Swiss pharmaceutical giant Novartis (NYSE: NVS) has received acceptance for its clinical trial application for the investigational drug PIT565 from the China National Medical Products Administration (NMPA). PIT565 is a potential “first-in-class” trispecific antibody targeting CD3, CD19, and CD2, which Novartis is developing to treat B-cell malignancies.
Preclinical research results for PIT565 were published in the journal Blood in 2022. The robust expression of the CD19 antigen in acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) has driven the development of T cell redirecting therapies targeting CD19, including bispecific T cell engagers and CD19-targeting CAR-T therapies. However, T cell exhaustion often leads to treatment failure.
To address this challenge, researchers have developed the IgG-like trispecific antibody PIT565, which targets CD19 on malignant B cells and engages both CD3 and CD2 on T cells, redirecting T cell cytotoxicity towards CD19-positive malignant B cells. Studies have shown that CD2 signaling is associated with a non-exhausted T cell phenotype. The interaction between CD2 and its ligand CD58 has been proven crucial for the efficacy of CD19 CAR-T cells in killing tumor cells, and the lack of CD58 expression on lymphoma cells is associated with resistance and relapse in patients treated with CD19 CAR-T therapy. Therefore, co-stimulation of CD2 by PIT565, compared to CD3 bispecifics, may overcome T cell exhaustion, increasing the depth and duration of patient responses.
Preclinical studies have also indicated that PIT565 mediates more effective and sustained antitumor T cell responses compared to CD3 bispecifics, with greater T cell proliferation, cytokine production, and tumor cell lysis in vitro.
Currently, PIT565 is being tested in an open-label, multicenter, Phase 1 study internationally to explore the preliminary efficacy and safety of the product in patients with relapsed or refractory B-NHL and R/R CD19-positive B-ALL. The study involves dosing PIT565 either weekly (Q1W) or every two weeks (Q2W), with the route of administration (intravenous [IV] or subcutaneous [SC]) being explored during the dose-escalation phase. Patients initially receive PIT565 IV Q1W for a 28-day cycle, with the possibility of exploring Q2W treatment for 28-day cycles if preliminary pharmacokinetic (PK), pharmacodynamic, efficacy, and safety results are supportive.
According to ClinicalTrials.gov, Novartis has also registered a Phase 1 clinical study to evaluate the safety, tolerability, and pharmacokinetics of PIT565 in patients with systemic lupus erythematosus (SLE), which has not yet begun recruiting participants.- Flcube.com
