A comparison of the in vitro and in vivo activities of IgG and F(ab′)2 fragments of a mixture of three monoclonal anti-Her-2 antibodies

被引:75
作者
Spiridon, CI
Guinn, S
Vitetta, ES
机构
[1] Univ Texas, SW Med Sch, Ctr Canc Immunobiol, Dallas, TX 75390 USA
[2] Univ Texas, SW Med Sch, Med Student Training Program, Dallas, TX 75390 USA
关键词
D O I
10.1158/1078-0432.CCR-03-0549
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: We have demonstrated previously that a mixture of three anti-Her-2 monoclonal antibodies (MAbs) that bind to different epitopes on the extracellular domain of Her-2 expressed on a human breast cancer cell line has more potent antitumor activity than the individual MAbs both in vitro and in xenografted severe combined immunodeficient mice. Because the activity of Herceptin is Fc dependent, we determined whether this would also be the, case when a mixture of these three anti-Her-2 MAbs was used. Experimental Design: IgG and highly purified F(ab')2 fragments of the anti-Her-2 MAbs and Herceptin were prepared and evaluated for their ability to induce cell death, inhibit vascular endothelial growth factor secretion, and mediate antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity in vitro. They were also compared for their abilities to induce regression of large BT474 tumors in severe combined immunodeficient mice. Results: All of the F(ab')2 fragments were >95% pure and, as expected, did not mediate antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity in vitro. The in vitro antiproliferative and proapoptotic effects of the IgGs and F(ab')2 fragments were similar. In contrast, the IgGs had significant antitumor activity in! vivo, whereas their F(ab')2 fragments were only marginally effective even at 5-fold higher doses to offset their shorter half-lives. Conclusions: These results confirm the importance of the Fc portion of Herceptin for optimal in vivo activity and demonstrate that even a mixture of three anti-Her-2 MAbs that are highly effective at inducing cell death in vitro requires Fc-mediated effector function for optimal in vivo activity.
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页码:3542 / 3551
页数:10
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[1]   The ErbB signaling network in embryogenesis and oncogenesis: Signal diversification through combinatorial ligand-receptor interactions [J].
Alroy, I ;
Yarden, Y .
FEBS LETTERS, 1997, 410 (01) :83-86
[2]   Clinical trials of Herceptin® (trastuzumab) [J].
Baselga, J .
EUROPEAN JOURNAL OF CANCER, 2001, 37 :S18-S24
[3]   Phase II study of weekly intravenous recombinant humanized Anti-p185(HER2) monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast [J].
Baselga, J ;
Tripathy, D ;
Mendelsohn, J ;
Baughman, S ;
Benz, CC ;
Dantis, L ;
Sklarin, NT ;
Seidman, AD ;
Hudis, CA ;
Moore, J ;
Rosen, PP ;
Twaddell, T ;
Henderson, IC ;
Norton, L .
JOURNAL OF CLINICAL ONCOLOGY, 1996, 14 (03) :737-744
[4]   EVIDENCE OF FUNCTIONAL LYMPHOCYTES IN SOME (LEAKY) SCID MICE [J].
BOSMA, GC ;
FRIED, M ;
CUSTER, RP ;
CARROLL, A ;
GIBSON, DM ;
BOSMA, MJ .
JOURNAL OF EXPERIMENTAL MEDICINE, 1988, 167 (03) :1016-1033
[5]   Fc receptors are required in passive and active immunity to melanoma [J].
Clynes, R ;
Takechi, Y ;
Moroi, Y ;
Houghton, A ;
Ravetch, JV .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (02) :652-656
[6]   Modulation of immune complex-induced inflammation in vivo by the coordinate expression of activation and inhibitory Fc receptors [J].
Clynes, R ;
Maizes, JS ;
Guinamard, R ;
Ono, M ;
Takai, T ;
Ravetch, JV .
JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 189 (01) :179-185
[7]   Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis [J].
Clynes, R ;
Dumitru, C ;
Ravetch, JV .
SCIENCE, 1998, 279 (5353) :1052-1054
[8]   CYTOTOXIC ANTIBODIES TRIGGER INFLAMMATION THROUGH FC-RECEPTORS [J].
CLYNES, R ;
RAVETCH, JV .
IMMUNITY, 1995, 3 (01) :21-26
[9]   Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets [J].
Clynes, RA ;
Towers, TL ;
Presta, LG ;
Ravetch, JV .
NATURE MEDICINE, 2000, 6 (04) :443-446
[10]   Natural killer cell cytotoxicity of breast cancer targets is enhanced by two distinct mechanisms of antibody-dependent cellular cytotoxicity against LFA-3 and HER2/neu [J].
Cooley, S ;
Burns, LJ ;
Repka, T ;
Miller, JS .
EXPERIMENTAL HEMATOLOGY, 1999, 27 (10) :1533-1541