Collaborative Project #1: New Tools to Address Chronic Disease
D&D (Gaithersburg, MD) develops therapeutics that promote healthy aging. A subsidiary, Precision Molecular (PMI), is a Johns Hopkins start-up develops imaging and theranostic agents, the former of which are used to characterize patients with neurodegenerative disorders. PlenaryAI is another Johns Hopkins start-up that partners with PMI by leveraging molecular imaging and clinical data for automated lesion detection and prognosis. D&D is the holding company for Theraly Fibrosis, which produced TLY01, which is completing
phase II trials in Europe for management of a variety of fibrotic conditions. Interim blinded analysis of NLY01, a GLP1R agonist for treatment of Parkinson’s disease produced by Neuraly, another subsidiary of D&D, has demonstrated promising results. As the population ages here and abroad, the technologies developed with CP1 gain in importance. A key aspect of the work products developed at D&D is that they focus on aspects of neurodegenerative and other chronic diseases in their earliest possible stages, such that actual disease-modifying agents can be actualized. Within CP1, the NCBIB will provide new imaging agents, discovered within the NCBIB, which will be used to select patients for these therapies, and enable therapeutic monitoring. The agents discovered will be tailored to the needs of D&D as well as to the broader community of interest in cancer, immunity and inflammation.
Collaborative Project #2: Quantitative Brain Metrics of Long-haul COVID
Dr. Nath leads a program at NINDS with three foci: neuropathogenesis of HIV infection, the role of endogenous retroviruses in neurological diseases and undiagnosed neuroimmune and neuroinfectious diseases. He has more recently become a thought leader regarding neurological aspects of infection with COVID, with a large cohort of individuals suffering from protracted post-infectious neurological symptoms [long-haul or post-acute sequelae of COVID (PASC)]. Those individuals suffer symptoms including impaired
concentration, headache, sensory disturbances, depression and psychosis that persist long after infection and may occur in younger individuals even after mild disease. The etiology and prognosis are unclear as are predisposing factors. Because tens of millions of individuals have been infected with COVID, if even a small percentage develop PASC a significant public health problem may emerge. There will also be substantial economic impact since those affected are often part of the workforce and have been heretofore vigorously active. There is an ongoing debate about the extent to which the virus has direct access to the CNS. However, evidence is pointing toward immune activation and CNS inflammation as the drivers of acute neuro-COVID. Because of the variety of symptoms of Long COVID and co-morbidities in affected individuals, mechanistic understanding and potential treatments remain elusive. Because patients with Long COVID are still alive, neuropathologic tissue is nonexistent.
Collaborative Project #3: Artificial Intelligence Boosted Evolution and Detection of Genetically Encoded Reporters for In Vivo Imaging
Magnetic resonance (MR) reporter genes have the potential to monitor transgene expression non-invasively in real time and high resolution. These genes can be employed to interrogate the efficacy of gene therapy, monitor viral therapeutics and viral gene delivery, assess cellular differentiation, cell trafficking, and specific metabolic activity, and also assess changes in the microenvironment. We have previously demonstrated that our lysine rich protein (LRP) reporter gene is detectable by chemical exchange saturation transfer (CEST) MRI. However, to build on the CEST reporter gene technology and bring it towards clinical translation, its sensitivity and specificity need to be improved. In this project we develop improved MRI reporter genes and quantitative MRI detection methods that will facilitate the clinical translation of these methods for imaging biological therapeutics, such as oncolytic virotherapy.
Collaborative Project #4: Quantitative PET Imaging of Hepatocellular Carcinoma (HCC)
Hepatocellular Carcinoma (HCC) is the most common primary tumor of the liver and represents a major healthcare challenge in the United States (US) and elsewhere. Improved tools to detect HCC at early, potentially curable stages, and tools to predict future tumor behavior are urgently needed. Molecular imaging with positron emission tomography (PET) is uniquely poised to provide those tools, yet novel tracers are required. The sensitivity of routine 18F-FDG PET, the most commonly utilized approach in clinical oncology, is limited in HCC, and other tracers that exhibit greater potential, such as 11C-acetate, suffer technical limitations that prevent their broad clinical use.
