Novel baff-receptor antibody to natively folded recombinant protein eliminates drug-resistant human b-cell malignancies in vivo

Hong Qin, Guowei Wei, Ippei Sakamaki, Zhenyuan Dong, Wesley A. Cheng, D. Lynne Smith, Feng Wen, Han Sun, Kunhwa Kim, Soungchul Cha, Laura Bover, Sattva S. Neelapu, Larry W. Kwak

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Purpose: 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. Experimental Design: 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 in vitro and in vivo monotherapy cytotoxicity. The chimeric mAbs were tested against human B-cell tumor lines, primary patient samples, and drug-resistant tumors. Results: 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 in vivo growth inhibition of drug-resistant tumor models in immunodeficient mice. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)1114-1123
Number of pages10
JournalClinical Cancer Research
Volume24
Issue number5
DOIs
StatePublished - Mar 1 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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