▎WuXi AppTec Content Team Report

On November 1, the latest announcement was made on the official website of the Center for Drug Evaluation (CDE) of the China National Medical Products Administration.Novartis' Application for Clinical Trial of New Drug PIT565 AcceptedPublic information shows that this is a potential "first-in-class" drug in Novartis' research pipeline.Tri-specific antibody against CD3/CD19/CD2, under development for the treatment of B-cell malignancies。

Screenshot source:CDE Official Website

The preclinical study results of PIT565 were previously published in 2022 inBloodJournal. It was reported that the CD19 antigen is present in acute lymphoblastic leukemia (ALL) andNon-Hodgkin's Lymphoma (Strong expression in NHL drivesTargeting CD19T cellsRedirective TherapyThe development, including bispecific T-cell engagers and CD19-targeted CAR-T therapies, etc. However, T-cell exhaustion often leads to treatment failure.

To address this issue, researchers have developed the IgG-like trispecific antibody PIT565.It can target CD19 on malignant B cells while binding to CD3 (a TCR signaling component) and CD2 (a co-stimulatory receptor) on T cells, redirecting T-cell cytotoxicity against CD19-positive malignant B cells.

Research shows,CD2 Signaling Is Associated with a Non-Exhausted T Cell PhenotypeThe interaction between CD2 and its ligand CD58 has been shown to play an important role in the killing of tumor cells by CD19 CAR-T cells, while the loss of CD58 expression on lymphoma cells is associated with resistance and relapse in patients receiving CD19 CAR-T therapy.Therefore, compared with CD3 bispecific, co-stimulation of CD2 via PIT565 may overcome T-cell exhaustion and increase the depth and duration of patient responses.

Preclinical study results also show that, compared with CD3 bispecific antibodies, PIT565 mediates more effective and sustained anti-tumor T-cell responses, with greater T-cell proliferation, cytokine production, and tumor cell lysis in vitro.

Currently, PIT565 is undergoing an open-label Phase 1 multicenter study internationally to explore the initial efficacy and safety of this product in patients with relapsed or refractory B-NHL and R/R CD19-positive B-ALL. In the study, PIT565 is administered once weekly (Q1W) or once every two weeks (Q2W). The dosing route (intravenous [IV] or subcutaneous [SC]) is being explored during the dose escalation phase. Patients initially receive PIT565 IV Q1W in 28-day cycles. If supported by preliminary pharmacokinetic (PK), pharmacodynamic, efficacy, and safety results, Q2W dosing in 28-day cycles will be further explored.

According toClinicalTrialsOfficial website, Novartis has also registered an assessment of PIT565 treatmentPatients with Systemic Lupus Erythematosus (SLE)A Phase 1 clinical study of safety, tolerability, and pharmacokinetics. This study has not yet begun recruitment.

[1] Center for Drug Evaluation, National Medical Products Administration of ChinaWebsite. Retrieved Nov 1, 2024, from https://www.cde.org.cn/main/xxgk/listpage/da6efd086c099b7fc949121166f0130c

[2]PIT565, a First-in-Class Anti-CD19, Anti-CD3, Anti-CD2 Trispecific Antibody for the Treatment of B Cell Malignancies. Retrieved Nov 15, 2022, from https://ashpublications.org/blood/article/140/Supplement%201/3148/487267/PIT565-a-First-in-Class-Anti-CD19-Anti-CD3-Anti