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Catalytic antibodies and their known roles in human pathologies.

Catalytic antibodies and their known roles in human pathologies. Chemical Basis for Catalytic Activity. Enzymes promote transition state ( TS ). Transition state favored by tight binding . Figure depicts anti-CCR-5 “protease”. Strategy : Raise against TS analogs. Animation (Left):

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Catalytic antibodies and their known roles in human pathologies.

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  1. Catalytic antibodies and their known roles in human pathologies.

  2. Chemical Basis for Catalytic Activity Enzymes promote transition state (TS). Transition state favored by tight binding. Figure depicts anti-CCR-5 “protease”. Strategy: Raise against TS analogs. Animation (Left): Serine protease active site. Black: Protease. Green: Peptide substrate.

  3. A Promising Platform for Various Purposes Catalytic antibodies are a triumph of biological engineering… Biomedical: Industrial: • Overdose/addiction therapy. - Bio-remediation. • Resistance to HIV infection. - Detoxification. • Neutralize toxins and venoms. - Chemical syntheses. • Clearance of amyloid plaques. - Greener chemistry. • Attack pathogens. …and have also been implicated in numerous human pathologies.

  4. Catalytic auto-antibodies in human pathologies Associated with numerous diseases and disease progression.

  5. Biogenesis of catalytic self-antibodies While no one seems to understand the mechanism of biogenesis and proliferation, we present a model that can account for both: First B-cell “tastes” antigens. Binds to self-antigen substrate. Hydrolysis of antigen. B-cell escapes.

  6. Multiple Sclerosis Demyelination of oligodendrocytes, attack by T cells. Inappropriate communication leads to multiple symptoms. Muscle spasms/weakness, optical problems. Breakdown of blood brain barrier. Endothelial cells wrap capillaries. Only small molecules can get through. Allows cABs, T cells to enter the brain. Catalytic, anti myelin antibodies gain access to myelin. Fc receptors allow for recruiting of NK cells and other lymphocytes like TCTL. http://cwx.prenhall.com/bookbind/pubbooks/morris5/chapter2/custom1/deluxe-content.html

  7. Resistance to hemophilia therapy Hemophilia A. Genetic disorder associated with severe/spontaneous bleeding. Deficit in FVIII or FVIII activity. Procoagulationcomponent. Pathology of cABs. Model for cAB“proliferation”. Good enough selection for inferior catalysis. Many antibodies involved, catalytic and non-catalytic. Slow catalysis compared to real enzymes, no selection. Bind substrate, extremely efficient cABs self-select out. Affinity maturation may explain presence. http://www.moondragon.org/health/disorders/hemophilia.html

  8. Developing models for immune dysfunction Antibodies catalyze desired and undesired reactions. Remains a flexible platform for biotechnology. Involvement in autoimmune disorders. Evade understood negative selection processes. Difficult to trace sensitization agent. A developing field with many questions. Biogenesis and activation of catalytic autoantibodies? Effective negative selection possible?

  9. Works Consulted Belogurov et al (2009). Catalytic antibodies: balancing between Dr. Jekyll and Mr. Hyde.BioEssays 31:1161-1171. Lacroix-Desmazes et al (2006). Catalytic IgG from Patients with Hemophilia A Inactivate Therapeutic Factor VIII. The Journal of Immunology 177: 1355-1362. Lacroix-Desmazes et al (2002). The Prevalence of Proteolytic Antibodies against Factor VIII in Hemophilia A. The New England Journal of Medicine 346: 662-667. Mitsudaet al (2004). Catalytic Antibody Light Chain Capable of Cleaving a Chemokine Receptor CCR-5 Peptide with a High Reaction Rate Constant. Wiley Periodicals 217-225. Nevinsky et al (2000). Natural Catalytic Antibodies (Abzymes) in Normalcy and Pathology. Biochemistry (Moscow) 65(11):1245-1255. Ponomarenko et al (2005). Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen. Proceedings of the National Academy of Sciences, USA 103(2): 281-286). Uda and Hifumi(2004). Super Catalytic Antibody and Antigenase. Journal of Bioscience and Bioengineering 97(3): 143-152.

  10. Slideshow Index. • Basis for catalysis. • Catalytic antibodies in technology and pathology. • Implicated in many diseases. • Evading negative selection. • Role in multiple sclerosis. • Role in acquired resistance to hemophilia A treatment. • Concluding remarks.

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