Catalytic antibodies and a method of producing same

Details Catalytic antibodies and a method of producing same Catalytic antibodies and a method of producing same

2000-11-09

2003-02-18

Patterson, Jr., Charles L. (Department: 1652)

Chemistry: natural resins or derivatives; peptides or proteins;

Proteins, i.e., more than 100 amino acid residues

C514S002600, C435S188500

Reexamination Certificate

active

06521741

ABSTRACT:

The present invention is directed generally to catalytic antibodies and, more particularly, to a novel method of producing same. The method of the present invention is predicated in part on the exploitation of the products of catalysis to induce B cell mitogenesis. In a preferred embodiment, a growth factor having an ability to induce B cell mitogenesis is linked to a target antigen to which catalytic antibodies are sought. B cell mitogenesis is then dependent on the catalytic cleavage of the antigen portion of the growth factor by catalytic antibodies on the surface of B cells. The method of the present invention is useful for generating catalytic antibodies for both therapeutic and diagnostic purposes.
Sequence Identity Numbers (SEQ ID NOs.) for the nucleotide and amino acid sequences referred to in the specification are defined following the Examples.
Throughout this specification, unless the context requires otherwise, the word “comprises”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.
The rapidly increasing sophistication of recombinant DNA technology is greatly facilitating research and development in the medical and allied health fields. A particularly important area of research is the use of recombinant antigens to stimulate immune response mechanisms and outcomes. However, until now, recombinant techniques have not been particularly effective in the generation of catalytic antibodies.
Catalytic antibodies are highly substrate specific catalysts which can be used, for example, to proteolytically activate or inactivate proteins. Catalytic antibodies have great potential a therapeutic agents in human diseases such as rheumatoid arthritis, AIDS and Alzhiemer's disease amongst many others.
Antibody therapy is already routinely used in patients. Antibodies have a half-life of about 23 days in the circulation of humans which is a clear advantage over other drugs. Catalytic antibodies, however, are considered to be even more effective. They are recycled after their antigenic encounter and are not bound to the antigen as occurs with “classical” antibodies. Catalytic antibodies should, therefore, function at a much lower dose than classical antibodies and could be used at sub-immunogenic doses. Catalytic antibodies would be particularly useful in long term therapy.
Traditionally, catalytic antibodies have been generated by immunising mice with transition state analogs. Such antibodies have been shown to catalyse several chemical reactions. However, this approach has a severe limitation in that it is difficult to predict the structure of transition state analogs which effect proteolysis of specific proteins. Immunising a mouse with a transition state analog is by definition inefficient since it selects B cells on the ability of surface immunoglobulins to bind the analogs and not on the catalytic activity of the surface immunoglobulins. This is one of the reasons why catalytic antibodies have relatively low turn-over rates and cannot compete with the naturally occurring enzyme counterparts. As a consequence, catalytic antibodies have not previously achieved prominence as therapeutic or diagnostic tools.
There is a need, therefore, to develop a more efficacious approach to generating catalytic antibodies having desired catalytic specificity. In accordance with the present invention, the inventors have developed such an approach based on a recombinant or a synthetic growth factor having an ability to induce B cell mitogenesis. A precursor form of the growth factor selects “catalytic” B cells. The present invention provides, therefore, for the exploitation of the products of catalysis for B cell activation which may and can be antigen binding site independent.
Accordingly, one aspect of the present invention is directed to a recombinant or synthetic growth factor or a precursor thereof comprising a B cell surface molecule binding portion wherein said growth factor or a catalytic product of said precursor is capable of inducing B cell mitogenesis.
More particularly, the present invention provides a recombinant or synthetic growth factor comprising a B cell surface molecule binding portion wherein said growth factor induces B cell mitogenesis.
In one aspect of the present invention, the recombinant or synthetic growth factor comprises a B cell surface molecule binding portion and a portion providing T cell dependent help for a B cell such that said growth factor induces B cell mitogenesis.
In another aspect, the portion providing T cell dependent help for a B cell is supplied independently of the growth factor. An example of an exogenously supplied portion having T cell dependent help for a B cell is anti-CD40 antibodies or functional equivalents thereof.
In a particularly preferred embodiment, the B cell surface molecule binding portion comprises a B cell surface immunoglobulin binding portion although the present invention extends to a range of B cell surface molecules the binding, interaction and/or cross-linking thereof leads to or facilitates B cell mitogenesis. Reference hereinafter to a “B cell surface molecule” includes reference to a B cell surface immunoglobulin. The portion providing T cell dependent help for a B cell is preferably but not exclusively a T cell epitope. Reference hereinafter to a portion providing T cell dependent help for a B cell includes a T cell epitope.
The present invention further contemplates a composition of matter capable of inducing B cell mitogenesis said composition of matter comprising components selected from:
(i) a recombinant or synthetic molecule comprising a B cell surface molecule binding portion;
(ii) a recombinant or synthetic molecule in multimeric form comprising a B cell surface molecule binding surface molecule binding portion;
(iii) a recombinant or synthetic molecule of (i) or comprising a further portion providing T cell dependent help for a B cell; and
(iv) separate compositions mixed prior to use or used sequentially or simultaneously comprising in a first composition a component having a B cell surface molecule binding portion and in a second composition a molecule capable of providing T cell dependent help for a B cell.
Preferably, the molecule capable of providing T cell dependent help for a B cell is a T cell epitope or is an anti-CD40 antibody or functional equivalents thereof.
Preferably, to ensure cross-liking of B cell surface molecules to induce blastogenesis, the growth factor comprises at least two B cell surface molecule binding portions. Alternatively, where the growth factor is present in multimeric form, the molecule may comprise a single B cell surface molecule binding portion.
Even more preferably, the growth factor comprises a T cell epitope portion flanked by, adjacent to or proximal with at least one B cell surface molecule-binding portion. The presentation of a T cell epitope on the surface of a B cell allows for B cell mitogenesis. The term “B cell mitogenesis” is used herein in its broadest context and includes B cell activation, clonal expansion, affinity maturation and/or antibody secretion as well as growth and differentiation. The term “mitogenic” as used herein means “mitogenesis”.
In another embodiment, the recombinant or synthetic growth factor comprises a further portion permitting multimerisation of the growth factor. A multimer comprises two or more growth factor molecules or a precursor thereof. Examples of portions inducing multimerisation include but are not limited to an antibody, a region facilitating formation of cross-linked molecules or a signal peptide. Cross-linkage in this context includes any interaction that provides bonding adequate to lead to multimer formation including but not limited to covalent linkage, ionic linkage, lattice association, ionic bridges, salt bridges and non-specific molecular association. A particularly preferred embodiment of the present invention is directe

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