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):Serine protease active site.Black: Protease.Green: Peptide substrate.

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.

Catalytic auto-antibodies in human pathologies

Associated with numerous diseases and disease progression.

Systemic lupus erythematosus.

Diabetes Type I.

Thyroiditis. Hepatitis B.

Multiple myeloma. Hemophilia A.

Rheumatoid arthritis. Multiple sclerosis.

B-cell lymphosarcoma. T-cell lymphoma.

Chronic B-cell leukemia. Scleroderma.

Anti-hemophilia treatment. Asthma.

Biogenesis of catalytic self-antibodiesWhile 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.

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.

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Resistance to hemophilia therapy

Hemophilia A.Genetic disorder associated with severe/spontaneous bleeding.Deficit in FVIII or FVIII activity.Procoagulation component.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

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?

Works ConsultedBelogurov 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.

Mitsuda et 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.

Slideshow Index.

1. Basis for catalysis.

2. Catalytic antibodies in technology and pathology.

3. Implicated in many diseases.

4. Evading negative selection.

5. Role in multiple sclerosis.

6. Role in acquired resistance to hemophilia A treatment.

7. Concluding remarks.