HLA-class II-restricted T Cell Receptors for PIK3CA “Hotspot” Mutations, E545K and N345K

Summary: 

The National Cancer Institute (NCI) seeks co-development partners and/or licensees for a collection of T cell receptors (TCRs) that specifically target PIK3CA mutations to treat patients with tumors expressing these mutations in the context of HLA-DPA1*01:03:01, HLA-DPB1*04:01:01 or HLA-DRB1*04:01.

Description of Technology:

A New Molecular Scaffold for Targeting hRpn13 as a Treatment for Cancer

This technology includes a new chemical scaffold (with lead compound XL5) against hRpn13 that induces apoptosis, which may have clinical efficacy against cancer. The structure of XL5-conjugated hRpn13 guided the design of XL5-PROTAC degrader compounds that exhibit greater efficacy than previous hRpn13-targeting compounds, as evaluated by selectivity for hRpn13, induction of apoptosis, and loss of cell viability. In cells, XL5-PROTACs revealed the presence of a truncated hRpn13 product that binds to proteasomes and is selectively degraded by XL5-PROTACs.

Next-Generation 5-HT-2B Serotonin-Receptor Antagonists for Anti-Fibrotic & Cardiopulmonary Therapy

This technology includes a family of small-molecule antagonists that selectively block the 5-HT2B serotonin receptor—an upstream driver of tissue-remodeling—to address fibrotic, cardiopulmonary and related disorders. Built on a conformationally-locked “(N)-methanocarba” nucleoside scaffold, the compounds show nanomolar potency, >30–400-fold selectivity over the closely related 5-HT2C receptor, and favorable oral bioavailability in rodents.

Bicistronic Chimeric Antigen Receptor (CAR) Constructs Targeting CD19 and CD20

CD19 and CD20 are promising targets for the treatment of B-Cell malignancies.  Unfortunately, some clinical studies have shown that there is a loss of CD19 or CD20 expression in various cases of lymphomas and leukemias, particularly after treatment with an agent that targets CD19 (e.g., anti-CD19 CAR-T). However, studies have shown that expression of one protein is retained when the other is lost. This suggests that a therapeutic with the ability to simultaneously target both CD19 and CD20 could represent a solution to the drawbacks of current therapies. 

Anti-SLAMF7 Chimeric Antigen Receptors

Immortalization of plasma cells leads to Multiple Myeloma (MM). Signaling Lymphocyte Activation Molecule F7 (SLAMF7) is highly expressed on the malignant plasma cells that constitute Multiple Myeloma. The expression of SLAMF7 by MM cells and lack of expression on nonhematologic cells makes SLAMF7 a promising target for chimeric antigen receptor (CAR) T cell therapies for the treatment of MM. 

Optimized Monospecific or Bicistronic Chimeric Antigen Receptor (CAR) Constructs Targeting CD19 and CD20

Patients with chemotherapy-refractory, diffuse large B-cell lymphoma (DLBCL) have poor prognoses. CD19 and CD20 are promising targets for the treatment of B-Cell malignancies. However, despite the initial promising results from anti-CD19 CAR therapy, only 30-35% of patients with DLBCL achieve remissions lasting longer than 2-3 years after anti-CD19 CAR T-cell therapy. Relapse and non-response are likely due to diminished CD19 expression after anti-CD19 therapy and low expression of CD19 in some lymphomas. 

Optical Trap Methods to Determine the Viscoelastic Properties of Biological Materials

Optical traps (optical tweezers) have a focused laser beam able to trap a small bead at its focus, and are used to measure the microrheology of gels and other materials. They have recently been used to characterize properties of living cells, however issues of image spatial resolution and limited depth of interrogation have prevented application of an optical trap to measure microrheological (flow of matter) properties in complex (non-uniform) materials, such as multi-cellular systems or living organisms. 

Humanized Mouse Model to Study Mesothelin (MSLN) -targeted Cancer Therapeutics: Bl6/TPO Mice

Mesothelin (MSLN) is an antigen highly expressed in several human cancers including mesotheliomas, ovarian cancers and pancreatic cancers. As such, human MSLN (hMSLN) is a target for many anti-cancer drugs. Most therapeutics targeting hMSLN do not recognize the mouse isoform of MSLN (mMSLN) and therefore cannot be tested in mouse cancer models. 

IgG4 Hinge Containing Nanobody-based CARs Targeting GPC3 for Treating Liver Cancer

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Globally, HCC is the sixth most prevalent cancer and third leading cause of cancer-related morbidity. Standard treatment for HCC is not suitable for a large proportion of liver cancer patients. Part of this is because less than a quarter of HCC patients are surgical candidates for curative-intent treatment. As a result, alternative treatments are needed. Chimeric antigen receptor (CAR) T cell therapy is a promising alternative approach selectively targets targeting tumors via tumor-specific antigens.

Cross Species Single Domain Antibodies Targeting PD-L1 for Treating Solid Tumors

Programed Death-Ligand 1 (PD-L1, also known as B7-H1 or CD274) is a cell surface protein that binds to Programmed Cell Death Protein 1 (PD-1, also known as CD279). An imbalance in PD-1/PD-L1 activity contributes to cancer immune escape.  PD-1 is expressed on the surface of antigen-stimulated T cells. The interaction between PD-L1 and PD-1 negatively regulates T cell-mediated immune responses. It has been suggested that disrupting the PD-L1/PD-1 signaling pathway can be used to treat cancers. The aberrant expression of PD-L1 on multiple tumor types supports this suggestion.