Immunotoxins comprising ribosome-inactivating proteins

• US 20050054835A1
• Filed: 11/18/2003
• Published: 03/10/2005
• Est. Priority Date: 11/04/1991
• Status: Active Grant

• Current Assignee: Research & Development Foundation
• Original Assignee: Xoma Technology Ltd. (Xoma Corp.)
• Inventors: Carroll, Stephen F., Better, Marc D., Studnicka, Gary M.
• Granted Patent: US 7,153,932 B2
• Time in Patent Office: Days
• US Class Current: 530/391.100
• CPC Class Codes: A61K 2121/00 Preparations for use in therapy
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/6825 Ribosomal inhibitory proteins, i.e. RIP-I or RIP-II, e.g. Pap, gelonin or dianthin
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 14/415 from plants
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/16 against material from plants
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/54 F(ab')2
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: Y10S 530/866 involving immunoglobulin or antibody fragment, e.g. fab', fab, fv, fc, heavy chain or light chain

Abstract

The present invention provides purified and isolated polynucleotides encoding Type I ribosome-inactivating proteins (RIPs) and analogs of the RIPs having a cysteine available for disulfide bonding to targeting molecules. Vectors comprising the polynucleotides and host cells transformed with the vectors are also provided. The RIPs and RIP analogs are particularly suited for use as components of cytotoxic therapeutic agents of the invention which include gene fusion products and immunoconjugates. Cytotoxic therapeutic agents or immunotoxins according to the present invention may be used to selectively eliminate any cell type to which the RIP component is targeted by the specific binding capacity of the second component of the agent, and are suited for treatment of diseases where the elimination of a particular cell type is a goal, such as autoimmune disease, cancer and graft-versus-host disease.

Claims

1. A fusion protein comprising gelonin as in SEQ ID NOS:

2 and 101 and an antibody or region of an antibody comprising an antigen-binding portion.

2. The fusion protein according to claim 1, wherein said antibody or said region is fused to the carboxyl terminus of said gelonin.

3. The fusion protein according to claim 1, wherein said antibody is an he3 antibody.

4. The fusion protein according to claim 1, wherein said region is an he3-Fab fragment.

5. The fusion protein according to claim 1, wherein said region is an he3 Fd fragment.

6. The fusion protein according to claim 1, wherein said region is an he3 F(ab′

)₂ fragment.

7. The fusion protein according to claim 1, wherein said region is an he3 Fab′

fragment.

8. The fusion protein according to claim 1, wherein said region is an he3 kappa fragment.

9. The fusion protein according to claim 1, wherein said antibody or said region is an he3 single-chain antibody.

10. The fusion protein according to claim 2, further comprising a peptide segment of a shiga-like toxin as in SEQ ID NO:

56 between said gelonin and said antibody or said region.

11. The fusion protein according to claim 2, further comprising a peptide segment of a rabbit muscle aldolase as in SEQ ID NO:

57 between said gelonin and said antibody of said region.

12. The fusion protein according to claim 1, wherein said antibody or said region is fused to the amino terminus of said gelonin.

13. The fusion protein according to claim 10, further comprising a peptide segment of a rabbit muscle aldolase as in SEQ ID NO:

59 between said antibody or said region.