Catalytic antibodies, development

An example of esterase behaviour is provided by a catalytic antibody developed by Tramontano et al. (1988), using a phosphonate transition state analogue [53] as the hapten. The antibody cleaves the carboxylic ester [54, R = Me] with enzyme-like efficiency (kc/ku = 6.25 X 106 = 1.5 mM ... 

In the line of catalytic antibodies development, Nimri and Keinan reported that the incorporation of the Ru(II) porphyrin (12 in Figure 10.11) within a specially raised monoclonal antibody (mAb) catalyzed the enantioselective oxidation of aromatic sulfides. Great care was taken in the design of the hapten from which the mAb was elicited so that it mimicked the transition state. For stability reasons, the hapten was an Sn(IV) porphyrin and one of the axial positions was occupied by an a-naphthoxy ligand. In the presence of excess mAb, the Ru porphyrin catalyzed the sulfoxidation of thioanisole and analogs (see Scheme 10.9) with up to 43% ee (S) [57]. 

Impressive developments in the area of immunology have culminated in the development of catalytic antibodies (186,187). These synthetic biocatalysts that have the potential to catalyze virtually any type of reaction with unsurpassed selectivity have great promise in the future. 

The safety of the cocaine vaccine TC-CD in former cocaine abusers has been evaluated in a Phase I clinical trial, and it was determined that the vaccine was well tolerated with dose-related increases in antibody levels.65 Two Phase II clinical trials have now been conducted.66,67 The vaccine was again well tolerated and subjects reported a reduction in cocaine s reinforcing effects. The antibody levels were detectable after the second dose, peaked at 8 to 12 weeks, and remained elevated for up to 6 months preliminary findings indicated a negative association between antibody level and cocaine use. Other anti-cocaine vaccines in development include a blocking antibody (ITAC-cocaine) and a monoclonal catalytic antibody (15A10). 

As impressive as these developments have been, chemists still have a way to go to catch up with Mother Nature . For enzymes KTS may be as low as 10 2( m, since is generally in the range 10-3 to IO m and kjku values are up to 1014 or more (Lienhard, 1973 Kraut, 1988) (see Enzymes, Section 6). Further lowering of KTS for artificial enzymes below 10 ,om will no doubt require more covalent interactions in the transition state, with better catalytic groups. Nevertheless, the transition state stabilization evident in Table 4 is comparable to that which has been achieved so far with catalytic antibodies (Section 6). 

In the last 5 years, catalytic antibodies have been generated for several reaction types, including the various types of hydrolysis, transesterification, amide bond formation, /3-elimination, cycloreversion, transacylation, redox reactions, E-Z isomerization, epoxidation, and Diels-Alder reactions. For more information on these and other recent developments, such as semi-synthetic antibodies, site-directed mutagenesis, and the bait-and-switch strategy, the reader should consult the appropriate authorities (Schultz, 1988, 1989a,b Benkovic et al., 1990 Janda et al., 1990, 1991 Janjic and Tramontano, 1990 Lerner et al., 1991). 

There is sufficient encouragement in these examples to show that out of all the prospects for the future development of catalytic antibodies, those in the field of medicine, where selectivity in transformation of unusual substrates may be of greater importance than sheer velocity of turnover of substrate, may well rank highest. 

In view of the tremendous interest in biocatalysis, it is not surprising that only a decade after the debut of catalytic antibodies a vast literature has developed... 

Interaction between chemistry and immunology has led to the development of the impressive field of catalytic antibodies [22]. 

First, based on the concept of catalytic antibodies as first described by Jencks, the use of a TSA of the target reaction to elicit antibodies during an immune response has been developed and identified as a classic strategy in the search for catalytic antibodies. Structural studies have in particular shown that this strategy has led to... 

After a postdoc in the US (Professor S. J. Benkovic, Pennsylvania State University) where he worked on catalytic antibodies, he was appointed in 1996 as Directeur de Recherches in the CNRS in the Laboratory of Pharmacological and Toxicological Chemistry and Biochemistry (Director Dr. D. Mansuy), at Paris 5, where he developed the field of hemoabzymes catalytic antibodies with an iron-porphyrin cofactor. ... 

Catalytic antibodies or abzymes are antibodies that have been developed for biocatalytic reactions. How are abzymes produced Why is it essential to know the detailed mechanism of a reaction for development of a catalytic antibody to catalyze it What are the main limitations of abzymes that have restricted the industrial use of such catalysts ... 

In 1997 the same group developed the first imprinted polymer able to catalyse a Diels-Alder reaction between tetrachlorothiophene dioxide (43) and maleic anhydride (44) to give the product (45). The imprinting strategy was inspired by previous work carried out by Hilvert et al. in 1989 for the development of catalytic antibodies with Diels-Alder capabilities [26]. The chlorendic anhydride (46) was used as a template because of its structural analogy with the transition state of the reaction (TSA). The resulting imprinted polymer showed a Michaelis-Menten behaviour and a ratio kcal/kunca equal to 270 (Scheme 8). 

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