- Email: [email protected]
Preclinical development of recombinant soluble T4 (sT4)
O r a l Session VI
Pharmacology and Animal Models
109 P r e e l l n i e u l Development of Recombinant Soluble T4 CsT4) P.3. Buselskl, K-L. L. Fong, H.A. Solleveld, A. Truneh, T.K. Hart, J.L. P e r r i , R. Kirnh sad D.G. Morgan. SmithKline Beecbu Pharmaceuticals Phil~ielphia~ PA USA Human immunodeficiency virus (HI~ i s helleved to be the cause of the acquired innunodeficiency disease (AIDS). I n f e c t i o n by HIY i s i n i t i a t e d by binding of the virus to CD4 (T4) on the surface of susceptible c e l l s . sT4 has been shown to i n h i b i t i n f e c t i v i t y and HlY-mediated syncy~ia fornstion in v i t r o and i s undergoing c l i n i c a l t r i a l s in AIDS. To f s c i l l t m t e these trlmlsp we conducted t o x i c i t y and pharmacukinetlc studies in rmts and cynomolKus macaques and g~mua scintigraphy studies in r a t s . sT4 vss admlnistered by i . v . bolus i n j e c t i o n . These studies showed t h a t sT4 has m short b i o l o g l c s l half l l f e ; the majority being eliminated during the mlpha elimination phane. Over 75S of the clearance of sT4 i s v i a the kidney. The studies revealed that the pri nci pal t o x i c i t y of sT4 was tubular cast nephropathy. Kidney lesions were observed in r a t s at or stove 200 nK/kg/dsy and in nonheys s t or stove 40 ng/kg/day. These doses are high n u l t l p l e s of the therapeutic dose. The lesions were charscterised by proteinsceous casts in d i s t a l convoluted tubules and c o l l e c t i n g ducts, associated with giant c e l l formation and PJ~s. An i n t e r s t i t i a l inflanmstory c e l l i n f i l t r a t e was associated with the affected tubules. The lesions are very similar to those observed in some patients with n u l t i p l e nyelona and in experimental Bence Jones protein nephropathy. There were no other siKnlficant t oxi c e f f e c t s i d e n t i f i e d in r a t s or nonkeys. The studies in monkeys revealed no evidence of innunosuppression i s assessed by l e c t i n medlsted blastogenesls sad mixed leukocyte reactions. There wore also no changes in leukocyte subsets sad no e f f e c t on delayed type hypersensitivity. An If~ response (anti-sT4 satibodies) wl8 foundj "~ndlc~tlnK that sT4 i s inmunoKenic in both r a t s and nonkeys.
Pharmacology and Animal Models
109 P r e e l l n i e u l Development of Recombinant Soluble T4 CsT4) P.3. Buselskl, K-L. L. Fong, H.A. Solleveld, A. Truneh, T.K. Hart, J.L. P e r r i , R. Kirnh sad D.G. Morgan. SmithKline Beecbu Pharmaceuticals Phil~ielphia~ PA USA Human immunodeficiency virus (HI~ i s helleved to be the cause of the acquired innunodeficiency disease (AIDS). I n f e c t i o n by HIY i s i n i t i a t e d by binding of the virus to CD4 (T4) on the surface of susceptible c e l l s . sT4 has been shown to i n h i b i t i n f e c t i v i t y and HlY-mediated syncy~ia fornstion in v i t r o and i s undergoing c l i n i c a l t r i a l s in AIDS. To f s c i l l t m t e these trlmlsp we conducted t o x i c i t y and pharmacukinetlc studies in rmts and cynomolKus macaques and g~mua scintigraphy studies in r a t s . sT4 vss admlnistered by i . v . bolus i n j e c t i o n . These studies showed t h a t sT4 has m short b i o l o g l c s l half l l f e ; the majority being eliminated during the mlpha elimination phane. Over 75S of the clearance of sT4 i s v i a the kidney. The studies revealed that the pri nci pal t o x i c i t y of sT4 was tubular cast nephropathy. Kidney lesions were observed in r a t s at or stove 200 nK/kg/dsy and in nonheys s t or stove 40 ng/kg/day. These doses are high n u l t l p l e s of the therapeutic dose. The lesions were charscterised by proteinsceous casts in d i s t a l convoluted tubules and c o l l e c t i n g ducts, associated with giant c e l l formation and PJ~s. An i n t e r s t i t i a l inflanmstory c e l l i n f i l t r a t e was associated with the affected tubules. The lesions are very similar to those observed in some patients with n u l t i p l e nyelona and in experimental Bence Jones protein nephropathy. There were no other siKnlficant t oxi c e f f e c t s i d e n t i f i e d in r a t s or nonkeys. The studies in monkeys revealed no evidence of innunosuppression i s assessed by l e c t i n medlsted blastogenesls sad mixed leukocyte reactions. There wore also no changes in leukocyte subsets sad no e f f e c t on delayed type hypersensitivity. An If~ response (anti-sT4 satibodies) wl8 foundj "~ndlc~tlnK that sT4 i s inmunoKenic in both r a t s and nonkeys.