Polyspecific immunoconjugates and antibody composites for targeting the multidrug resistant phenotype

• US 5,686,578 A
• Filed: 08/05/1994
• Issued: 11/11/1997
• Est. Priority Date: 08/05/1994
• Status: Expired due to Term

• Current Assignee: Immunomedics, Inc. (Gilead Sciences Inc.)
• Original Assignee: Immunomedics, Inc. (Gilead Sciences Inc.)
• Inventors: Goldenberg, David M.
• Primary Examiner(s): Eisenschenk, Frank C.
• Application Number:
  US08/286,430
• Time in Patent Office: 1,194 Days
• Field of Search: 530/387.3, 530/391.1-391.9, 530/389.7, 530/389.5, 530/388.8, 530/388.85, 530/389.1, 530/388.2, 530/388.4
• US Class Current: 530/387.3
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 47/68 the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
• CPC Class Codes: A61K 47/6898 using avidin- or biotin-conjugated antibodies
• CPC Class Codes: A61K 51/1084 the antibody being a hybrid immunoglobulin
• CPC Class Codes: A61K 51/1093 conjugates with carriers being antibodies
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/3007 Carcino-embryonic Antigens
• CPC Class Codes: C07K 2317/31 multispecific

Abstract

Polyspecific immunoconjugates and antibody composites that bind a multidrug transporter protein and an antigen associated with a tumor or infectious agent are used to overcome the multidrug resistant phenotype. These immunoconjugates and composites also can be used diagnostically to determine whether the failure of traditional chemotherapy is due to the presence of multidrug resistant tumor cells, multidrug resistant HIV-infected cells or multidrug resistant infectious agents.

Claims

1. A polyspecific immunoconjugate comprising:

(a) at least one antibody component that binds with a first epitope of a multidrug transporter protein;

(b) at least one antibody component that binds with a first epitope of an antigen, wherein said antigen is associated with a tumor or an infectious agent; and

(c) at least one diagnostic or therapeutic agent.

2. The polyspecific immunoconjugate of claim 1, wherein said antibody components are selected from the group consisting of:

(a) a murine monoclonal antibody;

(b) a humanized antibody derived from (a);

(c) a human monoclonal antibody;

(d) a subhuman primate antibody; and

(e) an antibody fragment derived from (a), (b), (c) or (d).

3. The polyspecific immunoconjugate of claim 2, wherein said antibody fragment is selected from the group consisting of F(ab'"'"')₂, F(ab)₂, Fab'"'"', Fab, Fv, sFv and minimal recognition unit.

4. The polyspecific immunoconjugate of claim 3, wherein said multidrug transporter protein is selected from the group consisting of P-glycoprotein, OtrB, Tel(L), Mmr, ActII, TcmA, NorA, QacA, CmlA, Bcr, EmrB, EmrD, AcrE, EnvD, MexB, Smr, QacE, MvrC, MsrA, DrrA, DrrB, TlrC, Bmr, TetA and OprK.

5. The polyspecific immunoconjugate of claim 4, wherein said diagnostic agent is selected from the group consisting of radioactive label, photoactive agent or dye, florescent label, enzyme label, bioluminescent label, chemiluminescent label, colloidal gold and paramagnetic ion.

6. The polyspecific immunoconjugate of claim 5, wherein said radioactive label is selected from the group consisting of γ

-emitters and positron-emitters.

7. The polyspecific immunoconjugate of claim 6, wherein said γ

-emitters have a gamma radiation emission peak in the range of 50-500 Kev.

8. The polyspecific immunoconjugate of claim 7, wherein said γ

-emitters with a gamma radiation emission peak in the range of 50-500 Kev are selected from the group consisting of ^99m Tc, ⁶⁷ Ga, ¹²³ I, ¹²⁵ I and ¹³¹ I.

9. The polyspecific immunoconjugate of claim 4, wherein said therapeutic agent is selected from the group consisting of radioisotope, boron addend, immunomodulator, toxin, photoactive agent or dye, cancer chemotherapeutic drug, antiviral drug, antifungal drug, antibacterial drug, antiprotozoal drug and chemosensitizing agent.

10. The polyspecific immunoconjugate of claim 9, wherein said radioisotope is selected from the group consisting of α

-emitters, β

-emitters, γ

-emitters, Auger electron emitters, neutron capturing agents that emit α

-particles and radioisotopes that decay by electron capture.

11. The polyspecific immunoconjugate of claim 9, wherein said radioisotope is selected from the group consisting of ¹⁹⁸ Au, ³² P, ¹²⁵ I, ¹³¹ I, ⁹⁰ Y, ¹⁸⁶ Re, ¹⁸⁸ Re, ⁶⁷ Cu and ²¹¹ At.

12. The polyspecific immunoconjugate of claim 4, further comprising an antibody component that binds with a second epitope of said multidrug transporter protein.

13. The polyspecific immunoconjugate of claim 12, further comprising an antibody component that binds with a second epitope of said tumor or infectious agent associated antigen, or with an epitope of a second antigen associated with said tumor or said infectious agent.

14. The polyspecific immunoconjugate of any one of claims 4, 12 or 13, further comprising an immunomodulator, wherein said immunomodulator is selected from the group consisting of cytokines, stem cell growth factors and hematopoietic factors.