antibody-drug conjugates (ADCs) are a new class of targeted drugs consisting of monoclonal antibodies (mAbs) chemically linked to cytotoxic drugs (payload). However, there are inherent limitations of ADCs: (i) acquired cancer resistance to the ADC’s payload; (ii) heterogeneity of target expression; and (iii) ineffective intracellular trafficking of the payload. These limitations can be circumvented by loading ADCs with diagnostic and therapeutic radionuclides. 

First, diagnostic radionuclides emitting gamma radiation (e.g., Flourine-18 or Technetium-99m) detectable by positron emission tomography (PET) or single-photon emission tomography (SPECT) will allow monitoring of the pharmacokinetics and biodistribution of ADCs. This will help select patients with tumors expressing adequate numbers of targeted antigens for effective treatment. Compared to current immunohistochemistry approaches for patient selection, the radiopharmaceutical
approach has the advantage that it allows whole body imaging of target antigen expression on metastases. Second, therapeutic radionuclides emitting cytotoxic beta (e.g., Lutetium-177) or alpha particles (e.g., Lead-212) will increase the therapeutic potential of ADCs in patients pre-selected based on radiopharmaceutical imaging. This will add a second therapeutic agent of radiation in addition to the chemical therapeutic already present, with independent mechanisms of action. Development of resistance to both therapeutics will be less likely than resistance to one, and neighboring tumor cells that do not express the targeted antigens can still be eliminated by radiation over distances of several cell-diameters (alphaparticles) to a few millimeters (beta particles) by a crossfire killing effect. Taken together, conjugating radionuclides to ADCs to reconfigure them as radiopharmaceuticals represents a new theranostic treatment strategy for diagnostic imagingbased patient selection followed by two-armed (chemical- and radiation-based) therapy.

Project Goals

This topic will facilitate arming the targeting moiety of ADCs with supplementary capabilities by adding theranostic radionuclides to provide both imaging and therapeutic capabilities. To be responsive to this solicitation, the proposed ADC for radionuclide conjugation must have already been validated by the offeror with in vivo biodistribution and pharmacokinetics studies showing that it targets cancer-specific antigens, does not accumulate in normal tissues, and has well-defined clearance kinetics. In addition, the offeror must commit to using the same targeting agent for diagnostic and therapeutic uses, with the primary difference being just the radionuclide used and potentially the chemistry of conjugation. 

Offerors may choose to focus their theranostic development proposal either on formation of only the diagnostic ADC radioconjugate, or on both the diagnostic and therapeutic ADC radioconjugates, depending on the current stage of development of these conjugates. Although this solicitation is written to highlight conventional ADCs and therefore conventional antibodies, other types of binding reagents (e.g., antibody fragments, peptides, and peptide nucleic acids) used to target tumor antigens for delivery of cytotoxic drugs may be proposed by offerors. Offerors are expected to focus their proposals on one cancer indication, even if the targeted antigen is expressed on several types of neoplasia.

Examples of appropriate radionuclides are as follows:

  • For diagnostic use (patient selection), examples of appropriate radionuclides include Fluorine-18, Gallium-68, Copper64, Zirconium-89, Yttrium-86, Bromine-76, and Indium-124 (positron emitters), and Technetium-99m, Indium-111, Iodine-123, Lead-203, and Gallium-67 (gamma emitters).
  • For therapeutic use, examples of appropriate radionuclides include Copper-67, Yttrium-90, Iodine-131, Samarium153, and Lutetium-177 (predominantly beta-emitters), and Astatine-211, Lead-212, Radium-223, Actinium-225, Thorium-227 (predominantly alpha-emitters), and Iodine-123/125, Gallium-67, Tellurium-201, Platinum191/193m/195m, Mercury-197/197m, Antimony-119 (all predominantly Auger electron-emitters), and Torbium-161 (both beta and Auger electron emitter).

The contract proposal must include:

  • A clearly identified patient population (single cancer indication) that will benefit from the availability of the defined ADC-radionuclide conjugate.
  • If the offeror proposes to use ADCs owned by another company, a letter of support or interest from the company that owns the underlying intellectual property should be included in the SBIR proposal.
  • An appropriate justification for the selection of radionuclides for the intended use, as discussed above.
  • Statistical validation of the proposed study endpoints, including power calculations and a rationale for the proposed sample sizes as appropriate.

Phase I Activities and Deliverables:

Phase I deliverables are provided below for both the diagnostic radiopharmaceutical (required of all offerors) and the therapeutic radiopharmaceutical (optional). Work on the therapeutic should only be proposed if the diagnostic work listed below is partly or fully completed at the time of proposal submission.

