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Monoclonal antibodies as pharmacological agents
Abstracts
629
MONOCLONAL ANTIBODIES AS PHARMACOLOGICAL AGENTS
C O M P A R I S O N OF T H E A N T I T U M O U R E F F E C T S OF T W O A N T I - T H Y PREPARED WITH DIFFERENT COUPLING AGENTS. P.E. T h o r p e , A.N. B r o w n and G.$. W a t s o n . I m p e r i a l C a n c e r R e s e a r c h Fund, L o n d o n .
1.1ABRIN
A CONJUGATES
52
Monoclonal a n t i - T h y 1.1 a n t i b o d y was l i n k e d to a b r i n A - c h a i n u s i n g e i t h e r the S P D P r e a g e n t or 2 - i m i n o t h i o l a n e . The l i n k a g e g e n e r a t e d by the S P D P reagent contains a disulphide bond and an amide bond, whereas that generated by 2 - i m i n o t h i o l a n e contains a disulphide b o n d and an a m i d i n e bond. T h e a n t i t u m o u r a c t i v i t y of the c o n j u g a t e m a d e w i t h 2 - i m i n o t h i o l a n e in m i c e bearing Thy 1.l-expressing l y m p h o m a a l l o g r a f t s w a s 100 to 1 0 0 0 - f o l d b e t t e r t h a n t h a t of the c o n j u g a t e m a d e w i t h the S P D P r e a g e n t . The r e a s o n For this difference is u n k n o w n . The c o n j u g a t e s are e q u a l l y t o x i c to the l y m p h o m a c e l l s in v i t r o , h a v e the same in v i v o h a l f - l i f e and s p l i t up at the s a m e r a t e in the b l o o d s t r e a m to r e l e a s e Free a n t i b o d y and A - c h a i n .
BREAST CANCER IMMUNOTOXINS. A. F r a n k e l , J. W i n k e l h a k e , D. Ring, A. C r e a s e y and L. H o u s t o n . Cetus Corporation, 1400 Fifty-third USA.
53 M.
Bjorn,
Street,
R. F e r r i s ,
Emeryville
C. Vitt,
California
94604
Mouse monoclonal antibodies reactive with breast cancer were prepared. A n u m b e r of t h e s e w e r e r e a c t i v e w i t h the m a j o r i t y of b r e a s t c a n c e r but b o u n d very few n o r m a l tissue substructures. These were conjugated with ricin A - c h a i n and some w e r e F o u n d to be h i g h l y t o x i c to b r e a s t c a n c e r c e l l l i n e s in v i t r o but not n o r m a l c e l l s . Some of t h e s e R T A c o n j u g a t e s w e r e a b l e to i n h i b i t e s t a b l i s h e d h u m a n g r o w t h in n u d e m i c e in vivo. Properties of the a n t i b o d y , linker and toxin were explored for t h e i r influence in the in vitro and in vivo efficacy of breast cancer immunotoxins.
MDP AND DERIVATIVES II THE DEVELOPMENT OF A NON-TOXIC MUI~;YL PIPTIDE ANALOG FORMULATION THAT EFFICIENTLY INCREASES CELL-MEDIATED AND HUMORAL IMMUNE RESPONSES TO ANTIGENS Anthony C. Allison, Nolene E. Byars and Ruth Waters, Institute of Biological Sciences, Syntex Research, Palo Alto, CA 94304 USA Antigens produced by recombinant DNA technology and peptide synthesis elicit protective immune responses only when administered in an efficient adjuvant formulation. The synthetic analog L-threonyl-L-alanyl-D-isoglutamine shows much greater separation of adjuvant activity from side effects (macrophage activation, pyrogenicity, inflammation at injection site, arthritis, anterior uveitis) than is found with naturally occuring muramyl dipeptide and available analogs. To be effective adjuvants, MDPs must be administered in a formulation such as pluronic polymer LI21, which forms a two-phase system with antigens localized at the interface. MDP seems to act by stimulating production of growth factors for lymphocytes. The role of different varieties of IL-I has been clarified by cloning and expressing two IL-I genes and sequencing IL-I~ and IL-18. Properties of IL-I~ will be discussed in the context of adjuvant activity. Administered with virus subunit and recombinant DNA produced antigens, the formulation described has protected cats against feline leukemia virus and pigs against foot-and-mouth disease virus. Good antibody responses against peptide antigens have also been obtained.
