Combined administration of antibodies to human interleukin 8 and epidermal growth factor receptor results in increased antimetastatic effects on human breast carcinoma xenografts.
OBJECTIVE
Current antibody-based immunotherapeutic approaches under evaluation for breast carcinoma are limited in target scope. For example, administration of the human epidermal growth factor receptor (EGFR) antibody, alone or in combination with a chemotherapeutic drug, is thought to primarily inhibit tumor cell proliferation. The aim of this study was to assess the effects of a combined blockade designed to inhibit tumor growth by inhibition of proliferation rate and the proinflammatory effects of interleukin (IL) 8.


METHODS
A human breast carcinoma cell line that produces high levels of IL-8 was injected s.c. into severe combined immunodeficient mice. IL-8 has been reported to augment the progression of some human tumors; thus, we used a human IL-8 antibody, ABXIL8, in combination with anti-EGFR, ABXEGFR, to inhibit the metastasis of MDA231 tumors.


RESULTS
Whereas anti-IL-8 alone had no appreciable antimetastatic effect, the combination of ABXIL8 significantly enhanced the antitumor effects of ABXEGFR, resulting in greater survival of SCID tumor-bearing mice. This effect on survival was correlated with decreased metastatic spread and decreased tumor size in mice receiving both antibodies. Intriguingly, in vitro studies indicate that this antibody combination markedly inhibited matrix metalloproteinase activity associated with MDA-231 cells to a greater degree than either antibody alone.


CONCLUSIONS
Combined administration of these two human antibodies using growth factor blockade in conjunction with chemokine blockade may thus provide a more effective approach for treatment of metastatic human breast carcinoma.
Salcedo
Rosalba
R
Laboratory of Molecular Immunoregulation, Division of Basic Sciences, Frederick Cancer Research and Development Center, National Cancer Institute, Maryland 21702-1201, USA.
Martins-Green
Manuela
M
Gertz
Barry
B
Oppenheim
Joost J
JJ
Murphy
William J
WJ
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D016209:Interleukin-8 / Q000276:immunology* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011233:Precipitin Tests; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000906:Antibodies; D000970:Antineoplastic Agents; D016209:Interleukin-8; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D018093:Gelatinases; D020780:Matrix Metalloproteinase 9