<p>Clinical application of obinutuzumab for treating chronic lymphocytic leukemia</p>

Abstract

Alkylators and nucleoside analogs were the main drugs for treatingchronic lymphoblastic leukemia (CLL), which have been replaced by monoclonal antibodies, such as rituximab in the past 10 years for refractory or relapsed CLL. The first-line immunochemotherapy regimen, rituximab combined with nucleoside analogs, significantly increased CLL patients’ first-reaction rate and improved progression-free survival. Despite the long-lasting remissions by the use of chemoimmunotherapy, most CLL patients will relapse eventually. The obinutuzumab (GA101), an updated CD20 antibody, that is thought to achieve a more durable response with unique molecular and functional characteristics. Obinutuzumab is a humanized, monoclonal type II CD20 antibody modified by glycoengineering. The glycoengineered Fc portion enhances the binding affinity to the FcγRIII receptor on immune effector cells, resulting in increased antibody-dependent cellular cytotoxicity and phagocytosis. In addition, the type II antibody binding characteristics of obinutuzumab to CD20 lead to an efficient induction of direct non-apoptotic cell death. This review summarizes the results of clinical studies using obinutuzumab and looks forward to its further application in treating CLL clinically.

Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861

“…Obinutuzumab (Gazyvaro ® , Gazyva ® ) is a humanized and glycoengineered monoclonal IgG 1 antibody against the CD20 type II epitope [ 2 ]. It is mainly applied for the treatment of chronic lymphatic leukemia in combination with chlorambucil, and follicular lymphoma in combination with bendamustine [ 3 , 4 , 5 ]. The type II mechanism of action together with glycoengineering of obinutuzumab results in augmented direct signaling-induced cell death as well as antibody-dependent cell-medicated cytotoxicity (ADCC) and phagocytosis (ADCP) while complement-dependent cytotoxicity (CDC) is diminished [ 4 , 6 ].…”

“…It is mainly applied for the treatment of chronic lymphatic leukemia in combination with chlorambucil, and follicular lymphoma in combination with bendamustine [ 3 , 4 , 5 ]. The type II mechanism of action together with glycoengineering of obinutuzumab results in augmented direct signaling-induced cell death as well as antibody-dependent cell-medicated cytotoxicity (ADCC) and phagocytosis (ADCP) while complement-dependent cytotoxicity (CDC) is diminished [ 4 , 6 ]. This distinguishes obinutuzumab from classical type I anti-CD20 monoclonal antibodies, such as rituximab and ofatumumab.…”

“…This is presumably caused by abnormal Fas signaling and can be overcome by combination therapies [ 9 , 10 ]. There are a large number of completed and ongoing studies of phase 1 to 3 with obinutuzumab to enable the application in further clinical indications and to increase efficacy by combining it with other anti-cancer drugs including acalabrutinib, bendamustine, chlorambucil, duvelisib, entospletinib, ibrutinib, idasanutlin, pixantrone, tirabrutinib, and venetocla [ 4 , 11 , 12 , 13 ]. For instance, 229 patients were included in a phase 3 study comparing obinutuzumab in combination with either chlorambucil or ibrutinib.…”

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

“…However, over the last 20 years, the treatment of either naïve or relapsed/refractory CLL patients has undergone dramatic changes due to the introduction of targeted therapeutics which include the Bruton tyrosine kinase (BTK) inhibitor ibrutinib [ 119 ] and the Bcl-2 inhibitor venotoclax [ 120 ], and the PI3K inhibitors idelalisib [ 121 ] and duvelisib [ 73 ]. These drugs are used either as monotherapy or in combination with the glycoengineered monoclonal antibody obinutuzumab [ 122 ]. Although the outcome of CLL patients is improved by all of these novel therapeutics, especially in high-risk disease [ 123 ], adaptive resistance to targeted therapy inevitably occurs, thereby leading to leukemia progression [ 124 ].…”

Current Treatment of Refractory/Relapsed Chronic Lymphocytic Leukemia: A Focus on Novel Drugs

“…In addition, patients with particularly poor prognosis, especially those refractory to previous therapy with fludarabine-containing regimens and those with a 17p deletion/TP53 mutation, were also treated. Currently, CLL patients have significantly better survival when treated with the novel targeted agents [2, [9][10][11][12][13][14][15][16]. The present review discusses a number of newly developed agents which are used in the therapy of R/R and have changed the treatment algorithm in CLL.…”