PIT565, a First-in-Class Anti-CD19, Anti-CD3, Anti-CD2 Trispecific Antibody for the Treatment of B Cell Malignancies

The robust expression of the CD19 antigen in ALL and NHL has resulted in the development of highly effective therapeutics targeting CD19 by leveraging redirected T cells, which include the bispecific T-cell engager blinatumomab and CD19-directed CAR-T therapies axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel. However, T cell exhaustion contributes to treatment failure following anti-CD19 bispecific T-cell engager and CAR-T therapies. To circumvent this issue, we have developed a first-in-class anti-CD19, anti-CD3, anti-CD2 IgG-like trispecific antibody, PIT565, that simultaneously engages CD19+ on tumor cells, CD3 (TCR signaling component) and CD2 (a costimulatory receptor) on T cells, which leads to redirected T-cell cytotoxicity towards CD19-positive malignant B cells. CD2 signaling has been associated with non-exhausted T cell phenotype. The interaction between CD2 and its ligand, CD58, has been shown to be important for tumor cell killing by CD19 CAR-T cells, while the loss of CD58 expression on lymphoma cells correlates with resistance and relapse in patients treated with CD19 CAR-T therapy. Therefore, CD2 co-stimulation via PIT565 may overcome T cell exhaustion and increase the depth and duration of response in patients compared to CD3 bispecifics. A redirected T cell cytotoxicity (RTCC) in vitro assay, employing co-cultures of CD19+ tumor cells and primary T-cells, demonstrated dose-dependent T-cell proliferation, cytokine production, and tumor cell lysis, which was more potent than the bispecific counterpart. Furthermore, in repeat-challenge RTCC assays, PIT565 mediated more sustained T cell activity in tumor cell killing and proliferation compared to control bispecifics. In addition, PIT565 demonstrated a more robust anti-tumor response than a control bispecific against an established diffuse large B cell lymphoma tumor in the human peripheral blood mononuclear cell adoptive transfer model. In safety and pharmacology studies, PIT565 showed IgG-like pharmacokinetics and an expected pharmacology and tolerability profile similar to CD3 bispecifics in cynomolgus monkey. Taken together, the findings from the preclinical studies suggest that PIT565 may achieve deeper and more durable responses compared to competitor CD3 bispecifics. First-in-human trial of PIT565 (NCT05397496) has been initiated and will be conducted in patients who are diagnosed with relapsed and/or refractory adult NHL after receiving two or more lines of chemotherapy and patients with relapsed and/or refractory B-ALL.