Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma

Yu Tzu Tai, Patrick A. Mayes, Chirag Acharya, Mike Y. Zhong, Michele Cea, Antonia Cagnetta, Jenny Craigen, John Yates, Louise Gliddon, William Fieles, Bao Hoang, James Tunstead, Amanda L. Christie, Andrew L. Kung, Paul Richardson, Nikhil C. Munshi, Kenneth C. Anderson

Research output: Contribution to journalArticle

Abstract

B-cell maturation antigen (BCMA), highly expressed on malignant plasma cells in human multiple myeloma (MM), has not been effectively targeted with therapeutic monoclonal antibodies. We here show that BCMA is universally expressed on the MM cell surface and determine specific anti-MM activity of J6M0-mcMMAF (GSK2857916), a novel humanized and afucosylated antagonistic anti-BCMA antibody-drug conjugate via a noncleavable linker. J6M0-mcMMAF specifically blocks cell growth via G2/M arrest and induces caspase 3-dependent apoptosis in MM cells, alone and in coculture with bone marrow stromal cells or various effector cells. It strongly inhibits colony formation by MM cells while sparing surrounding BCMA-negative normal cells. J6M0-mcMMAF significantly induces effector cell-mediated lysis against allogeneic or autologous patient MM cells, with increased potency and efficacy compared with the wild-type J6M0 without Fc enhancement. The antibody-dependent cell-mediated cytotoxicity and apoptotic activity of J6M0-mcMMAF is further enhanced by lenalidomide. Importantly, J6M0-mcMMAF rapidly eliminates myeloma cells in subcutaneous and disseminated mouse models, and mice remain tumor-free up to 3.5 months. Furthermore, J6M0-mcMMAF recruits macrophages and mediates antibody-dependent cellular phagocytosis of MM cells. Together, these results demonstrate that GSK2857916 has potent and selective anti-MM activities via multiple cytotoxic mechanisms, providing a promising next-generation immunotherapeutic in this cancer.

Original languageEnglish
Pages (from-to)3128-3138
Number of pages11
JournalBlood
Volume123
Issue number20
DOIs
Publication statusPublished - May 15 2014

Fingerprint

B-Cell Maturation Antigen
Multiple Myeloma
Antibodies
Pharmaceutical Preparations
Macrophages
Cell growth
Cytotoxicity
Caspase 3
Tumors
Bone
Monoclonal Antibodies
Apoptosis
Plasmas
Antibody-Dependent Cell Cytotoxicity
Coculture Techniques
Plasma Cells
Mesenchymal Stromal Cells
Phagocytosis

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. / Tai, Yu Tzu; Mayes, Patrick A.; Acharya, Chirag; Zhong, Mike Y.; Cea, Michele; Cagnetta, Antonia; Craigen, Jenny; Yates, John; Gliddon, Louise; Fieles, William; Hoang, Bao; Tunstead, James; Christie, Amanda L.; Kung, Andrew L.; Richardson, Paul; Munshi, Nikhil C.; Anderson, Kenneth C.

In: Blood, Vol. 123, No. 20, 15.05.2014, p. 3128-3138.

Research output: Contribution to journalArticle

Tai, YT, Mayes, PA, Acharya, C, Zhong, MY, Cea, M, Cagnetta, A, Craigen, J, Yates, J, Gliddon, L, Fieles, W, Hoang, B, Tunstead, J, Christie, AL, Kung, AL, Richardson, P, Munshi, NC & Anderson, KC 2014, 'Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma', Blood, vol. 123, no. 20, pp. 3128-3138. https://doi.org/10.1182/blood-2013-10-535088
Tai, Yu Tzu ; Mayes, Patrick A. ; Acharya, Chirag ; Zhong, Mike Y. ; Cea, Michele ; Cagnetta, Antonia ; Craigen, Jenny ; Yates, John ; Gliddon, Louise ; Fieles, William ; Hoang, Bao ; Tunstead, James ; Christie, Amanda L. ; Kung, Andrew L. ; Richardson, Paul ; Munshi, Nikhil C. ; Anderson, Kenneth C. / Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. In: Blood. 2014 ; Vol. 123, No. 20. pp. 3128-3138.
@article{c7404c2fc6f244ebb3485b5207d7567a,
title = "Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma",
abstract = "B-cell maturation antigen (BCMA), highly expressed on malignant plasma cells in human multiple myeloma (MM), has not been effectively targeted with therapeutic monoclonal antibodies. We here show that BCMA is universally expressed on the MM cell surface and determine specific anti-MM activity of J6M0-mcMMAF (GSK2857916), a novel humanized and afucosylated antagonistic anti-BCMA antibody-drug conjugate via a noncleavable linker. J6M0-mcMMAF specifically blocks cell growth via G2/M arrest and induces caspase 3-dependent apoptosis in MM cells, alone and in coculture with bone marrow stromal cells or various effector cells. It strongly inhibits colony formation by MM cells while sparing surrounding BCMA-negative normal cells. J6M0-mcMMAF significantly induces effector cell-mediated lysis against allogeneic or autologous patient MM cells, with increased potency and efficacy compared with the wild-type J6M0 without Fc enhancement. The antibody-dependent cell-mediated cytotoxicity and apoptotic activity of J6M0-mcMMAF is further enhanced by lenalidomide. Importantly, J6M0-mcMMAF rapidly eliminates myeloma cells in subcutaneous and disseminated mouse models, and mice remain tumor-free up to 3.5 months. Furthermore, J6M0-mcMMAF recruits macrophages and mediates antibody-dependent cellular phagocytosis of MM cells. Together, these results demonstrate that GSK2857916 has potent and selective anti-MM activities via multiple cytotoxic mechanisms, providing a promising next-generation immunotherapeutic in this cancer.",
author = "Tai, {Yu Tzu} and Mayes, {Patrick A.} and Chirag Acharya and Zhong, {Mike Y.} and Michele Cea and Antonia Cagnetta and Jenny Craigen and John Yates and Louise Gliddon and William Fieles and Bao Hoang and James Tunstead and Christie, {Amanda L.} and Kung, {Andrew L.} and Paul Richardson and Munshi, {Nikhil C.} and Anderson, {Kenneth C.}",
year = "2014",
month = "5",
day = "15",
doi = "10.1182/blood-2013-10-535088",
language = "English",
volume = "123",
pages = "3128--3138",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "20",

