IMMUNOTHERAPY OF HUMAN TUMOR XENOGRAFTS OVEREXPRESSING THE EGF RECEPTOR WITH RAT ANTIBODIES THAT BLOCK GROWTH FACTOR-RECEPTOR INTERACTION

被引:65
作者
MODJTAHEDI, H [1 ]
ECCLES, S [1 ]
BOX, G [1 ]
STYLES, J [1 ]
DEAN, C [1 ]
机构
[1] INST CANC RES,HADDOW LABS,IMMUNOL SECT,15 COTSWOLD RD,SUTTON SM2 5NG,SURREY,ENGLAND
关键词
D O I
10.1038/bjc.1993.49
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Athymic mice bearing xenografts of human tumours that overexpress the receptor (EGFR) for EGF and TGFalpha have been used to evaluate the therapeutic potential of three new rat monoclonal antibodies (mAbs) directed against two distinct epitopes on the extracellular domain of the human EGFR. The antibodies, ICR16 (IgG2a), ICR62 (IgG2b) and ICR64 (IgG1), have been shown (Modjtahedi et al., 1993) to be potent inhibitors of the growth in vitro of a number of human squamous cell carcinomas because they block receptor-ligand interaction. When given i.p. at 200 mug dose, the three antibodies were found to induce complete regression of xenografts of the HN5 tumour if treatment with antibody commenced at the time of tumour implantation (total doses: ICR16, 3.0 mg; ICR62, 1.2 mg; ICR64, 2.2 mg). More importantly when treatment was delayed until the tumours were established (mean diam. 0.5 cm) both ICR16 and ICR62 induced complete or almost complete regression of the tumours. Furthermore, treatment with a total dose of only 0.44 mg of ICR62 was found to induce complete remission of xenografts -of the breast carcinoma MDA-MB 468, but ICR16 was less effective at this dose of antibody and only 4/8 tumours regressed completely. ICR16 and ICR62 were poor inhibitors of the growth in vitro of the vulval carcinoma A431, but both induced a substantial delay in the growth of xenografts of this tumour and 4/8 tumours regressed completely in the mice treated with ICR62 (total dose 2.2 mg). Although ICR16 and ICR64 were more effective than ICR62 as growth inhibitors in vitro, ICR62 was found to be substantially better at inducing regression of the tumour xenografts due perhaps to additional activation of host immune effector functions by the IgG2b antibody. We conclude that these antibodies may be useful therapeutic agents that can be used alone without conjugation to other cytotoxic moieties.
引用
收藏
页码:254 / 261
页数:8
相关论文
共 37 条
  • [1] EFFICACY OF ANTIBODIES TO EPIDERMAL GROWTH-FACTOR RECEPTOR AGAINST KB CARCINOMA INVITRO AND IN NUDE-MICE
    ABOUDPIRAK, E
    HURWITZ, E
    PIRAK, ME
    BELLOT, F
    SCHLESSINGER, J
    SELA, M
    [J]. JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1988, 80 (20) : 1605 - 1611
  • [2] BRADY LW, 1991, INT J RADIAT ONCOL, V22, P225
  • [3] INCREASED EGF RECEPTORS ON HUMAN SQUAMOUS CARCINOMA CELL-LINES
    COWLEY, GP
    SMITH, JA
    GUSTERSON, BA
    [J]. BRITISH JOURNAL OF CANCER, 1986, 53 (02) : 223 - 229
  • [4] DEAN CJ, 1984, CLIN EXP IMMUNOL, V57, P358
  • [5] DERYNCK R, 1987, CANCER RES, V47, P707
  • [6] DIMARCO E, 1990, NAT IMMUN CELL GROW, V9, P209
  • [7] DIMARCO E, 1989, ONCOGENE, V4, P831
  • [8] PHASE-I AND IMAGING TRIAL OF INDIUM-111-LABELED ANTIEPIDERMAL GROWTH-FACTOR RECEPTOR MONOCLONAL-ANTIBODY 225 IN PATIENTS WITH SQUAMOUS-CELL LUNG-CARCINOMA
    DIVGI, CR
    WELT, S
    KRIS, M
    REAL, FX
    YEH, SDJ
    GRALLA, R
    MERCHANT, B
    SCHWEIGHART, S
    UNGER, M
    LARSON, SM
    MENDELSOHN, J
    [J]. JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1991, 83 (02) : 97 - 104
  • [9] DYER MJS, 1989, BLOOD, V73, P1431
  • [10] EASTY DM, 1981, BRIT J CANCER, V43, P772, DOI 10.1038/bjc.1981.115