Hexamerization-enhanced CD20 antibody mediates complement-dependent cytotoxicity in serum genetically deficient in C9

被引：10

作者：

Taylor, Ronald P. ^{[1
,8
]}

Lindorfer, Margaret A. ^{[1
,8
]}

Cook, Erika M. ^{[1
,8
]}

Beurskens, Frank J. ^{[2
]}

Schuurman, Janine ^{[2
]}

Parren, Paul W. H. I. ^{[2
,3
,9
]}

Zent, Clive S. ^{[4
]}

VanDerMeid, Karl R. ^{[4
]}

Burack, Richard ^{[5
]}

Mizuno, Masashi ^{[6
]}

Morgan, B. Paul ^{[7
,10
]}

机构：

[1] Univ Virginia, Sch Med, Dept Biochem & Mol Genet, Charlottesville, VA 22903 USA

[2] Genmab, NL-3584 CM Utrecht, Netherlands

[3] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, Leiden, Netherlands

[4] Univ Rochester, Med Ctr, Wilmot Canc Inst, Rochester, NY 14627 USA

[5] Univ Rochester, Med Ctr, Pathol Dept, Rochester, NY 14627 USA

[6] Nagoya Univ, Grad Sch Med, Nagoya, Aichi, Japan

[7] Cardiff Univ, Sch Med, Div Infect & Immun, Cardiff, S Glam, Wales

[8] Univ Virginia, Sch Med, Biochem & Mol Genet, Box 800733, Charlottesville, VA 22908 USA

[9] Leiden Univ, Med Ctr, NL-2333 ZA Leiden, Netherlands

[10] Cardiff Univ, Sch Med, Cardiff CF14 4XN, S Glam, Wales

来源：

CLINICAL IMMUNOLOGY | 2017年 / 181卷

关键词：

Complement; Immunotherapy; Monoclonal antibodies; CHRONIC LYMPHOCYTIC-LEUKEMIA; CELL-LYSIS; IN-VITRO; RITUXIMAB; HEXAMERS; CD59;

D O I：

10.1016/j.clim.2017.05.016

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

We examined complement-dependent cytotoxicity (CDC) by hexamer formation-enhanced CD20 mAb Hx-7D8 of patient-derived chronic lymphocytic leukemia (CLL) cells that are relatively resistant to CDC. CDC was analyzed in normal human serum (NHS) and serum from an individual genetically deficient for C9. Hx-7D8 was able to kill up to 80% of CLL cells in complete absence of C9. We conclude that the narrow C5b-8 pores formed without C9 are sufficient for CDC due to efficient antibody-mediated hexamer formation. In the absence of C9, we observed transient intracellular increases of Ca2+ during CDC (as assessed with FLUO-4) that were extended in time. This suggests that small C5b-8 pores allow Ca2+ to enter the cell, while dissipation of the fluorescent signal accompanying cell disintegration is delayed. The Ca2+ signal is retained concomitantly with TOPRO-3 (viability dye) staining, thereby confirming that Ca2+ influx represents the most proximate mediator of cell death by CDC. (C) 2017 Elsevier Inc. All rights reserved.

引用

页码：24 / 28

页数：5

共 33 条

[31] A complement-dependent cytotoxicity-enhancing anti-CD20 antibody mediating potent antitumor activity in the humanized NOD/Shi-scid, IL-2Rγnull mouse lymphoma model
Fumihiko Sato
Asahi Ito
Takashi Ishida
Fumiko Mori
Hisashi Takino
Atsushi Inagaki
Masaki Ri
Shigeru Kusumoto
Hirokazu Komatsu
Shinsuke Iida
Noriko Okada
Hiroshi Inagaki
Ryuzo Ueda
Cancer Immunology, Immunotherapy, 2010, 59 : 1791 - 1800
[32] A complement-dependent cytotoxicity-enhancing anti-CD20 antibody mediating potent antitumor activity in the humanized NOD/Shi-scid, IL-2Rγnull mouse lymphoma model
Sato, Fumihiko
Ito, Asahi
Ishida, Takashi
Mori, Fumiko
Takino, Hisashi
Inagaki, Atsushi
Ri, Masaki
Kusumoto, Shigeru
Komatsu, Hirokazu
Iida, Shinsuke
Okada, Noriko
Inagaki, Hiroshi
Ueda, Ryuzo
CANCER IMMUNOLOGY IMMUNOTHERAPY, 2010, 59 (12) : 1791 - 1800
[33] Binding of Submaximal C1q Promotes Complement-Dependent Cytotoxicity (CDC) of B Cells Opsonized with Anti-CD20 mAbs Ofatumumab (OFA) or Rituximab (RTX): Considerably Higher Levels of CDC Are Induced by OFA than by RTX
Pawluczkowycz, Andrew W.
Beurskens, Frank J.
Beum, Paul V.
Lindorfer, Margaret A.
van de Winkel, Jan G. J.
Parren, Paul W. H. I.
Taylor, Ronald P.
JOURNAL OF IMMUNOLOGY, 2009, 183 (01): : 749 - 758

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