CNTO 328, a monoclonal antibody to IL-6, inhibits human tumor-induced cachexia in nude mice.
IL-6 is a multifunctional cytokine implicated in several cancers. IL-6 is a growth factor for certain tumors and contributes to drug resistance, cachexia and bone resorption. Cachexia is characterized by progressive weight loss and depletion of host reserves of adipose tissue and skeletal muscle. We have developed CNTO 328 (cCLB8), a human-mouse chimeric MAb to IL-6 (K(d) approx. 10(-12) M) that inhibits IL-6 function. A phase I study with CNTO 328 in multiple myeloma patients demonstrated that the antibody was safe and had a circulating half-life of approximately 17 days. Since IL-6 is implicated in cachexia, we hypothesized that CNTO 328 could inhibit tumor-induced cachexia. We used 2 human tumor-induced cachexia models in nude mice. In the first model, human melanoma cells were inoculated in female nude mice. Control treated animals lost 19% (+/-7.7%) body weight from day 0 to day 31, whereas CNTO 328 (10 mg/kg)-treated animals lost only 1.5% (+/-1.3%) body weight from day 0 to day 31 (p = 0.023). In the second cachexia model, human prostate tumor cells were injected into male nude mice. By day 29, control treated animals lost 6% (+/-3.5%) body weight, whereas CNTO 328 (10 mg/kg)-treated animals gained 7% (+/-4%) body weight (p = 0.01). Since CNTO 328 blocks human IL-6 but not mouse IL-6, the data indicate that tumor cell-secreted IL-6 directly contributes to body weight loss, highlighting the potential role for CNTO 328 as an anticachectic agent.
Zaki
Mohamed H
MH
Oncology Research, Centocor, Inc., Malvern, PA 19355-1307, USA.
Nemeth
Jeffrey A
JA
Trikha
Mohit
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001835:Body Weight; D002100:Cachexia / Q000276:immunology* / Q000628:therapy*; D004195:Disease Models, Animal; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology* / Q000494:pharmacology*; D008297:Male; D008545:Melanoma / Q000150:complications* / Q000662:veterinary; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000150:complications* / Q000662:veterinary; D012878:Skin Neoplasms / Q000150:complications* / Q000662:veterinary; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D015850:Interleukin-6