Diagnostic Radiopharmaceutical

  • Proof-of-concept of the chemical conjugation of an appropriate diagnostic radionuclide (see examples above) to the ADC including its efficiency/yield.
  • Physicochemical characterization of the new radioconjugate in vitro, including stability, target specificity in the single tumor type chosen, and affinity.
  • Proof of concept in vivo imaging studies using PET, SPECT, or other imaging modality in an appropriate animal model of the single cancer type chosen to collect preliminary data on image quality, time course, sensitivity, specificity (including binding of normal tissues), biodistribution, and radiodosimetry.
  • Detailed pharmacokinetics and toxicity studies are optional for Phase I- they can be included in Phase I or later in Phase II (see Phase II deliverables below).
  • In the Final Report, commit to a specific timeframe for a pre-submission/IND meeting with FDA, which must take place before the Phase II proposal is submitted.

Therapeutic Radiopharmaceutical (Optional)

  • Proof-of-concept of the chemical conjugation of an appropriate therapeutic radionuclide (see examples above) to the ADC including its efficiency/yield.
  • Physicochemical characterization of the new radioconjugate in vitro, including stability, target specificity in the single tumor type chosen, and anti-cancer activity.
  • Proof of concept in vivo anti-cancer efficacy studies in an appropriate animal model of the single cancer type chosen, comparing the therapeutic radiopharmaceutical and the nonradioactive parent ADC with only a chemical payload. Also collect preliminary data on biodistribution (including binding of normal tissues), and radiodosimetry.
  • Detailed pharmacokinetics and toxicity studies are optional for Phase I- they can be included in Phase I or later in Phase II (see Phase II deliverables below).
  • In the Final Report, commit to a specific timeframe for a pre-submission/IND meeting with FDA, which must take place before the Phase II proposal is submitted.

Phase II Activities and Deliverables:

Phase II deliverables are provided below for both the diagnostic radiopharmaceutical (required of all offerors) and the Therapeutic radiopharmaceutical (optional). The exact mix of Phase II deliverables will depend on the nature of the Phase I work completed (development of the diagnostic radiopharmaceutical only, or of both the diagnostic and therapeutic radiopharmaceuticals). Where collaboration with other parties is critical for development/commercialization of the proposed technology, the offeror should provide evidence of such cooperation (through written partnering agreements or letters of intent to enter into such agreements) as part of the Phase II proposal.

Diagnostic Radiopharmaceutical

  • Demonstration of the manufacturing scale-up scheme.
  • Optimization of the protocol for imaging in vivo (route, dose, time course).
  • Large scale in vivo imaging studies using PET, SPECT, or other imaging modality using an optimized protocol in an appropriate animal model of the single cancer type chosen to collect statistically significant data on image quality, time course, sensitivity, specificity (including binding of normal tissues), biodistribution, and radiodosimetry.
  • IND-enabling preclinical studies (e.g. pharmacokinetics, toxicology) utilizing an appropriate animal model and protocol per FDA guidance.
  • Submission of an IND application to FDA.
  • Optional- first-in-human safety study using the diagnostic radiopharmaceutical.
  • Provide two letters of commercial interest in the product from potential customers at the end of year 1.
  • Provide two letters of commercial commitment to buy the product at the end of year 2.
  • In the Final Report, discuss plans to seek insurance reimbursement for use of the diagnostic radiopharmaceutical for selection of patients expressing the targeting antigen, a critical part of commercial adoption.


Therapeutic Radiopharmaceutical (Optional)

  • Demonstration of the manufacturing scale-up scheme.
  • Optimization of the protocol for anti-cancer efficacy in vivo (route, dose, time course)
  • Large scale, statistically significant in vivo anti-cancer efficacy studies in an appropriate animal model of the single cancer type chosen, comparing the therapeutic radiopharmaceutical and the nonradioactive parent ADC with only a chemical payload. Also collect additional data on biodistribution (including binding of normal tissues), and radiodosimetry.
  • IND-enabling preclinical studies (e.g. pharmacokinetics, toxicology) utilizing an appropriate animal model and protocol per FDA guidance.
  • Submission of an IND application to FDA.
  • Optional: first-in-human safety study using the therapeutic radiopharmaceutical.
  • Provide two letters of commercial interest in the product from potential customers at the end of year 1.
  • Provide two letters of commercial commitment to buy the product at the end of year 2.

 

Receipt date: Friday, October 18, 2024, 5:00 p.m. ET

Apply for this topic on the Contract Proposal Submission (eCPS) website.

View the full PHS2025-1 Contract Solicitation.

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