Therapeutic potential of an anti-CD79b antibody–drug conjugate, anti–CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma

Abstract

Here we describe the generation of an antibody-drug conjugate (ADC) consisting of a humanized anti-CD79b antibody that is conjugated to monomethylauristatin E (MMAE) through engineered cysteines (THIOMABs) by a protease cleavable linker. By using flow cytometry, we detected the surface expression of CD79b in almost all non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia patients, suggesting that anti-CD79b-vcMMAE could be widely used in these malignancies. By using NHL cell lines to simulate a patient population we discovered that a minimal cell-surface expression level of CD79b was required for in vitro activity. Within the subpopulation of cell lines above this minimal threshold, we found that sensitivity to free MMAE, mutation of cancer genes, and cell doubling time were poorly correlated with in vitro activity; however, the expression level of BCL-XL was correlated with reduced sensitivity to anti-CD79b-vcMMAE.

DCDT2980S, an Anti-CD22-Monomethyl Auristatin E Antibody–Drug Conjugate, Is a Potential Treatment for Non-Hodgkin Lymphoma

“…Xenograft experiments were conducted as previously described (15). Briefly, all animal studies were conducted in compliance with NIH (NIH, Bethesda, MD) guidelines for the care and use of laboratory animals and were approved by the Institutional Animal Care and Use Committee (IACUC) at Genentech, Inc.…”

“…In these studies, we compared the activity of a single dose of DCDT2980S with a single cycle of CHOP, rituximab, or R-CHOP. Rituximab was given above the maximum efficacious dose and CHOP was given close to the maximum tolerated dose for mice (15). As the exposure equivalent of the maximum tolerated dose of DCDT2980S was approximately 4 mg/kg for a single dose exposure, we dosed DCDT2980S once at 5 mg/kg as top end of our exposure and 2 mg/kg once to provide a very conservative dose.…”

Synthesis of a Covalent Epirubicin-(C3-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

“…7,[26][27][28][29][30]35,40 Discussion A small spectrum of molecular platforms has been applied to facilitate selective ''targeted'' delivery of a variety of biological agents and conventional chemotherapeutics that can exert significant cytotoxic anti-neoplastic properties. Biological agents utilized in this regard include various immunotoxin preparations synthesized to enhance selective ''targeted'' delivery of Pseudomonas exotoxin, 64 84 and monomethyl auristatin E. [86][87][88][89] Several different chemical characteristics of the anthracycline class of chemotherapeutics can be utilized to develop multiple molecular designs and synthesis strategies allowing their covalent incorporation into immunoglobulin fractions or receptor ligands applying a variety of organic chemistry reactions. One method entails the reaction of both the carbohydrate C 3 monoamine group of anthracyclines and the e-amine of lysine residues within the amino acid sequence of immunoglobulin with the aldehyde groups found in sodium periodate oxidized dextran.…”

An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer

“…29 According to the previous studies, therapeutic antibodies conjugated with MMAE showed high antitumor efficiency in patients with hematologic malignancies and solid tumors. [30][31][32][33][34][35][36] We utilized a humanized anti-HER2 antibody, hertuzumab, conjugated with MMAE via a cleavable linker to generate hertuzumab-MC-Val-Cit-PAB-MMAE (hertuzumabvcMMAE for short). Our previous study has proven this ADC agent has a potent antitumor activity in HER2 positive breast cancer.…”