We employ biologic-based approaches that are designed to enhance the ability of the patient’s own immune system to detect and destroy cancer cells. Our leading clinical programs, TTI-621 and TTI-622, are immune checkpoint inhibitors targeting CD47. We also have several discovery projects addressing novel immunologic targets.
Target
Target
Target
TTI-621 is a novel SIRPαFc fusion protein that harnesses the innate immune system by blocking the activity of CD47. TTI-621 consists of the CD47-binding domain of human SIRPα linked to the Fc region of human immunoglobulin G1 (IgG1). It is designed to act as a soluble decoy receptor, preventing CD47 from delivering its inhibitory signal. Neutralization of the inhibitory CD47 signal enables the activation of macrophage anti-tumor effects by the pro-phagocytic “eat” signals. The IgG1 Fc region of TTI-621 may also assist in the activation of macrophages by engaging Fc receptors. Therefore, TTI-621 is considered a dual function decoy receptor, based on its ability to both block the inhibitory CD47 signal and deliver an activating signal through the IgG1 Fc.
TTI-621 is being evaluated in two clinical studies.
TTI-621-01 (NCT02663518) is a multicenter, open-label phase 1a/b trial of intravenously administered TTI-621 in patients with relapsed or refractory hematologic malignancies. In this study, TTI-621 is being evaluated as a monotherapy or in combination with rituximab (in patients with CD20-positive lymphomas), or in combination the PD-1 checkpoint inhibitor nivolumab (in patients with Hodgkin lymphoma).
TTI-621-02 (NCT02890368) is a multicenter, open-label phase 1 study of intratumoral injections of TTI-621 in patients with relapsed and refractory solid tumors and mycosis fungoides, the most common form of cutaneous T cell lymphoma. This study involves detailed evaluation of serial, on-treatment tumor biopsies of both injected and non-injected cancer lesions to help characterize tumor microenvironment changes anticipated with CD47 blockade.
More details regarding these clinical studies can be found in the Patients section.
Weekly intravenous administration of TTI-621 has been shown to be well tolerated in over 100 treated patients and has resulted in objective clinical responses in patients with heavily pre-treated relapsed/refractory DLBCL as both monotherapy and in combination with rituximab
Intratumoral TTI-621 was well tolerated and a rapid reduction in CAILS scores, which measures local lesion responses, was observed in 9 out of 10 mycosis fungoides patients and a reduction in circulating leukemic Sézary cells was observed in 3 out of 3 patients
The IgG1 Fc region of TTI-621 is believed to contribute to its potency. We have observed clinical responses in patients at a dose that is 100-fold lower than a competitor CD47 blocking agent with an IgG4 Fc
TTI-621, unlike CD47-specific antibodies, does not bind appreciably to human red blood cells. This lack of binding reduces the likelihood of inducing anemia in patients and minimizes loss of drug due to removal by red blood cells
TTI-621 has recently been granted an Orphan Drug Designation by the FDA for the treatment of cutaneous T-cell lymphoma
A combination of molecular design, novel fluorine-based chemical synthesis, and extensive biological testing led to the identification of TTI-2341, a novel orally available brain-penetrant, second generation, covalent EGFR inhibitor. EGFR is a validated drug target in oncology, and while the use of EGFR inhibitors has been approved for some cancer applications (non-small cell lung cancer, pancreatic cancer, head and neck cancer, and colorectal cancer), use in cancers of the brain has been relatively ineffective, due in part to the low level central nervous system penetration of existing EGFR inhibitors.
In preclinical studies we have benchmarked TTI-2341 against a second- and third-generation EGFR inhibitor (both approved for the treatment of non-small cell lung cancer). This comparison demonstrated that TTI-2341 achieves superior free drug exposure levels in the brain. We are currently evaluating different options for TTI-2341 development, including possible partnerships.
Efforts to discover novel cancer therapeutic targets are ongoing. We are applying our proprietary fluorine-based medicinal chemistry platform to generate novel, patentable compounds against undisclosed immuno-oncology targets. These programs are currently in the discovery phase.
