Monotherapy with LF 15-0195, an analogue of 15-deoxyspergualin, significantly prolongs renal allograft survival in monkeys

• Published in: Transplantation Vol. 75; no. 8; p. 1166
• Main Authors: Yang, Hongji, Chen, Gang, Kanai, Nobuyuki, Shum, Jeffrey, Garcia, Bertha, Huang, Xuyan, Min, Weiping, Luo, Yigang, Dutartre, Patrick, Zhong, Robert
• Format: Journal Article
• Language: English
• Published: United States 27.04.2003
• Subjects: Animals; Diarrhea - chemically induced; Dose-Response Relationship, Drug; Graft Rejection - prevention & control; Graft Survival - drug effects; Guanidines - administration & dosage; Guanidines - adverse effects; Guanidines - pharmacology; Immunoglobulin G - analysis; Immunoglobulin M - analysis; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - pharmacology; Kidney - drug effects; Kidney - pathology; Kidney - physiopathology; Kidney Transplantation; Lymphocyte Count; Macaca fascicularis; Osmolar Concentration; Time Factors; Transplantation, Homologous
• ISSN: 0041-1337
• DOI: 10.1097/01.TP.0000062841.89728.CF

LF 15-0195 is a novel, more potent, and less toxic analogue of 15-deoxyspergualin, an antibiotic used as an immunosuppressive agent to prevent rejection of organ transplants. This study was undertaken to determine whether LF 15-0195 monotherapy would prevent renal allograft rejection in a nonhuman primate model. In the study groups, recipients received LF 15-0195 monotherapy at doses of 0.065 mg/kg per day (group 2, n=4), 0.13 mg/kg per day (group 3, n=4), or 0.2 mg/kg per day (group 4, n=4), administered subcutaneously, on postoperative days 0 to 14. Group 1 consisted of untreated control recipients, all of which developed advanced graft rejection after surviving for an average of 6.5+/-0.6 days. LF 15-0195 treatment significantly prolonged graft survival in groups 2, 3, and 4, to 20+/-20 days, 49+/-5 days, and 39+/-4 days, respectively. Animals in groups 3 and 4 demonstrated no evidence of rejection during LF 15-0195 treatments. The animals maintained stable renal function for 2 weeks after LF 15-0195 withdrawal but gradually developed rejection at 5 to 6 weeks. Pathologic studies demonstrated that vascular graft rejection was attenuated in LF 15-0195-treated allografts, compared with control specimens. These groups also demonstrated transient reductions in lymphocyte counts during treatment, which returned to normal levels 2 weeks after LF 15-0195 withdrawal. Total serum concentrations of IgM and IgG decreased by a mean of 20.4% and a mean of 31.4%, respectively, at the end of LF 15-0195 treatment (postoperative day 14). LF 15-0195 did not significantly alter thrombocyte counts or hemoglobin levels. Necropsy studies showed no evidence of drug toxicity in the heart, liver, spleen, intestines, stomach, or colon. LF 15-0195 monotherapy significantly prolonged renal allograft survival in monkeys. These encouraging data suggest that this novel agent may be of future value in clinical transplantation.