Single-domain monoclonal antibodies for the treatment of hepatocellular carcinoma

The National Cancer Institute seeks parties to license human monoclonal antibodies and immunoconjugates and co-develop, evaluate, and/or commercialize large-scale antibody production and hepatocellular carcinoma (HCC) xenograft mouse models. An advantage of these monoclonal antibodies as a potential therapeutic is their specificity, which would reduce deleterious side-effects. HCC is the most common form of liver cancer, and is among the more deadly cancers in the world. There is a need for new treatments that can be successfully applied to a large population of patients.

Antibody and Immunotoxin Treatments for Mesothelin-expressing Cancers

Mesothelin is a cell surface protein that is highly expressed in aggressive cancers such as malignant mesothelioma, ovarian cancer, pancreatic cancer, lung cancer, breast cancer, cholangiocarcinoma, bile duct carcinoma and gastric cancer. As a result, mesothelin is an excellent candidate for tumor targeted immunotherapeutics. However, the antibodies against mesothelin that are available for clinical trials are of murine origin. These antibodies have the potential to elicit immune responses in patients, which may adversely affect the ability to provide patients with repeated doses.

Chimeric Antigen Receptors (CAR)-T Cells that Target the Non-Shed Portion of Mesothelin as a Therapeutic Agent

Mesothelin (MSLN) is an excellent target for antibody-based therapies of cancer because of its high expression in many malignancies but lack of expression on essential normal tissues. Unfortunately, a large fragment of MSLN is shed from cancer cells, causing the currently available anti-MSLN antibodies (and immunoconjugates thereof) which bind to the shed portion of MSLN to quickly lose their therapeutic effectiveness over time. Indeed, the shed portion of MSLN can act as a decoy for these antibodies, further limiting them from reaching and destroying tumor cells.

Monoclonal Antibodies and Immunoconjugates Directed to the Non-ShedPortion (“Stalk”) of Mesothelin are Excellent Candidates for Developing Therapeutic Agents

Human mesothelin is overexpressed by various cancers such as synovial sarcoma, mesothelioma, and ovarian, lung, esophageal, and gastric cancers. This selective expression on certain cancers suggests that mesothelin is an excellent target for anticancer therapeutics. However, a large fragment (“the shed portion”) of mesothelin is constantly shed from cells, and all current anti-mesothelin antibodies bind to the shed portion.

Improved PE-based Targeted Toxins: A Therapeutic with Increased Effectiveness

Targeted toxins (e.g., immunotoxins) are therapeutics that have at least two important components: (1) a toxin domain that is capable of killing cells and (2) a targeting domain that is capable of selectively localizing the toxic domain to only those cells which should be killed. By selecting a targeting domain that binds only to certain diseased cells (e.g., a cell which only expresses a cell surface receptor when in a diseased state), targeted toxins can kill the diseased cells while allowing healthy, essential cells to survive.

New Class of Immunotoxins with Extended Half-Life and High Anti-Tumor Activity

Recombinant immunotoxins (RITs) constitute a promising solution to hematologic cancers (e.g., Multiple Myeloma [MM]). RITs are chimeric proteins composed of a targeting domain fused to a bacterial toxin. Upon binding to a cancer cell displaying the target antigen, RITs are internalized, metabolized and the released toxin kills the cell. While highly active and effective, current RITs have short half-lives, requiring them to be used in high concentrations for treatment. At such high concentrations, RITs may show nonspecific activity and kill healthy cells.

Method to Detect and Quantify In Vivo Mitophagy

This technology includes a transgenic reporter mouse that expresses a fluorescent protein called mt-Keima, to be used to detect and quantify in vivo mitophagy. This fluorescent protein was originally described by a group in Japan and shown to be able to measure both the general process of autophagy and mitophagy. We extended these results by creating a living animal so that we could get a measurement for in vivo mitophagy. Our results demonstrate that our mt-Keima mouse allows for a straightforward and practical way to quantify mitophagy in vivo.

Using FDA-approved Small Molecule Drug Reserpine and related compounds (especially Halofantrine) To Protect Photoreceptors In Inherited Retinal Degenerations And Age-Related Macular Degeneration

Summary: 
The National Eye Institute seeks research co-development partners and/or licensees for a therapy using an FDA-approved small molecule drug reserpine (and related compounds especially halofantrine) that prevents photoreceptor cell death in retinal degenerations.