TTI-621

TTI-621 is a novel SIRPαFc fusion protein that harnesses the innate immune system by blocking the activity of CD47. TTI-621 is a protein that 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. 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 (see Figure below).

TTI-621

The anti-tumor activity of TTI-621 has been extensively tested in preclinical laboratory studies.

The key findings from these studies are summarized below:

TTI-621 is currently being evaluated in two clinical studies (TTI-621-01 and TTI-621-02).

TTI-621-01 (NCT02663518) is a multicenter, open-label phase 1a/b trial of intravenously administered TTI-621 in subjects with relapsed or refractory hematologic malignancies and selected solid tumors. The phase 1a part of the trial has been completed and a well-tolerated dose of 0.2 mg/kg/week and preliminary evidence of anti-tumor activity was observed in lymphoma patients. The phase 1b expansion part of the trial is currently in progress, with TTI-621 being tested as a monotherapy across a range of hematologic malignancies and in patients with small cell lung cancer. In two combination drug cohorts, TTI-621 is being administered in combination with rituximab for patients with CD20-positive lymphomas, and 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. Patients are being enrolled in sequential dose cohorts to receive intratumoral injections of TTI-621 that increase in dose and dosing frequency to characterize safety, pharmacokinetics, pharmacodynamics and preliminary evidence of antitumor activity. In addition, detailed evaluation of serial, on-treatment tumor biopsies of both injected and non-injected cancer lesions will help characterize tumor microenvironment changes anticipated with CD47 blockade. We believe the study of TTI-621 delivered by intratumoral injections could lead to a more thorough understanding of its mechanism of action and could provide insight into the tumor micro-environment before, during and after treatment with TTI-621. One of the TTI-621-02 investigators presented a case report of anti-tumor activity in a mycosis fungoides patient after a single injection of TTI-621 that was further enhanced by subsequently treatment with PEGylated Interferon-α2a.

TTI-621 has recently been granted an Orphan Drug Designation by the FDA for the treatment of cutaneous T-cell lymphoma. 

More details regarding these clinical studies can be found in the CLINICAL TRIALS section.

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