We employ biologic and small molecule-based approaches that are designed to enhance the ability of the patient’s own immune system to detect and destroy cancer cells. Our clinical programs, TTI-621 and TTI-622, are immune checkpoint inhibitors targeting CD47. We also have a discovery-stage small molecule STING agonist program.
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-621-02 (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.
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).
More details regarding these clinical studies can be found in the Patients section.
TTI-621 has been extensively tested in preclinical laboratory studies. Key findings from these studies are summarized below:
Intratumoral TTI-621 was well tolerated and a rapid reduction in CAILS scores, which measures local lesion responses, was observed in 91% (20/22) mycosis fungoides patients, with emerging evidence of systemic effects
Weekly intravenous administration of TTI-621 has been shown to be well tolerated in over 179 treated patients and has resulted in objective clinical responses in relapsed/refractory CTCL, PTCL and DLBCL patients as a monotherapy and in DLBCL patients in combination with rituximab
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 been granted an Orphan Drug Designation by the FDA for the treatment of cutaneous T-cell lymphoma
TTI-10001 is a discovery-stage, small molecule STING agonist.
STING (stimulator of interferon genes) is an adaptor protein involved in sensing cytosolic DNA that plays a key role in promoting tumor immunity. STING has recently emerged as an attractive target in immuno-oncology, though the most advanced STING agonists currently in clinical trials are based on high molecular weight cyclic dinucleotide (CDN) scaffolds that possess certain undesirable drug properties. TTI-10001 exhibits favorable potency, cell permeability, and tumor retention properties that could potentially overcome the common limitations of current CDN-derived STING agonists. TTI-10001 is well tolerated in mice at relevant doses after intratumoral or intravenous delivery. Upon intratumoral administration, TTI-10001 monotherapy induced complete regressions in both injected and distal tumors and protected mice from subsequent tumor challenge, demonstrating the induction of durable immunity.
Efforts to discover novel cancer therapeutic targets are ongoing. We are applying our expertise in biologics and medicinal chemistry to generate novel, patentable compounds against undisclosed immuno-oncology targets.
