Novel BAFF-Receptor Antibody to Natively Folded Recombinant Protein Eliminates Drug-Resistant Human B-cell Malignancies In Vivo

• Published in: Clinical cancer research 2018-03, Vol.24 (5), p.1114-1123
• Main Authors: Qin, Hong, Wei, Guowei, Sakamaki, Ippei, Dong, Zhenyuan, Cheng, Wesley A, Smith, D Lynne, Wen, Feng, Sun, Han, Kim, Kunhwa, Cha, Soungchul, Bover, Laura, Neelapu, Sattva S, Kwak, Larry W
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antibodies; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antibody-Dependent Cell Cytotoxicity - drug effects; Antibody-Dependent Cell Cytotoxicity - immunology; Anticancer properties; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Antitumor activity; B-Cell Activation Factor Receptor - antagonists & inhibitors; B-Cell Activation Factor Receptor - genetics; B-Cell Activation Factor Receptor - immunology; Biocompatibility; BLyS protein; Cancer; CD20 antigen; Cell Line, Tumor; Cell surface; Cytotoxicity; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - immunology; Experimental design; Growth inhibition; Humans; Hybridomas; Immunodeficiency; Immunoglobulins; Inhibitory Concentration 50; Leukemia; Lymphocytes B; Lymphoma; Lymphoma, B-Cell - blood; Lymphoma, B-Cell - drug therapy; Lymphoma, B-Cell - pathology; Mice; Mice, Inbred BALB C; Monoclonal antibodies; Patients; Protein Folding; Recombinant Proteins - genetics; Recombinant Proteins - immunology; Rituximab; Targeted cancer therapy; Therapy; Toxicity; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-1193

mAbs such as anti-CD20 rituximab are proven therapies in B-cell malignancies, yet many patients develop resistance. Novel therapies against alternative targets are needed to circumvent resistance mechanisms. We sought to generate mAbs against human B-cell-activating factor receptor (BAFF-R/TNFRSF13C), which has not yet been targeted successfully for cancer therapy. Novel mAbs were generated against BAFF-R, expressed as a natively folded cell surface immunogen on mouse fibroblast cells. Chimeric BAFF-R mAbs were developed and assessed for and monotherapy cytotoxicity. The chimeric mAbs were tested against human B-cell tumor lines, primary patient samples, and drug-resistant tumors. Chimeric antibodies bound with high affinity to multiple human malignant B-cell lines and induced potent antibody-dependent cellular cytotoxicity (ADCC) against multiple subtypes of human lymphoma and leukemia, including primary tumors from patients who had relapsed after anti-CD20 therapy. Chimeric antibodies also induced ADCC against ibrutinib-resistant and rituximab-insensitive CD20-deficient variant lymphomas, respectively. Importantly, they demonstrated remarkable growth inhibition of drug-resistant tumor models in immunodeficient mice. Our method generated novel anti-BAFF-R antibody therapeutics with remarkable single-agent antitumor effects. We propose that these antibodies represent an effective new strategy for targeting and treating drug-resistant B-cell malignancies and warrant further development. .