75
629
MONOCLONAL ANTIBODIES AS PHARMACOLOGICAL AGENTS
C O M P A R I S O N OF T H E A N T I T U M O U R E F F E C T S OF T W O A N T I - T H Y PREPARED WITH DIFFERENT COUPLING AGENTS. P.E. T h o r p e , A.N. B r o w n and G.$. W a t s o n . I m p e r i a l C a n c e r R e s e a r c h Fund, L o n d o n .
1.1ABRIN
A CONJUGATES
52
Monoclonal a n t i - T h y 1.1 a n t i b o d y was l i n k e d to a b r i n A - c h a i n u s i n g e i t h e r the S P D P r e a g e n t or 2 - i m i n o t h i o l a n e . The l i n k a g e g e n e r a t e d by the S P D P reagent contains a disulphide bond and an amide bond, whereas that generated by 2 - i m i n o t h i o l a n e contains a disulphide b o n d and an a m i d i n e bond. T h e a n t i t u m o u r a c t i v i t y of the c o n j u g a t e m a d e w i t h 2 - i m i n o t h i o l a n e in m i c e bearing Thy 1.l-expressing l y m p h o m a a l l o g r a f t s w a s 100 to 1 0 0 0 - f o l d b e t t e r t h a n t h a t of the c o n j u g a t e m a d e w i t h the S P D P r e a g e n t . The r e a s o n For this difference is u n k n o w n . The c o n j u g a t e s are e q u a l l y t o x i c to the l y m p h o m a c e l l s in v i t r o , h a v e the same in v i v o h a l f - l i f e and s p l i t up at the s a m e r a t e in the b l o o d s t r e a m to r e l e a s e Free a n t i b o d y and A - c h a i n .
BREAST CANCER IMMUNOTOXINS. A. F r a n k e l , J. W i n k e l h a k e , D. Ring, A. C r e a s e y and L. H o u s t o n . Cetus Corporation, 1400 Fifty-third USA.
53 M.
Bjorn,
Street,
R. F e r r i s ,
Emeryville
C. Vitt,
California
94604
Mouse monoclonal antibodies reactive with breast cancer were prepared. A n u m b e r of t h e s e w e r e r e a c t i v e w i t h the m a j o r i t y of b r e a s t c a n c e r but b o u n d very few n o r m a l tissue substructures. These were conjugated with ricin A - c h a i n and some w e r e F o u n d to be h i g h l y t o x i c to b r e a s t c a n c e r c e l l l i n e s in v i t r o but not n o r m a l c e l l s . Some of t h e s e R T A c o n j u g a t e s w e r e a b l e to i n h i b i t e s t a b l i s h e d h u m a n g r o w t h in n u d e m i c e in vivo. Properties of the a n t i b o d y , linker and toxin were explored for t h e i r influence in the in vitro and in vivo efficacy of breast cancer immunotoxins.
MDP AND DERIVATIVES II THE DEVELOPMENT OF A NON-TOXIC MUI~;YL PIPTIDE ANALOG FORMULATION THAT EFFICIENTLY INCREASES CELL-MEDIATED AND HUMORAL IMMUNE RESPONSES TO ANTIGENS Anthony C. Allison, Nolene E. Byars and Ruth Waters, Institute of Biological Sciences, Syntex Research, Palo Alto, CA 94304 USA Antigens produced by recombinant DNA technology and peptide synthesis elicit protective immune responses only when administered in an efficient adjuvant formulation. The synthetic analog L-threonyl-L-alanyl-D-isoglutamine shows much greater separation of adjuvant activity from side effects (macrophage activation, pyrogenicity, inflammation at injection site, arthritis, anterior uveitis) than is found with naturally occuring muramyl dipeptide and available analogs. To be effective adjuvants, MDPs must be administered in a formulation such as pluronic polymer LI21, which forms a two-phase system with antigens localized at the interface. MDP seems to act by stimulating production of growth factors for lymphocytes. The role of different varieties of IL-I has been clarified by cloning and expressing two IL-I genes and sequencing IL-I~ and IL-18. Properties of IL-I~ will be discussed in the context of adjuvant activity. Administered with virus subunit and recombinant DNA produced antigens, the formulation described has protected cats against feline leukemia virus and pigs against foot-and-mouth disease virus. Good antibody responses against peptide antigens have also been obtained.
75