Pasotuxizumab is a recombinant T-cell engaging bispecific monoclonal antibody (BiTE) directed against human prostate specific membrane antigen (PSMA) and the CD3 epsilon (CD3E) subunit of the T cell receptor complex, with potential immunostimulating and antineoplastic activities. It was developed by Amgen and Bayer HealthCare Pharmaceuticals and has shown high response rates and durable remissions in patients with relapsed or refractory acute lymphocytic leukemia and non-Hodgkin's lymphoma. The BiTE antibody was produced in Chinese hamster ovary cells as a secreted protein of 55 kDa, showing high serum and thermal stability. In cell culture studies bispecific binding of pasotuxizumab selectively redirected human T cells against several PSMA-positive human prostate cancer cell lines as well as PSMA cDNA-transfected cell lines and potently induced specific target cell lysis using non-stimulated human peripheral blood mononuclear cells as effector cells.
Prostate cancer is the most common type of cancer in men in the United States and is the second leading cause of cancer death in men after lung cancer. Relapse after primary therapy by radical prostatectomy remains a common problem in prostate cancer patients because an estimated 30% to 40% of men experience recurrence within 10 years. Prostate specific membrane antigen (PSMA), is a unique membrane bound glycoprotein, which is overexpressed manifold on prostate cancer as well as neovasculature of most of the solid tumors, but not in the vasculature of the normal tissues. Antibodies that target PSMA are a potential addition to the armentarium of prostate cancer therapies. Developments comprise naked humanized or human IgG1 antibodies, and antibodies of enhanced activity such as antibody drug conjugates and radioimmunoconjugates. PSMA is also an established marker for imaging of residual prostate cancer and metastases using the radiolabeled diagnostic antibody ProstaScint. The antigen is expressed in a high percentage of prostate cancer patients across all stages of the disease. A highly promising approach to enhance the anticancer activity of antibodies is the engagement of T cells by using bispecific antibodies and related constructs. Pasotuxizumab is a recombinant T-cell engaging bispecific monoclonal antibody (BiTE). This anti-PSMA/CD3 BiTE monoclonal antibody possesses two antigen-recognition sites, one for PSMA, and one for the CD3 complex, a group of T cell surface glycoproteins that complex with the T cell receptor (TCR). This bispecific monoclonal antibody brings PSMA-expressing tumor cells and cytotoxic T lymphocytes (CTLs) together, which may result in the CTL-mediated cell death of PSMA-expressing cells.
Fig 1. Mechanism of Action of Pasotuxizumab