Collaborative Projects
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 that develops imaging and theranostic agents, the former of which are used to characterize patients with neurodegenerative disorders. D&D is the holding company for Theraly Fibrosis, which produced TLY01, which is soon to begin clinical trials for management of a variety of fibrotic conditions. Recent analysis of a phase 2 trial of NLY01, a GLP1R agonist for treatment of Parkinson’s disease produced by Neuraly, another subsidiary of D&D, has demonstrated promising results in young patients. 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 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: Site-specific Immune Cell Activation Detection for Improving Individualized Cancer Immunotherapy
Drug development in immunotherapy has rapidly expanded, creating a large demand for patients whose outcomes from these trials will not be known for many months or longer. The development of PET-based diagnostic that can identify patients who will respond to immunotherapy, characterize their response after therapy has begun, and detect adverse events before clinical symptoms would be of immense value. That can be accomplished through a single agent, targeting granzyme B that is currently under investigational new drug status review at the FDA. Granzyme B is an enzyme released by immune cells that induces tumor killing, and it has been shown to be present in high amounts in tumors that are undergoing response to immunotherapy. Dr. Larimer has designed a PET imaging agent that only detects the active and released form of granzyme B, effectively distinguishing between immune cells that are present but exhausted and immune cells that are engaged in tumor killing.
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: Fibrogenesis Targeted Manganese-based MRI Contrast Agent
Most nonalcoholic fatty liver disease (NAFLD) is benign, but up to 30% of NAFLD patients will develop a progressive form of nonalcoholic steatohepatitis (NASH). Reveal Pharmaceuticals has developed a new proprietary class of manganese (Mn)-based MR imaging probes that are capable of quantifying fibrogenesis and have shown in animal models that molecular MR of fibrogenesis has exquisite sensitivity for early fibrosis detection. Specifically, the probes target extracellular protein-bound aldehydes that are generated during collagen crosslinking. Recently, it has been reported that persistent fibrotic scarring in the CNS can occur following immune cell infiltration in the EAE mouse model of MS. Interestingly, it was found that the majority of the fibrotic scar was derived from proliferative CNS fibroblasts and not pericytes or infiltrating bone marrow-derived cells. There are few reports that have evaluated fibrosis in the CNS, mostly within the context of spinal cord injury. Since so little is known about the presence or extent of fibrosis in the CNS in response to neuroinflammation and its role in disease recovery, a non-invasive assessment of the co-existence of inflammation and fibrogenesis would be of great value.
Collaborative Project #6: Tumor Microenvironment Crosstalk Drives Early Lesions in Pancreatic Cancer
Collaborative Project #6: Tumor Microenvironment Crosstalk Drives Early Lesions in Pancreatic Cancer
Invasive neoplasia in the pancreas represents the culmination of a multistep progression that begins with non-invasive precursor lesions, which remain an untapped window of opportunity for early detection and cancer interception. Two major histological subtypes of precursor lesions are recognized - the more common non-cystic pathway, represented by pancreatic intraepithelial neoplasia or PanIN lesions, estimated to precede ~90% of PDAC, and the cystic pathway, most commonly represented by intraductal papillary mucinous neoplasms or IPMNs, accounting for the remaining 10%.
Collaborative Project #7: Unique α-emitting Theranostics for Cancer Therapy
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: Complement-mediated Injury of the Kidney: New Mechanisms and Novel Therapies
Systemic lupus erythematosus (SLE) is a severe autoimmune disease that can affect multiple organs throughout the body. The complement system is integrally involved with several aspects of SLE. The classical pathway protects against the development of SLE. On the other hand, evidence suggests that C3d covalently bound to antigens lowers the threshold for developing autoimmunity through its interaction with complement receptor 2 (CR2). Thurman et al. have developed a monoclonal antibody, designated mAb 3d8b, that binds C3d and blocks autoantigen complex from ligating CR2 and is testing it in the (NZBxNSW)F1 model of SLE, in part with a view to examining the effects of targeted and untargeted complement inhibitors on myeloid and lymphoid populations. Push: Our need is to test our cellular imaging agents in relevant central and peripheral models, SLE being an unmet medical need. During the initial funding period the NCBIB has been able to image quantitatively the development of SLE in this model with a 125I-labeled anti-C3d antibody, and will continue to do so longitudinally, and in the context of therapeutic monitoring. Pull: The technology is being transferred to CU Anschutz, which has a new Research Imaging Center, ultimately with a view to image SLE nephritis and its effects on immune cells clinically at that site with the corresponding SPECT (123I) and/or PET (124I) agents. Those are first-generation agents with sub-optimal imaging characteristics. Dr. Thurman’s group will also be needing newer agents radiolabeled with 99mTc (SPECT), 89Zr (PET) and 64Cu (PET), which will require chelation chemistry and careful selection of labeling site on the molecule. We have also begun and have had some success in a new complement-based imaging program (C3aR) using small-molecule probes (TR&D3).
