see also Proteoytic antibodies and IVIG preparations under “protein purification”

The terms “abzyme” or “catalytic immunoglobulin” are used to describe antibodies possessing enzymatic activity. Examples of catalytic reactions that may be catalyzed by the immunoglobulins include amid bond cleavage, and peptide bond cleavage. (Paul, US 11988761) 

The earliest speculations that antibodies may possess catalytic activity date back half a century ago when it was suggested that if exposed to an antigen for a sufficiently long period, the immune system may develop catalytic antibodies. Sequence homlogy between certain antibody light chain and serine proteases was later revealed. Several years later, antibodies with esterase activity were reported. Further studies discovered antibodies capable of hydrolyzing peptides or proteins. Catalytic antibodies can be isolated form the natural immune repertoire, but seem to be produced at an elevated level in various autoimmune disease states. Analyses of catalytic antibody components have shown that enzymatic activity often resides in the light chains, and antibody light chains isolated form myltiple myeloma patients frequently demonstrate proteolytic activity.  (US 2006/0088883).

Development of Catalytic Antibodies

Very little is known about the developmental aspects of Ab catalysis. Noncovalent occupancy of the B cell receptor (BCR) by antigens is well knwon to drive the clonal selection of B cells, resulting eventually in production of mature IgG, IgA and IgE Abs capable of specific binding to individual polypeptide antigens. However, production of antigen-specific catalytic IgGs under normal cirucmstances is a rare event, and the IgGs generally hydrolze the model peptide substrates at levels considerably lower than IgMs. This suggests that catalytic hydrolysis of peptide antigens by IgG type BCRs is an immunoglobidally disfavored event. 

Stabilization of catalytic antibodies:

–By metal binding

It is known that antibody constant regions of both light and heavy contain a short sequence Cys-X3-His (X = any amino acid) and that divalent metal ion like Zn2+ may increase the stability of these immunogloublin domains and promote dimerization of immunoglobulin monomers. (Radulescu, “Antibody Constant region: potentail to bind metal and nucleic acid, Medical Hypothesis (1995) 44; 137-145). 

Oita (US Patent Applicaiton NO: 14/912444, published as US 2019/0256576) discloses that in order to clinically use an abzyme as a pharmacetuical product it is important to stably mass produce an abbzyme having sufficient activity. However, when many abzymes are artificially synthesized by an intracellular or extracellular pexpression system, using a genetic recombinantion technique, there is a problem in that performance is not stable. In this respect, the inventors that a compoistion containing a human antibody k type light chain complex containing complex can be stablized by binding the human antibody k type light chain to one or more metal ions selected from the Group 10-12 elements, where the k type light chain is a dimer and cysteines at C terminals of the two k type light chains are bound to each other via the metal ion. 

Types of Catalytic Antibodies

Autoantibodies: Paul (US 5,236,836) discloses autoantibodies which enahce the rate of a chemical reaction of a substrate. The autoantibody is prepared by identifying an animal with autoantibodies to a self-antigen of the animal, isolating the autoantibodies and screening the autoantibodies to identify an autoantibody which enahcnes the rate of the chemical reaction.

Antibodies with Protein Kinase activity: Kit (Academy of Sciences of the Ussr, 1991, 2(2): 201-4) showed that the sIgA fraction of human milk has the ability to phosphorylate casein.

Pooled catalytic immunoglobulins: (Paul, US 11988761) discloses pooled human catalytic imunoglobulins designed as “CIVIG” used to refer to pooled IgG, IgM and IgA. Pooling of the catalytic immunoglobulins from many individual humans diversifies the range of catalysts with differing specificites and catalytic activities. Unlike with conventional IViG fractionation methods, CIVIG fractionation methods are designed to minimize loss of catalytic activity. For example, Paul discloses that the superior activity of the CIVIG preprations can be attributed to the comparatively gentle method of isolating the immunoglobulins with immunoaffinity chromatography as opposed to harsh treatments with organic solvents employed in conventional IVIG preparations. 

Therapeutic Applications

Antibody-Catalytic – antibody fusions: The combination of antibody specificity with the catalytic power of enzymes has the potential of generating potent therapeutic agents such as catalytic antibodies capable of specifically hydrolyzing key viral coat proteins, tumor specific proteins, or endogenous proteins involved in disease. Through somatic rearrangement, the mammalian immune system is capable of generating more than 10 to the 10th different antigen specificities, using only a limited number of germ line genes. In contrast, most known proteases or peptidases often target particular peptide bonds but can cleave a relatively broad spectrum of polypeptides without a high level of specificities for individual substrates. Combining a human antibody light chain that houses proteoytic activity with a heterologous human antibody heavy chain that provides polyeptide bind specificity, Smider (US 2006/0088883) discloses that proteases that allows the specific hydrolysis of pre selected target proteins without undersired effect on untargeted polypeptides can be obtained.

HIV neutralization: catalytic antibodies to the superantigenic site of gp120 envlope glycoprotein degrades gp120 and hold the potential of controlling HIV infection given that gp120 is responsible for CD4 receptors on host cells. (Paul, US 11988761)