Collaborative Project #5: Imaging Disease Heterogeneity and Response to Therapy in Myelofibrosis
Myelofibrosis (MF) is a chronic, ultimately fatal hematologic malignancy characterized by progressive fibrosis of bone marrow, leading to severe anemia, hepatosplenomegaly, and debilitating constitutional symptoms with cachexia. It may occur years after successful treatment of an initial malignancy. To advance pre-clinical studies in pathophysiology of MF, drug development, and ultimately clinical oncology, this project continues to investigate bone marrow MR imaging as a quantitative biomarker for disease status and response to therapy. The ability to define imaging treatment response metrics for the marrow will have a major clinical impact as it would provide for non-invasive measurements of disease heterogeneity and assessment of drugs designed to reverse bone marrow fibrosis and allele burden. The ability to track heterogeneity of disease throughout the skeleton by imaging represents a transformative advance over bone marrow biopsy that ultimately will improve quality of life and care for patients with MF.
Collaborative Project #6: Clinical Trials for Imaging and Therapy
Dr. Lapi's first project is part of a program project led by the Proteogenomics Research Institute for Systems Medicine (La Jolla, CA). Caveolae are organelles that allow proteins and other molecules to traverse cellular barriers and may enable a path toward precision cancer therapy. Their expression can also be associated with tumor resistance to certain types of therapies. The overall hypothesis of Project 3 is that the humanized monoclonal antibody targeting AnnA1 on tumor endothelium can safely, precisely, and effectively deliver high levels of imaging and therapeutic agents to solid tumors. This project is concerned with developing a 89Zr-labeled caveolae-targeting hAnnA1-antibody-drug conjugate for human PET imaging. This project leverages extensive expertise in the Lapi group with 89Zr agents. This project is translational in that it is designed to provide preclinical data sufficient for an IND filing.
Collaborative Project #7: Unique α-emitting Cancer Theranostics
Michael K. Schultz, Ph.D. is the CSO of Viewpoint Molecular Targeting, Inc. (Viewpoint, Coralville, IA). Viewpoint is an early stage biotechnology company that is pioneering the use of 203Pb/212Pb radiopharmaceuticals for image-guided alpha-particle therapy for cancer. The company develops proprietary targeting peptide-based ligands that are designed to bind with high affinity and avidity to cellular proteins upregulated in cancer cells, but with low to no expression in normal cells and tissues. Viewpoint further develops proprietary chelation technologies for these peptide-based ligands that ensures efficient delivery of 203Pb, 212Pb (and daughter radionuclides) to the tumor microenvironment, with low risk of accumulation and retention in other organs and tissues. In addition, the company develops proprietary 212Pb production devices (212Pb generators; VMT-α-GEN) that will ensure a robust supply chain for 212Pb radiopharmaceuticals – a critical aspect of radiopharmaceutical translation to clinical relevance. Their current products, VMT01 and VMT-α-NET, are being developed to treat melanoma and neuroendocrine tumors, respectively. Generator manufacturing facilities for 212Pb generators are complete for North America distribution in 2022 – with expansion underway in Europe and Asia. All product development is supported by peer-reviewed publications on the potential for 203Pb/212Pb radiopharmaceuticals for image-guided alpha-particle therapy for cancer. The company is unique in that the team has established a ultra-strong scientific foundation for technologies under development through the National Cancer Institute’s Small Business Innovation Research (SBIR) program and has secured over $14M in SBIRs since 2015. Dr. Schultz has also been successful in securing NIH funding for his research as an academic and is a Co-PI on a current NIH R01 application and has also been a Project Co-Leader of the University of Iowa Neuroendocrine Tumor SPORE program since 2016. The company couples these milestones with successes also in securing capital for financing operations through private equity and has secured over $15M to further accelerate technologies to clinical translation. The company strategy includes partnering with academic institutions to access innovative technologies and ligands and providing isotopes and chelator technologies to promote development of 203Pb/212Pb radiopharmaceuticals for image-guided alpha-particle therapy for cancer.
