Ocaratuzumab

Overview

Ocaratuzumab (AME-133v, LY2469298) is a humanized monoclonal antibody(mAb) directed against human CD20 for the treatment of cancer and autoimmune diseases. The antibody is engineered in the Fc region to enhance its affinity to B lymphocyte CD20 antigen, promote antibody-dependent cell-mediated cytotoxicity (ADCC), and improve treatment of low-affinity FcγRIIIa allotypes. Compared with rituximab, the affinity of ocaratuzumab for CD20 was significantly increased by 13 to 20-fold, and the effective ADCC was increased by 6-fold. The drug is currently being developed by Mentrik Biotech, LLC, and a phase II clinical trial is underway.

ADCC Enhancement Technology for Ocaratuzumab

Ocaratuzumab is a novel Fc-engineered humanized anti-CD20 mAb optimized for superior ADCC. Using single-point codon-substitutions strategy, the amino acid substitutions are engineered into the IgG1 Fc domain, resulting in increased binding to FcγR. Ocaratuzumab has greater ADCC potency and maximum cytotoxicity than rituximab that is replaced in the wild-type Fc domain.

Fig.1 Fc-optimized Ocaratuzumab. (Source: Mentrik Biotech, LLC)

Mechanism of Action of Ocaratuzumab

Ocaratuzumab is a secondary mAb derived from a parent antibody—rituximab. Ocaratuzumab and rituximab bind to the same epitope of CD20 and thus, allow for competition and substitution between the two antibodies. Similar to the MOA of rituximab, Ocaratuzumab is thought to mediate its therapeutic activity against CD20-positive tumors by working on ADCC, CDC, and ADCP efficacy. Details are shown in the figure below:

Fig.2 Mechanisms of action of CD20 antibodies.

ADCC Activity

• Comparing to rituximab, ocaratuzumab exhibits significantly enhanced ADCC activity.

Ocaratuzumab Binding Characterization

• Ocaratuzumab exhibits optimized binding kinetics on lymphoma cells compared to rituximab.

Preclinical Research

• B cell depletion and immunogenicity of Ocaratuzumab were assessed on 48 cynomolgus monkeys with 3 different dosages. The results showed Ocaratuzumab significantly reduced peripheral circulating B lymphocyte counts in cynomolgus monkeys, who received subcutaneous administrations of antibodies.

Ongoing Clinical Trial for Ocaratuzumab

• B cell depletion of Ocaratuzumab provides a therapeutic benefit for patients with rheumatoid arthritis (RA). Patients with RA who received a single intravenous (IV) dose of ocaratuzumab all had rapid consumption of B cells.

• Analysis of B cell depletion in 50 patients with recurrent follicular lymphoma treated with Ocaratuzumab. All patients showed rapid B cell depletion.

• A phase 1/2 Study of ocaratuzumab in low-affinity FcγRIIIa patients with previously treated follicular lymphoma. Kaplan – Meier estimates of progression-free survival after treatment in all patients is shown.

Clinical Development Status

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Reference

1. Ganjoo KN.; et al. Phase 1/2 Study of Ocaratuzumab, an Fc-Engineered Humanized Anti-CD20 Monoclonal Antibody, in Low-Affinity FcγRIIIa Patients with Previously Treated Follicular Lymphoma. Leuk Lymphoma. 2015, 56(1):42-48.