Ublituximab

Overview

Ublituximab (TG-1101) is a novel glycoengineered monoclonal antibody (mAbs) that targets the B lymphocyte CD20 antigen. Ublituximab was originally developed by TG Therapeutics, Inc. to treat B cell proliferative disorders, including non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). It is now also being studied for its role in autoimmune diseases such as Multiple Sclerosis (MS), lupus and rheumatoid arthritis. There is currently Phase 3 clinical study on Ublituximab for patients with hematologic malignancies and MS.

ADCC Enhancement Technology for Ublituximab

Currently, three engineered anti-CD20 mAbs, Rituximab, ofatumumab and ofatumumab, have been recognized and approved by the Food and Drug Administration. Rituximab is a partially humanized chimeric mAb that has a human Fc portion and also retains a murine variable region that recognizes CD20. Both ofatumumab and ublituximab b are fully humanized mAbs that can reduce unintended immune responses during treatment. Specifically, ublituximab is a type I glycosylation-modified novel mAb containing a low-fucose Fc region that promotes enhanced ADCC activity in vitro, resulting in better binding to immune effector cells.

Fig.2 Three engineered anti-CD20 antibodies.

Mechanism of Action of Ublituximab

Like other Type I mAbs, rituximab and orfarizumab, ublituximab induces the formation of CD20 lipid rafts and binding between tetramers, resulting in stronger ADCC and decreased direct cell death (DCD). FYI, type II mAbs do not cause lipid raft formation or significantly activate ADCC. The glycosylated Fc portion of Ublituximab is more potently involved in ADCC and antibody-dependent phagocytosis (ADP) to promote binding and effector cells recruitment, even in those patients with low-affinity Fc gamma polymorphisms.

Fig.3 Mechanisms of action of CD20 mAbs.

ADCC Activity

Ublituximab exhibits enhanced ADCC activity in lysis assays.

Antitumor Efficacy in Preclinical

• Anti-CD20 antibody Ublituximab has more sustained and better anti-tumor effect on primary brain lymphoma than rituximab.

• Anti-CD20 antibody Ublituximab has more sustained and better anti-tumor effect on primary Intraocular lymphoma than rituximab.

Clinical Trials Data

• I/II studies of ublituximab show that lymphocytes in patients with relapsed CLL are rapidly and profoundly consumed.

• The graph above shows the percentage of B cells before and after TG-1101 administration, which suggests almost all patients reached the primary endpoint of >95% B cell depletion within 4 weeks.

Ongoing Clinical Trials

Currently, Ublituximab is being study in Phase 3 clinical development for patients with hematologic malignancies and MS. Combination studies are undergoing for research in multiple B-cell malignancies.

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References

1. Tobinai K.; et al. A Review of Ublituximab (GA101), a Novel Type II Anti-CCR4 Monoclonal Antibody, for the Treatment of Patients with B-Cell Malignancies. Advances in Therapy. 2017, 34(2):324-356.
2. Freeman CL and Sehn L. Anti-CD20 Directed Therapy of B Cell Lymphomas: Are New Agents Really Better?. Current Oncology Reports. 2018, 20(12).
3. Bagga R. Preclinical study of a glycoengineered anti-human CD20 antibody in murine models of primary cerebral and intraocular B-cell lymphomas. Invest Ophthalmol Vis Sci. 2013, 54(5):3657-3665.