Collaborative Project #8: Optimizing Systemic Immunotherapy for Personalized Brain Metastasis Treatment
Glioblastoma (GBM) is the most common and aggressive primary brain tumor, and it remains one of the most lethal cancers in humans with a median survival of less than 2 years after initial diagnosis even with the best current therapies. The characteristics of the tumor, such as high invasiveness, a high proliferative index, immunological escape capabilities, genetic heterogeneity, and genetic instability, have limited the efficacy of standard chemotherapeutic agents. Gene therapy represents one of the most promising strategies for the treatment of brain cancer. However, its clinical application has been hampered because viruses, the most commonly used vectors, pose safety concerns, such as insertional mutagenesis, life-threatening immune responses, limitations to cargo size, and manufacturing challenges. As tumor cells already intrinsically express signal 1, their tumor antigen, they would only need to be able to also express a co-stimulatory signal 2 in order to mimic the function of antigen-presenting cells (aAPCs) and direct a cytotoxic T cell anti-tumor response against their own displayed signal 1 antigen. We will use non-viral NPs to transfect glioma cells with the signal 2 co-stimulatory molecule 4-1BBL and in addition the signal 3 cytokine IL-12. This innovative strategy will reprogram malignant glioma cells to stimulate T cell activation in situ and thereby induce tumor rejection, allowing us to induce a personalized antigen-specific anti-tumor immune response.
Collaborative Project #9: Novel Therapies for Lupus Nephritis
SLE is a complex autoimmune disease that is influenced by genetic and environmental factors. It is a lifelong disease marked by flares and remissions. In individual patients the disease may affect different organs over time, and the severity of inflammation within specific organs can also wax and wane. Up to 80% of patients with SLE develop renal abnormalities at some point in their lives, but the renal prognosis varies greatly within this population. Aggressive and prolonged immunosuppression reduces - but does not eliminate - the risk of future flares. Consequently, even patients who have remained in remission for prolonged periods are continually monitored for evidence of a disease flare.
Clinically, SLE activity is monitored through the measurement of serum autoantibodies, complement levels, measurement of urine protein and microscopic examination of the urine. Plasma complement levels (C3 and C4) are depressed in ~75% of patients with active nephritis, but these changes are non-specific and are poor predictors of either a response to therapy or relapse. Tissue C3d is a valuable biomarker of lupus activity. The abundance of C3 deposits within the kidney predicts the progression renal damage in patients with lupus nephritis, and is one of the most important prognostic findings within the biopsy.
There are no non-invasive methods to detect intra-renal C3d deposition. We have developed murine monoclonal antibodies (mAbs) to C3d that specifically recognize epitopes displayed on tissue bound C3d fragments but do not bind to intact C3 in plasma. We have also generated preliminary data that radiolabeled 3d29 can be used to non-invasively detect tissue C3d in several models of disease, including a mouse model of lupus. Importantly, mAb 3d29 recognizes both mouse and human C3d, facilitating the development of humanized probes for use in in human patients.
Collaborative Project #10: Small Molecule PSMA-Targeted Alpha Therapy
Despite the expanding array of new targeted agents to treat castration-resistant prostate cancer (CRPC), the disease remains incurable with nearly half of men with this form of PC developing bone metastases at two years. Zalutsky et al. focus on 211At (t1/2=7 h), which emits a single α-particle per decay. They have a clinical lead, [211At]YF2, and will be translating it over this funding period. Radiotheranostics for prostate cancer have contributed to a renaissance in nuclear medicine and promise to add an important new and badly needed modality to managing patients with CRPC – or perhaps patients earlier in their journey with this disease. The β-particle emitter, [177Lu]PSMA-617, has recently been approved by the FDA and has seen worldwide use. The recent VISION trial demonstrated the utility of [177Lu]PSMA-617 in patients who have completed chemotherapy, showed a prolongation of life with very few adverse effects. The TheraP trial tested [177Lu]PSMA-617 head-to-head and proved that the latter was superior to cabazitaxel, the current standard-of-care, and again had fewer side effects. Other trials, such as SPLASH, attempt to move [177Lu]PSMA-617 to patients in the pre-chemotherapy state. But β-particle emitter are insufficient alone to cure prostate cancer. Combination therapies and/or use of a more powerful particle emitter, such as an α-particle emitter, which has high linear energy transfer, may provide better results. Early studies with [225Ac]PSMA-617 suggest that. However, [225Ac]PSMA-617 tends to promote severe salivary gland toxicity and 225Ac is not readily available in quantities needed to meet demand. Zalutsky and the NCBIB intend to combat those issues by producing compounds built on a PSMA-targeting scaffold (PSMA-R2) that does not accumulate in salivary glands and that utilizes the tamer α-particle emitter, 211At, which has only one α-particle emission per decay.