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GSJ: Received Jan. 27, 2006: http://wbabin.net/saba/saba60.htm

Monoclonal Antibody Therapy Utilizing Proximity-Based Liberation of Coupled Toxin

James Saba

Perviously described was the use of two different antibodies, each of which had been coupled to and oligonucleotide.

Immunoassays and Arrayassays Utilizing Oligonucleotide-coupled Antibodies

The relevant concept of that article is reproduced in Figure 1.

The present invention is analogous to the proximity-based process in Figure 1 except that one of the molecules coupled to one of the antibodies functions to chemically modify the molecule coupled to the second antibody.

The primary but not exclusive utility of of the present invention is to enhance site-specific antibody-mediated delivery of a molecule which kills or modulates the growth of a cell.

Figure 2 exemplifies the concept.

In this example we start with two epitopes, which may reside on one molecular target (for example a cancer cell surface protein) or on separate molecules (for example infected cell surface proteins). We next provide the antibodies coupled to proteins, either simultaneously or sequentially. For simplicity, each antibody is shown coupled to only one molecule.

Upon binding of antibodies to epitopes, one antibody-coupled molecule chemically modifies the other antibody-coupled molecule, which in this example involves the protease liberation of a toxin.

Chemical modification need not involve liberating the cell killing of growth modifying molecule from the antibody. For example, a latently toxic peptide could be activated by protease liberation of ‘masking’ section.

Other chemical modifications include oxidation, reduction, alkylation, acylation, deacylation, phosphorylation, and dephosphorylation. Furthermore, one of both of the molecules coupled to antibodies need not be polypeptides, and could for example be relative small organic molecules which selectively react with each other.

Importantly, the molecule being chemical modified could be a proenzyme, which subsequent to activation could effect the killing of a cell or virus, or catalyze the conversion of prodrugs or even other proenzymes.

Conceivably enzymatic functioning of one of the antibody-conjugated molecules could reside in one of the paratopes of a bispecific mAb. Therein the enzymatic portion of the antibody would be considered the antibody-coupled enzyme.

Covalent coupling of polypeptides to antibodies can be achieved during translation of recombinant mRNA. Alternatively coupling could be subsequent to their individual synthesis. Noncovalent coupling of polypeptides and other molecules is also possible, for example by the use a biotin bridge, or a bispecific antibody wherein one of its paratopes binds the molecule to be coupled.

While use of the invention in therapeutics is the primary objective of the invention, it is also has utility in diagnostics and technology.

"Antibody" refers to whole or truncated versions (including Fab single chain antibodies) with a one or more paratopes. In the broadest sense of the invention, other proteins which specifically bind a target could conceivably be used.

If it should be that the above invention is indeed novel, any patentable rights I may have I freely give away. It is hoped that others will honor the invention as delineated by the following claims.

Claims

1) A process wherein two or more chemically reactive molecules are brought into proximity, due to the target-binding of antibodies to which the molecules are conjugated.

2) The process in claim 1, wherein the chemical reaction results in liberation of part or all of one of the antibody conjugated molecules.

3) The process in claim 2, wherein the liberated molecule kills or modulates the growth of a cell.

4) The process of claim 3, wherein the cell is prokaryotic or transformed eukaryotic cell.

5) Any of the processes above wherein the targets are proteins residing on the surface of a cell.

6) A kit useful in performing any of the processes above.

References

1) Engineering of protease variants exhibiting high catalytic activity and exquisite substrate selectivity. Varadarajan, et al Proc Natl Acad Sci U S A. 2005 May 10;102(19):6855-60

2) Selective activation of anthracycline prodrugs for use in conjunction with antibody directed enzyme prodrug therapy strategy (ADEPT). HariKrishna, et al Drug News Perspect. 2003 Jun;16(5):309-18

3) Arming antibodies: prospects and challenges for immunoconjugates. Wu, et al Nat Biotechnol. 2005 Sep;23(9):1137-46

4) Recent advances in tumor-targeting anticancer drug conjugates. Jaracz, et al Bioorg Med Chem. 2005 Sep 1;13(17):5043-54

5) Novel approaches for targeted cancer therapy. Guillemard, et al Curr Cancer Drug Targets. 2004 Jun;4(4):313-26

6) Recombinant immunotoxins for the treatment of haematological malignancies. Kreitman RJ Expert Opin Biol Ther. 2004 Jul;4(7):1115-28

7) Drug-conjugated monoclonal antibodies for the treatment of cancer. Lambert JM. Curr Opin Pharmacol. 2005 Oct;5(5):543-9