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CD8 monoclonal antibodies
Comparative Efficacy of Liposomal FK 506 With FK 506 (Tacrolimus) With and Without Anti-CD4/CD8 Monoclonal Antibodies S.D. Moffatt, V. McAlister, R.Y. Calne, and S.M. Metcalfe
F
K 506 is a potent immunosuppressant that has improved clinical outcomes in kidney and liver transplantation both as a primary and as a rescue agent.1 Despite these clear benefits, associated toxic side effects of this drug narrow its therapeutic index.2 Liposomal FK 506 (LipoFK506) was developed to minimize the side effect profile of FK 506 without lessening the immunosuppressive effectiveness of the drug.3 We test, in vivo, the efficacy of this novel formulation. We also examine if LipoFK506 can be used in combination with anti-CD4/CD8 monoclonal antibodies (MAbs).
tion by anti-CD4/CD8 MAbs (Table 1). Moreover, when tested by donor type and third-party type skin grafts, the tolerance generated by CD4/CD8 blockade in the presence of LipoFK506 remained donor specific. CONCLUSIONS
The liposomal formulation of FK 506 is efficacious at low blood drug levels. This potential for improved therapeutic index of LipoFK506 over tacrolimus may benefit patients requiring immunosuppression.
CERVICAL HEART TRANSPLANTATION The murine cervical heart allograft model was used.4 CBA/Ca (H2k) recipients were grafted with BALB/c (H2d) hearts, representing both minor and major histocompatibility mismatches. Untreated allografts and liposome-alone–treated allografts rejected on day 7.
IMMUNOSUPPRESSION Tacrolimus or LipoFK506 (1 mg/kg) (Moffatt et al, unpublished data, 1999) was given intraperitoneally (IP) daily for 14 days starting on day 0. Anti-CD4/CD8 (2 mg) MAbs were administered every second day from day 0 to day 12. Plasma FK 506 levels were measured on day 7.
RESULTS
Blood trough level of FK 506 in the tacrolimus group was 10-fold higher than that measured in the LipoFK506 group. In both groups, the median heart allograft survival time was 26 days. LipoFK506 did not interfere with tolerance induc-
REFERENCES 1. Pichlmayr R, Winkler M, Neuheus P, et al: Transplant Proc 29:2499, 1997 2. Mayer AD, Dmitrewski J, Squifflet JP, et al: Transplantation 64:436, 1997 3. Ko S, Nakajima Y, Kanehiro H, et al: Transplantation 59:1384, 1995 4. Chen Z: Transplantation 52:1099, 1991
From the Department of Surgery, Addenbrooke’s Hospital, Cambridge, United Kingdom; and the Department of Surgery, Dalhousie University, Halifax N.S., Canada. Supported by the Canadian Surgical Research Fund, the NATO International Scientific Exchange Program, and the Killam Postgraduate Research Fund (S.D.M.). Address reprint requests to Dr S.D. Moffatt, Department of Surgery, Addenbrooke’s Hospital, Cambridge UK, CB2 2QQ.
Table 1.
Group
BALB/c to CBA Heart Allografts Group Treatment
Median Graft Survival (d)
Range (d)
1 2 3 4 5 6 7
Nil Liposome LFK506 FK 506 LFK506 ⫹ MAbs FK 506 ⫹ MAbs MAbs
7 6 25 29 ⬎100 ⬎100 ⬎100
6, 7, 7, 7, 7, 7 6, 7, 6, 5, 6, 6 14, 25, 25, 25, 27, ⬎100 5,* 25, 27, 29, ⬎100, ⬎100 10,* 11,* ⬎100, ⬎100, ⬎100, ⬎100 9,* ⬎100, ⬎100, ⬎100, ⬎100, ⬎100 ⬎100 (all)
Mean Serum FK 506 (g/L) (d 7)
N/A 2.4 ⫾ 0.71SD 25.1 ⫾ 2.8 SD 6.9 ⫾ 1.7 SD 15.5 ⫾ 3.3 SD N/A
*Death.
