Methods of inhibiting human immunodeficiency virus infection through the administration of synergistic combinations of anti-CCR5 monoclonal antibodies, fusion inhibitors, and CD4-GP120 binding inhibitors
View Patent ↗This invention provides a composition which comprises an admixture of three compounds, wherein: (a) one compound is an antibody which binds to a CCR5 receptor; (b) one compound retards attachment of HIV-1 to a CD4+ cell by retarding binding of HIV-1 gp120 envelope glycoprotein to CD4 on the surface of the CD4+ cell; and (c) one compound retards gp41 from adopting a conformation capable of mediating fusion of HIV-1 to a CD4+ cell by binding noncovalently to an epitope on a gp41 fusion intermediate; wherein the relative mass ratio of any two of the compounds in the admixture ranges from about 100:1 to about 1:100, the composition being effective to inhibit HIV-1 infection of the CD4+ cell. This invention also provides a method of inhibiting HIV-1 infection of a CD4+ cell which comprises contacting the CD4+ cell with an amount of the composition of the subject invention effective to inhibit HIV-1 infection of the CD4+ cell so as to thereby inhibit HIV-1 infection of the CD4+ cell.
1. A method of inhibiting HIV-1 infection of a CD4+ cell in a subject which comprises administering to the subject a first compound which is a monoclonal antibody PA14 (produced by hybridoma PA14 having ATCC Accession No. HB-12610) or a portion thereof which binds to a CCR5 receptor, or a humanized PA14 antibody or a portion of thereof which binds to a CCR5 receptor, or a chimeric PA14 antibody or a portion thereof which binds to a CCR5 receptor; and (b) administering to the subject a second compound which is T-20 having the amino-acid sequence set forth in SEQ ID NO:1, so as to thereby inhibit HIV-1 infection of the CD4+ cell in the subject.
2. The method of claim 1 , wherein the first and second compounds are administered to the subject separately.
3. The method of claim 1 , wherein the first and second compounds are administered to the subject simultaneously.
4. The method of claim 1 , wherein the first and second compounds are administered to the subject at different times.
5. The method of claim 4 , wherein the first compound is administered to the subject following the administration of the second compound.
6. The method of claim 1 , wherein the first and second compounds are administered to the subject by different routes of administration.
7. The method of claim 1 , wherein the first compound is a humanized PA14 antibody or portion thereof.
8. The method of claim 1 , wherein the first compound is a chimeric PA14 antibody or portion thereof.
9. The method of claim 1 , wherein the relative mass ratio of the first compound to the second compound ranges from 100:1 to 1:100.
10. A method of inhibiting HIV-1 infection of a CD4+ cell in a subject which comprises (a) administering to the subject a first compound which is a monoclonal antibody PA14 (produced by hybridoma PA14 having ATCC Accession No. HB-12610) or a portion thereof which binds to a CCR5 receptor, or a humanized PA14 antibody or a portion of thereof which binds to a CCR5 receptor, or a chimeric PA14 antibody or a portion thereof which binds to a CCR5 receptor; (b) administering to the subject a second compound which is a CD4-IgG2 chimeric heterotetramer comprising two heavy chains and two light chains, wherein the heavy chains are encoded by expression vector CD4-IgG2HC-pRcCMV having ATCC Accession No. 75193 and the light chains are encoded by expression vector CD4-kLC-pRcCMV having ATCC Accession No. 75194; and (c) administering to the subject a third compound which is T-20 having the amino-acid sequence set forth in SEQ ID NO:1, so as to thereby inhibit HIV-1 infection of the CD4+ cell.
11. The method of claim 10 , wherein the first and second compounds are administered to the subject separately.
12. The method of claim 10 , wherein the compounds are administered to the subject simultaneously.
13. The method of claim 10 , wherein the compounds are administered to the subject at different times.
14. The method of claim 13 , wherein the first compound is administered to the subject following the administration of the third compound.
15. The method of claim 13 , wherein the first and second compounds are administered to the subject following the administration of the third compound.
16. The method of claim 10 , wherein the compounds are administered to the subject by different routes of administration.
17. The method of claim 10 , wherein the first compound is a humanized PA14 antibody or portion thereof, or is a chimeric PA14 antibody or portion thereof.
18. The method of claim 10 , wherein the relative mass ratio of any two of the compounds of (a)-(c) ranges from 100:1 to 1:100.
19. A method of inhibiting HIV-1 infection of a CD4+ cell in a subject who is receiving or has recently received treatment with a compound T-20 having the amino acid sequence set forth in SEQ ID NO:1, comprising administering to the subject a second compound which is a monoclonal antibody PA14 (produced by hybridoma PA14 having ATCC Accession No. HB-12610), or a portion thereof which binds to a CCR5 receptor, or a humanized PA14 antibody or a portion of thereof which binds to a CCR5 receptor, or a chimeric PA14 antibody or a portion thereof which binds to a CCR5 receptor, in an amount effective to inhibit HIV-1 infection of the CD4+ cell in the subject.
20. The method of claim 19 , wherein the second compound is a humanized PA14 antibody or a portion of thereof which binds to a CCR5 receptor, or a chimeric PA14 antibody or a portion thereof which binds to a CCR5 receptor.
21. The method of claim 1 , wherein the first compound is monoclonal antibody PA14 (produced by hybridoma PA14 having ATCC Accession No. HB-12610) or a portion thereof.
22. The method of claim 10 , wherein the first compound is monoclonal antibody PA14 (produced by hybridoma PA14 having ATCC Accession No. HB-12610) or a portion thereof.
23. The method of claim 19 , wherein the second compound is monoclonal antibody PA14 (produced by hybridoma PA14 having ATCC Accession No. HB-12610) or a portion thereof.