Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients

Abstract

Whereas the chimeric type I anti-CD20 Ab rituximab has improved outcomes for patients with B-cell malignancies significantly, many patients with non-Hodgkin lymphoma (NHL) remain incurable. Obinutuzumab (GA101) is a glycoengineered, humanized anti-CD20 type II Ab that has demonstrated superior activity against type I Abs in vitro and in preclinical studies. In the present study, we evaluated the safety, efficacy, and pharmacokinetics of GA101 in a phase 1 study of 21 patients with heavily pretreated, relapsed, or refractory CD20 ؉ indolent NHL. Patients received GA101 in a doseescalating fashion (3 per cohort, range 50/100-1200/2000 mg) for 8 ؋ 21-day cycles. The majority of adverse events (AEs) were grades 1 and 2 (114 of 132 total AEs). Seven patients reported a total of 18 grade 3 or 4 AEs. Infusion-related reactions were the most common AE, with most occurring during the first infusion and resolving with appropriate management.Three patients experienced grade 3 or 4 drug-related infusion-related reactions. The best overall response was 43%, with 5 complete responses and 4 partial responses. Data from this study suggest that GA101 was well tolerated and demonstrated encouraging activity in patients with previously treated NHL up to doses of 2000 mg. This trial is registered at www.clinicaltrials.gov as NCT00517530.

Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity

“…Two prime examples of successful therapeutic development leveraging the effects of protein glycosylation are the development of a long-acting erythropoietin (darbepoetin alfa; Aranesp; Amgen) with increased sialylation content, which reduces the clearance facilitated by the asialoglycoprotein receptor (37), and the development of an anti-CD20 antibody (obinutuzumab; GAZYVA; Genentech) that is devoid of Fc fucosylation, which has enhanced effector function and antitumor properties (38). Identification of the important role of terminal sialic acid-containing IgG glycoforms for IVIg activity in 2006 (23) and its confirmation by several independent laboratories in the past few years .…”

Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics

“…given for 4 decreased after subsequent infusions because of a reduction in the available target antigen. 54,57 Absorption. After i.v.…”

Glycoengineering of Therapeutic Antibodies Enhances Monocyte/Macrophage-Mediated Phagocytosis and Cytotoxicity

“…In line with these properties, a number of preclinical studies demonstrated that Ab Fcafucosylation translates into significantly enhanced activity in vivo (6,9,17), and this has led to the approval of new therapeutic GE Abs. GA101 (obinutuzumab) is a GE, type II anti-CD20 mAb that has recently been approved by the U.S. Food and Drug Administration for the first line treatment of patients with chronic lymphocytic leukemia (CLL) in combination with chlorambucil (18)(19)(20). In Japan, the GE CCR4 Ab mogamulizumab has been approved for treatment of patients with relapsed or refractory CCR4 + T cell leukemia-lymphoma (21).…”