Rapamycin in Experimental Renal Allografts in Primates
`D. st. J. Collier, R.Y. Caine, S.G. Pollard, P.J: Friend, and S. Thiru
`
`WE have reported' that rapamycin, a lipophylic mac(cid:173)
`
`rolide antifungal antibiotic, produced by Strepto(cid:173)
`myces hydroscopiclIs, prolongs survival of rat cardiac
`allografts in a dose-dependent fashion. In the pig renal
`'allograft model, a state of operational tolerance was
`achieved in three of nine animals after dosing at 2 mg/kg
`for up to 64 days following transplantation, and the five
`remaining animals died of the effects of overimmunosup(cid:173)
`pression with functioning grafts. In dogs receiving rap a(cid:173)
`mycin, vomiting and bloody diarrhea associated with ul(cid:173)
`ceration of the gastrointestinal tract and thrombocytopenia
`occurred at doses from 5 to 0.25 mg/kg per day. Histolog(cid:173)
`ical examination of the ulcers showed an underlying ne(cid:173)
`crotising fibrinoid vasculitis of arterioles and small arteries
`similar to that seen in dogs receiving FK 506.
`
`MATERIALS AND METHODS
`
`Renal allografts were performed between nephrectomised young
`outbred baboons with a negative crossmatch selected into pairs on
`the basis of histoincompatibility, using mixed lymphocyte reac(cid:173)
`tions.
`
`Dosing Schedule
`
`Controls (n = 3). No drug administered.
`Group 1 (11 = 4). Rapamycin was given 2 mg/kg orally days -1
`through 9.
`Group 2 (11 = 3). Four hundred sixty-four received rapamycin
`orally 2 mg/kg days -1 to 6, then 2 mg/kg intramuscularly days 7
`to 13, I mg/kg days 14 to 15,0.5 mg/kg days 16 to 19; 739 received
`rapamycin orally 50 mg/kg days 0 to 5, 5 mg/kg days 6 to 7, then
`intravenously I mg/kg days 12 to 15, 17 to 12; 526 received
`rapamycin intravenously 2 mg/kg days 0 to 7, 1 mg/kg days 8 to 11,
`0.5 mg/kg days 12 to 17.
`Group 3 (n = 3). Rapamycin given intravenously 1 mg/kg days
`o to 1, then orally either 25 or 10 mg/kg on alternate days, with
`individualised dose modifications.
`
`RESULTS
`
`In all animals, loss of appetite for formulated diet was
`noted, together with intermittent episodes of vomiting and
`
`Table 1. Survival of and Histological Findings in Baboons
`Receiving Rapamycin Following Renal Allografting
`
`.....
`
`." l
`
`f."I
`Z
`.....
`Z
`(::
`~
`~
`U
`
`::;:l -:
`
`f."I
`Z
`Z
`(::
`~
`f."I
`~
`U
`
`~
`El
`f."I
`Z
`Z
`~
`~
`U
`
`4
`
`2
`
`2
`
`0
`
`-1
`
`2
`
`0
`
`GROUP]
`
`--<>-
`--+--
`
`571
`
`756
`
`-- 596
`
`-<>- 454
`
`·1
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9 10
`
`DAY
`
`GROUP 2
`
`-<>--
`---a--
`--+--
`
`464
`739
`526
`
`19
`
`24
`
`29
`
`14
`DAY
`
`GROUP 3
`
`-<>--
`
`474
`
`-- 476
`- 736
`
`-1
`
`4
`
`9
`
`14 19 24 29 34 39 44 49
`DAY
`
`Fig 1. Serum creatinine of baboons given rapamycin after renal
`allografting.
`
`Group
`
`Controls
`1
`2
`3
`
`'Rejection.
`tVasculitis.
`"Granulomatous infection.
`
`2246
`
`Survival in Days
`
`8,9,11
`6*, 7,* 9,t 9t
`25*, 18,t" 25"
`32,*t 36,*t 40*t
`
`From the Departments of Surgery and Pathology, University of
`Cambridge, Addenbrooke's Hospital, Cambridge, England.
`Address reprint requests to D. Sl. J. Collier, Departments of
`Surgery and Pathology, University of Cambridge, Addenbrooke's
`Hospital, Cambridge, CB2 2QQ UK.
`© 1991 by Appleton & Lange
`0041-1345/91/$3.00/+0
`
`Transplantation Proce~dings, Vol 23, No 4 (August), 199j: pp 2246-2247
`
`NOVARTIS EXHIBIT 2144
`Par v Novartis, IPR 2016-00084
`Page 1 of 2
`
`

`
`RAPAMYCIN IN RENAL ALLOGRAFTS
`
`2247
`
`diarrhea. The survival of animals is shown in Table 1 and
`the serum creatinine in Fig 1. In group 1, two animals
`developed severe rejection in a time similar to that found in
`controls. The remaining animal was -killed because of
`severe vomiting and collapse, had moderate focal rejection
`and fibrinoid vasculitis affecting the gut. In group 2, two
`animals were killed because they became lethargic and
`unwell, both had granulomatous infection but no rejection;
`however, one had a vasculitis affecting the gut. The third
`animal developed very painful injection sites, dosing was
`withdrawn, and death from rejection occurred. In group 3,
`all three animals showed evidence of toxicity with leth(cid:173)
`argy, vomiting, and diarrhea, and even a small dose
`reduction of 1 mg/kg lead to irreversible rejection; all
`showed evidence of vasculitis affecting the gut.
`
`DISCUSSION
`
`The results of the pig are encouraging-in three animals, a
`state of operational tolerance appeared to develop, further(cid:173)
`more, rapamycin seemed effective in the rat with few side
`effects. Rapamycin was immunosuppressive in the ba(cid:173)
`boon, but the development of vasculitis in the baboon
`similar to that seen in the dog, is of concern as thi~
`phenomenon can no longer be described as species spe(cid:173)
`cific. Further toxicology and the development of an assay
`must precede clinical trials.
`
`REFERENCE
`1. Caine RY, Collier DS, Lim S, et al: Lancet ii:227, 1989
`
`NOVARTIS EXHIBIT 2144
`Par v Novartis, IPR 2016-00084
`Page 2 of 2