0041-1345/99/$–see front matter PII S0041-1345(99)00553-9 2754
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 31, 2754 (1999)
F
K 506 is a potent immunosuppressant that has improved clinical outcomes in kidney and liver transplantation both as a primary and as a rescue agent.1 Despite these clear benefits, associated toxic side effects of this drug narrow its therapeutic index.2 Liposomal FK 506 (LipoFK506) was developed to minimize the side effect profile of FK 506 without lessening the immunosuppressive effectiveness of the drug.3 We test, in vivo, the efficacy of this novel formulation. We also examine if LipoFK506 can be used in combination with anti-CD4/CD8 monoclonal antibodies (MAbs).
tion by anti-CD4/CD8 MAbs (Table 1). Moreover, when tested by donor type and third-party type skin grafts, the tolerance generated by CD4/CD8 blockade in the presence of LipoFK506 remained donor specific. CONCLUSIONS
The liposomal formulation of FK 506 is efficacious at low blood drug levels. This potential for improved therapeutic index of LipoFK506 over tacrolimus may benefit patients requiring immunosuppression.
CERVICAL HEART TRANSPLANTATION The murine cervical heart allograft model was used.4 CBA/Ca (H2k) recipients were grafted with BALB/c (H2d) hearts, representing both minor and major histocompatibility mismatches. Untreated allografts and liposome-alone–treated allografts rejected on day 7.
IMMUNOSUPPRESSION Tacrolimus or LipoFK506 (1 mg/kg) (Moffatt et al, unpublished data, 1999) was given intraperitoneally (IP) daily for 14 days starting on day 0. Anti-CD4/CD8 (2 mg) MAbs were administered every second day from day 0 to day 12. Plasma FK 506 levels were measured on day 7.
RESULTS
Blood trough level of FK 506 in the tacrolimus group was 10-fold higher than that measured in the LipoFK506 group. In both groups, the median heart allograft survival time was 26 days. LipoFK506 did not interfere with tolerance induc-
REFERENCES 1. Pichlmayr R, Winkler M, Neuheus P, et al: Transplant Proc 29:2499, 1997 2. Mayer AD, Dmitrewski J, Squifflet JP, et al: Transplantation 64:436, 1997 3. Ko S, Nakajima Y, Kanehiro H, et al: Transplantation 59:1384, 1995 4. Chen Z: Transplantation 52:1099, 1991
From the Department of Surgery, Addenbrooke’s Hospital, Cambridge, United Kingdom; and the Department of Surgery, Dalhousie University, Halifax N.S., Canada. Supported by the Canadian Surgical Research Fund, the NATO International Scientific Exchange Program, and the Killam Postgraduate Research Fund (S.D.M.). Address reprint requests to Dr S.D. Moffatt, Department of Surgery, Addenbrooke’s Hospital, Cambridge UK, CB2 2QQ.
Table 1.
Group
BALB/c to CBA Heart Allografts Group Treatment
Median Graft Survival (d)
Range (d)
1 2 3 4 5 6 7
Nil Liposome LFK506 FK 506 LFK506 ⫹ MAbs FK 506 ⫹ MAbs MAbs
7 6 25 29 ⬎100 ⬎100 ⬎100
6, 7, 7, 7, 7, 7 6, 7, 6, 5, 6, 6 14, 25, 25, 25, 27, ⬎100 5,* 25, 27, 29, ⬎100, ⬎100 10,* 11,* ⬎100, ⬎100, ⬎100, ⬎100 9,* ⬎100, ⬎100, ⬎100, ⬎100, ⬎100 ⬎100 (all)
Mean Serum FK 506 (g/L) (d 7)
N/A 2.4 ⫾ 0.71SD 25.1 ⫾ 2.8 SD 6.9 ⫾ 1.7 SD 15.5 ⫾ 3.3 SD N/A
*Death.
0041-1345/99/$–see front matter PII S0041-1345(99)00553-9 2754
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 31, 2754 (1999)