VIS832, a novel CD138-targeting monoclonal antibody, potently induces killing of human multiple myeloma and further synergizes with IMiDs or bortezomib in vitro and in vivo

  • Blood Cancer J. 2020 Nov 2;10(11):110. doi: 10.1038/s41408-020-00378-z.
Tengteng Yu  1  2 ,  Bharat Chaganty  3 ,  Liang Lin  1 ,  Lijie Xing  1 ,  Boopathy Ramakrishnan  3 ,  Kenneth Wen  1 ,  Phillip A Hsieh  1 ,  Andrew Wollacott  3 ,  Karthik Viswanathan  3 ,  Hedy Adari  3 ,  Shih-Feng Cho  1  4  5 ,  Yuyin Li  1  6 ,  Hailin Chen  1  7 ,  Wenjuan Yang  1 ,  Yan Xu  1  2 ,  Gang An  2 ,  Lugui Qiu  2 ,  Nikhil Munshi  1 ,  Gregory Babcock  3 ,  Zachary Shriver  3 ,  James R Myette  3 ,  Kenneth C Anderson  8 ,  Yu-Tzu Tai  9
Affiliations
  • 1. Jerome Lipper Multiple Myeloma Center, LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 2. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Hematological Disorders, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China.
  • 3. Visterra Inc., Waltham, MA, USA.
  • 4. Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
  • 5. Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
  • 6. School of Biotechnology, Tianjin University of Science and Technology, Key Lab of Industrial Fermentation Microbiology of the Ministry of Education, State Key Laboratory of Food Nutrition and Safety, Tianjin, 300457, China.
  • 7. Hematology Department, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 8. Jerome Lipper Multiple Myeloma Center, LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. [email protected].
  • 9. Jerome Lipper Multiple Myeloma Center, LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. [email protected].
PMID: 33149123 DOI: 10.1038/s41408-020-00378-z
Abstract

Therapeutically targeting CD138, a define multiple myeloma (MM) antigen, is not yet approved for patients. We here developed and determined the preclinical efficacy of VIS832, a novel therapeutic monoclonal antibody (MoAb) with differentiated CD138 target binding to BB4 that is anti-CD138 MoAb scaffold for indatuximab ravtansine (BT062). VIS832 demonstrated enhanced CD138-binding avidity and significantly improved potency to kill MM cell lines and autologous patient MM cells regardless of resistance to current standard-of-care therapies, via robust antibody-dependent cellular cytotoxicity and phagocytosis mediated by NK and macrophage effector cells, respectively. Specifically, CD38-targeting daratumumab-resistant MM cells were highly susceptible to VIS832 which, unlike daratumumab, spares NK cells. Superior maximal cytolysis of VIS832 vs. daratumumab corresponded to higher CD138 vs. CD38 levels in MM cells. Furthermore, VIS832 acted synergistically with lenalidomide or bortezomib to deplete MM cells. Importantly, VIS832 at a sub-optimal dose inhibited disseminated MM1S tumors in vivo as monotherapy (P < 0.0001), and rapidly eradicated myeloma burden in all mice concomitantly receiving bortezomib, with 100% host survival. Taken together, these data strongly support clinical development of VIS832, alone and in combination, for the therapeutic treatment of MM in relapsed and refractory patients while pointing to its potential therapeutic use earlier in disease intervention.

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