}

TY - JOUR

T1 - Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma

AU - Tai, Yu Tzu

AU - Mayes, Patrick A.

AU - Acharya, Chirag

AU - Zhong, Mike Y.

AU - Cea, Michele

AU - Cagnetta, Antonia

AU - Craigen, Jenny

AU - Yates, John

AU - Gliddon, Louise

AU - Fieles, William

AU - Hoang, Bao

AU - Tunstead, James

AU - Christie, Amanda L.

AU - Kung, Andrew L.

AU - Richardson, Paul

AU - Munshi, Nikhil C.

AU - Anderson, Kenneth C.

PY - 2014/5/15

Y1 - 2014/5/15

N2 - B-cell maturation antigen (BCMA), highly expressed on malignant plasma cells in human multiple myeloma (MM), has not been effectively targeted with therapeutic monoclonal antibodies. We here show that BCMA is universally expressed on the MM cell surface and determine specific anti-MM activity of J6M0-mcMMAF (GSK2857916), a novel humanized and afucosylated antagonistic anti-BCMA antibody-drug conjugate via a noncleavable linker. J6M0-mcMMAF specifically blocks cell growth via G2/M arrest and induces caspase 3-dependent apoptosis in MM cells, alone and in coculture with bone marrow stromal cells or various effector cells. It strongly inhibits colony formation by MM cells while sparing surrounding BCMA-negative normal cells. J6M0-mcMMAF significantly induces effector cell-mediated lysis against allogeneic or autologous patient MM cells, with increased potency and efficacy compared with the wild-type J6M0 without Fc enhancement. The antibody-dependent cell-mediated cytotoxicity and apoptotic activity of J6M0-mcMMAF is further enhanced by lenalidomide. Importantly, J6M0-mcMMAF rapidly eliminates myeloma cells in subcutaneous and disseminated mouse models, and mice remain tumor-free up to 3.5 months. Furthermore, J6M0-mcMMAF recruits macrophages and mediates antibody-dependent cellular phagocytosis of MM cells. Together, these results demonstrate that GSK2857916 has potent and selective anti-MM activities via multiple cytotoxic mechanisms, providing a promising next-generation immunotherapeutic in this cancer.

AB - B-cell maturation antigen (BCMA), highly expressed on malignant plasma cells in human multiple myeloma (MM), has not been effectively targeted with therapeutic monoclonal antibodies. We here show that BCMA is universally expressed on the MM cell surface and determine specific anti-MM activity of J6M0-mcMMAF (GSK2857916), a novel humanized and afucosylated antagonistic anti-BCMA antibody-drug conjugate via a noncleavable linker. J6M0-mcMMAF specifically blocks cell growth via G2/M arrest and induces caspase 3-dependent apoptosis in MM cells, alone and in coculture with bone marrow stromal cells or various effector cells. It strongly inhibits colony formation by MM cells while sparing surrounding BCMA-negative normal cells. J6M0-mcMMAF significantly induces effector cell-mediated lysis against allogeneic or autologous patient MM cells, with increased potency and efficacy compared with the wild-type J6M0 without Fc enhancement. The antibody-dependent cell-mediated cytotoxicity and apoptotic activity of J6M0-mcMMAF is further enhanced by lenalidomide. Importantly, J6M0-mcMMAF rapidly eliminates myeloma cells in subcutaneous and disseminated mouse models, and mice remain tumor-free up to 3.5 months. Furthermore, J6M0-mcMMAF recruits macrophages and mediates antibody-dependent cellular phagocytosis of MM cells. Together, these results demonstrate that GSK2857916 has potent and selective anti-MM activities via multiple cytotoxic mechanisms, providing a promising next-generation immunotherapeutic in this cancer.

UR - http://www.scopus.com/inward/record.url?scp=84901433313&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901433313&partnerID=8YFLogxK

U2 - 10.1182/blood-2013-10-535088

DO - 10.1182/blood-2013-10-535088

M3 - Article

C2 - 24569262

AN - SCOPUS:84901433313

VL - 123

SP - 3128

EP - 3138

JO - Blood

JF - Blood

SN - 0006-4971

IS - 20

ER -