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. But β-particle emitters 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.
Service Projects
Service Project #1: PET Detection of CCR2 in Human Atherosclerosis
Dr. Gropler’s group has developed a new PET radiotracer for the monocyte chemoattractant protein-1/C-C chemokine receptor type 2 (MCP-1/CCR2) axis. They are using this to image the inflammatory component of atherosclerosis. Push: This SP focuses on using chemokine imaging for inflammation. We will provide complementary, including clinical agents for inflammation, which they can benchmark against their CCR2 agent for human atherosclerosis. They can cross-reference our INDs. For example, PET atherosclerosis imaging at Washington University may benefit from our CSF1R imaging agents.
Service Project #2: Cellular Senescence Network: New Imaging Tools for Arthritis Imaging
Senescent cells play a key role in the pathogenesis of rheumatoid and osteoarthritis and osteoarthritis. The Daldrup-Link group is developing new PET imaging biomarkers that are selectively taken up by senescent cells through cleavage by b-galactosidase, a senescent cell-specific enzyme in these cells. They are evaluating their novel 18F-PyGal PET radiotracer for imaging of inflammation in an antigen-induced mouse model of arthritis and a swine cartilage defect model, where MSCs are implanted to regenerate joint tissue. Developing new biomarkers that can detect local or systemic inflammation may aid in assessing the need for initiating immunosuppressive therapy and/or cell therapy regimens and be used for monitoring treatment outcome.
Service Project #3: Molecular Imaging of Transient and Remote Activation of Brain Microglia in vivo
The Michaelides lab at NIDA has made fundamental discoveries with respect to chemogenetics, in part in collaboration with the NCBIB during the first funding period. They have a particular interest in designer receptors exclusively activated by designer drugs (DREADD) technology. They also study chemical mechanisms of drugs of abuse. The NCBIB will continue to provide them suitably radiolabeled PET reporter molecules, e.g, [18F]JHU37107, [11C]clozapine and [18F]ASEM, and assist with their validation.
Service Project #4: Imaging B Cells in the Brain and Beyond: Developing an Immuno-PET Toolbox to Improve Understanding and Treatment of Multiple Sclerosis
To date, only one PET tracer for CD20+ B cells has undergone preliminary evaluation in MS, and no PET tracers have been developed for imaging CD19, expressed on a broader range of B cells (including suspected pathogenic antibody-secreting plasmablasts and circulating plasma cells). James et al. propose to develop novel immuno-PET tracers based on clinically approved CD19 and CD20 monoclonal antibody therapeutics for translation. As precision medicine enables subtyping of individuals with MS, who may benefit from a variety of new treatments coming online, imaging – for prognosis and therapeutic monitoring – becomes more important than ever. Imaging agents in the NCBIB are complementary to the B cell agents under way in Dr. James’ group.
Service Project #5: Arginine Metabolism Regulates Myeloid Immune Suppression in Glioblastoma
Tumor-associated myeloid cells (TAMCs), which consist of tumor associated macrophages and myeloid- derived suppressor cells, comprise a majority of cellular infiltrates in glioma. TAMCs are potently immunosuppressive, and represent a major barrier to successful immunotherapy. The overall goal of the grant associated with SP5 is to determine how arginine is catabolized into polyamines by TAMCs, and to determine if inhibition of this metabolic pathway can enhance immunotherapy for glioma. Dr. Lesniak does not have a cell-specific way to study TAMCs non-invasively or clinically.
Service Project #6: Characterization of whole brain demyelination and axon damage using high-resolution magnetic resonance imaging
While MRI is being used routinely in the clinic for the diagnosis of CNS diseases, conventional methods are not specific to MS pathology and hence have limited prognostic values. Another unmet need is the lack of sensitive MRI detection of the lesions in cortical gray matter, recently identified as a major site of MS pathology.
