Targeting CD19 in B-cell lymphoma: emerging role of SAR3419

Abstract

Non-Hodgkin lymphoma symbolizes a heterogeneous group of diseases resulting from malignant transformation of lymphocytes with differing patterns of behavior and responses to treatment. The potential curability of non-Hodgkin lymphoma differs among the various histologic subtypes and is associated in part with the stage at presentation. CD19 antigen is a type I transmembrane glycoprotein belonging to the immunoglobulin Ig superfamily. CD19 is specifically expressed in normal and neoplastic B-cells. Recent study showed that in a mouse model, CD19 and c-Myc synergize functionally to accelerate B-cell lymphomagenesis, which is associated with increased disease severity. Specificity is the most important challenge in cancer therapeutics. Antibody–drug conjugates have the prospect of enhancing the therapeutic efficacy over unconjugated monoclonal antibodies through the selective delivery of cytotoxic agents to cancer cells. The ubiquitous expression of CD19 in these tumors, especially at an earlier stage and the property of efficient internalization, makes CD19 an attractive and affective target for antibody–drug conjugate therapy as compared to CD20. SAR3419 (huB4-DM4) is a novel antibody–drug conjugate that is composed of a humanized monoclonal IgG1 anti-CD19 antibody (huB4) attached to the potent cytotoxic drug, a maytansine derivative (DM4), through a cleavable disulfide cross-linking agent N-Succinimidyl-4-2-pyridyldithio butanoic acid (SPDB). The preclinical efficacy of maytansine derivative–anti-CD19 conjugate was demonstrated in our laboratory, and SAR3419 was found to be more effective than CHOP in a xenograft model. Phase I trials have also been conducted on the basis of preclinical studies that demonstrated promising antitumor activity with acceptable safety results in human B-cell lymphoma models. Additional trials are ongoing and will provide additional insight into the full potential of this novel drug.

Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment

“…Although the initial clinical evaluation of CAR-T cells focused on B cell non-Hodgkin’s lymphoma (B-NHL) (Kochenderfer et al, 2010 ; Till et al, 2008 ), the most striking outcomes have been obtained in B-ALL by targeting CD19, a B cell-lineage antigen expressed on the surface of normal B cells and many malignant B cells (Scheuermann and Racila, 1995 ; Depoil et al, 2008 ). Another pan-B cell marker, CD20, is also an attractive target for CAR-T cell therapy in B cell malignancies (Raufi et al, 2013 ). Preliminary clinical trials evaluating anti-CD20 CAR-T cells for patients with B-NHL revealed minimal toxicities with modest efficacy (Wang et al, 2014 ; Till et al, 2008 , 2012 ), until recently a phase IIa clinical trial performed at PLAGH demonstrated an objective remission rate (ORR) of 82% (complete remission (CR) 6/11, partial remission (PR) 3/11) with well-tolerated toxicity (Zhang et al, 2016a ).…”

Novel Targeted Agents in Hodgkin and Non-Hodgkin Lymphoma Therapy

“…CD19 is a desirable target for ADC therapy because it is quickly internalized upon antibody binding [ 50 ]. SAR3419 is a novel ADC which combines the humanized anti-CD19 monoclonal antibody with the tubulin inhibitor DM4.…”

Antibody Therapy for Pediatric Leukemia

“…It has threefold higher expression in mature B cells compared with immature B cells (57) and is one of the earliest B cell restricted antigens. It plays an important role in maintaining balance between immunity and autoimmunity.…”