In his R01 project, Dr. Wang proposes to combine advanced diffusion MRI (dMRI) and Quantitative Susceptibility Mapping (QSM) technologies at high spatial resolution to afford robust and quantitative imaging-based biomarkers of MS by detecting the progression of iron dysregulation, demyelination, and axon damage through the whole brain. The quantitative diffusion MRI metrics can be used to distinguish different stages of demyelination and may serve as an imaging biomarker for demyelination. In particular, the neurite density index (NDI) derived from the neurite orientation dispersion and density imaging (NODDI) biophysical model has been able to distinguish the acute demyelination and the chronic demyelination stages. He also will perform quantitatively validation of MRI findings using the state-of-the-art whole-brain light sheet microscopy (LSM). Dr. Wang plans to use animal models such as the cuprizone mouse model and the experimental autoimmune encephalomyelitis (EAE) model to study the relationship between neuroinflammation and brain connectivity alterations.
Service Project #7: Imaging acidosis and immune therapy in PDAC
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal of all cancers and is largely resistant to all therapies, including immune therapies (IT). Despite that resistance, there are no fewer than 12 open clinical trials investigating treatment of PDAC with checkpoint blockade IT. Gillies et al. have shown that neutralization of tumor acidosis with oral NaHCO3 in murine models of PDAC can lead to dramatic improvements in response to checkpoint blockade. Because phase I and IIa clinical trials using that strategy have failed to dose-escalate, other ways are sought to neutralize tumor acidity, e.g., by using a CEACAM-6-targeted urease. Current strategies in the grant associated with SP9 include imaging pharmacokinetics of such tumor-alkalinizing agents through chemical exchange saturation transfer (CEST) MR imaging of pH. Carbonic anhydrase 9 is a hypoxia-responsive protein (CAIX) that may be used to report on the tumor microenvironment. Antibody-based clinical molecular imaging of CAIX has been accomplished. The NCBIB has developed and refined the first small-molecule CAIX imaging agents for SPECT and PET.
Service Project #8: Cell Manipulation Tools
Hematopoietic stem cell (HSC) gene therapy is a promising treatment option for a variety of genetic diseases affecting the hematopoietic system, e.g., sickle cell disease (SCD), HIV/AIDS, and certain malignancies. Current ex vivo HSC gene therapy is inefficient, expensive, and limited in availability. Dr. Kiem is a pioneer in stem-cell and gene therapy. His focus has been the development of improved treatment and curative approaches for patients with genetic and infectious diseases or cancer. While historically focused on viral approaches, he and his lab are also very interested in non-viral technologies to facilitate gene therapy and gene editing as enabling tools. These nanotechnology tools would be useful for next generation ex vivo HSC engineering as well as in vivo HSC engineering.
Service Project #9: Center for Molecular Imaging Technology and Translation (CMITT)
The mission of the CMITT is to develop, validate and disseminate cutting-edge imaging technologies that leverage simultaneous PET/MR to improve accuracy of diagnosis, characterization and follow-up of disease in the very early stages. PET/MR enables novel radiochemistry, kinetic modeling, quantitative methods, image reconstruction and AI that exploit properties of PET and MR signals. Push: We will provide a number of our PET probes (or their precursors) for neuroinflammation, e.g., [11C]CPPC or a newer 18F-labeled analog, and cancer to validate the methods under development in the CMITT and learn if they can be enhanced by concurrent MR imaging. PET/MR of PSMA-targeted agents in the JHU NCBIB, e.g., a dual-targeting FAP-PSMA agent (TR&D3), would be of particular interest, as would agents developed for CEST (TR&D1). We will also be able to provide AI algorithms under development in the JHU NCBIB, e.g., for automated segmentation of PSMA PET.
Service Project #10: Magnetic Resonance Fingerprinting of Tumor Vascular Perfusion and Acidosis
As a major limitation in contrast enhanced MRI studies is that current MRI methods lack the combination of accuracy, precision, and temporal resolution to quantitatively measure contrast agents in vivo. Dr. Pagel and team have addressed that problem by developing dynamic Magnetic Resonance Fingerprinting (MRF) methods that can rapidly measure T1 or T2 relaxation times with outstanding accuracy and precision.