Compositions and methods for non-myeloablative conditioning
Disclosed herein are non-myeloablative antibody-toxin conjugates and compositions that target cell surface markers, such as the CD34, CD45 or CD117 receptors, and related methods of their use to effectively conditioning a subject's tissues (e.g., bone marrow tissue) prior to engraftment or transplant. The compositions and methods disclosed herein may be used to condition a subject's tissues in advance of, for example, hematopoietic stem cell transplant and advantageously such compositions and methods do not cause the toxicities that are commonly associated with traditional conditioning methods.
1. A method of conditioning a subject for engraftment, the method comprising selectively depleting or ablating an endogenous hematopoietic stem cell (HSC) or progenitor cell population in a target tissue of an immunocompetent subject comprising administering to the subject an effective amount of an antibody coupled to a toxin, wherein the toxin is internalized by an endogenous HSC or progenitor cell population, thereby depleting or ablating the endogenous hematopoietic stem cell or progenitor cell population in the target tissue, wherein the method does not induce anemia in the subject.
2. The method of claim 1 , wherein the target tissue is bone marrow.
3. The method of claim 1 , wherein the toxin is selected from the group consisting of saporin, diphtheria toxin, pseudomonas exotoxin A, Ricin A chain derivatives, a small molecule toxin, and combinations thereof.
4. The method of claim 1 , wherein the toxin comprises an RNA polymerase II and/or III inhibitor.
5. The method of claim 4 , wherein the RNA polymerase II and/or III inhibitor comprises an amatoxin.
6. The method of claim 5 , wherein the amatoxin is selected from the group consisting of α-amanitin, β-amanitin, γ-amanitin, £-amanitin, amanin, amaninamide, amanullin, amanullinic acid and any functional fragments, derivatives or analogs thereof.
7. The method of claim 1 , wherein the toxin comprises a DNA-damaging molecule.
8. The method of claim 7 , wherein the DNA-damaging molecule is selected from the group consisting of an anti-tubulin agent, a DNA crosslinking agent, a DNA alkylating agent and a mitotic disrupting agent.
9. The method of claim 7 , wherein the DNA-damaging molecule comprises maytansine or a functional fragments, derivatives or analogs thereof.
10. The method of claim 1 , wherein the antibody is indirectly coupled to the toxin.
11. The method of claim 1 , wherein the antibody is coupled to a streptavidin-toxin chimera.
12. The method of claim 1 , wherein the antibody is biotinylated.
13. The method of claim 1 , wherein the method does not deplete or ablate the subject's endogenous neutrophils.
14. The method of claim 1 , wherein the method does not deplete or ablate the subject's endogenous platelets.
15. The method of claim 1 , wherein the antibody binds to a cell surface protein selected from the group consisting of CD45, CD49d (VLA-4), CD49f (VLA-6), CD51, CD84, CD90, CD133, CD134 and CD184 (CXCR4).
16. The method of claim 1 , wherein the antibody binds to a cell surface protein selected from the group consisting of HLA-DR, CD11a, CD18, CD34, CD41/61, CD43, CD58, CD71, CD97, CD162, CD166, CD205 and CD361.
17. The method of claim 1 , wherein the antibody binds to a cell surface protein selected from the group consisting of: CD13, CD33, CD34, CD44, CD4, CD59, CD84/CD150, CD90/Thy1, CD93, CD105/Endoglin, CD123/IL-3R, CD126/IL-6R, CD133, CD135/Flt3 receptor, CD166/ALCAM, Prominin 2, Erythropoietin R, Endothelial Cell-Selective Adhesion Molecule, CD244, Tie1, Tie2, MPL, G-CSFR, CSF3R, IL-1R, gp130, Leukemia inhibitory factor Receptor, oncostatin M receptor, Embigin and IL-18R.
18. The method of claim 1 , wherein the antibody binds to a cell surface protein selected from the group consisting of: CD7, CDw12, CD13, CD15, CD19, CD21, CD22, CD29, CD30, CD33, CD34, CD36, CD38, CD40, CD41, CD42a, CD42b, CD42c, CD42d, CD43, CD45RA, CD45RB, CD45RC, CD45RO, CD48, CD49b, CD49d, CD49e, CD49f, CD50, CD53, CD55, CD64a, CD68, CD71, CD72, CD73, CD81, CD82, CD85A, CD85K, CD90, CD99, CD104, CD105, CD109, CD110, CD111, CD112, CD114, CD115, CD123, CD124, CD126, CD127, CD130, CD131, CD133, CD135, CD138, CD151, CD157, CD162, CD164, CD168, CD172a, CD173, CD174, CD175, CD175s, CD176, CD183, CD191, CD200, CD201, CD205, CD217, CD220, CD221, CD222, CD223, CD224, CD225, CD226, CD227, CD228, CD229, CD230, CD235a, CD235b, CD236, CD236R, CD238, CD240, CD242, CD243, CD277, CD292, CDw293, CD295, CD298, CD309, CD318, CD324, CD325, CD338, CD344, CD349 and CD350.
19. The method of claim 1 , wherein the antibody binds to a cell surface protein selected from the group consisting of: CD11a, CD18, CD37, CD47, CD52, CD58, CD62L, CD69, CD74, CD97, CD103, CD132, CD156a, CD179a, CD179b, CD184, CD232, CD244, CD252, CD302, CD305, CD317 and CD361.
20. The method of claim 1 , wherein the antibody is anti-CD45 antibody clone 104 or anti-CXCR4 antibody clone 2B11.
21. The method of claim 1 , wherein the antibody is selected from the group consisting of clone L243, clone TS2/4, clone TS1/18, clone 581, clone 4H11, clone A2A9/6, clone CD43-10G7, clone BHPT-1, clone orb12060, clone 2D1, clone CC2C6, clone TS2/9, clone CY1G4, clone OKT9, clone CD84.1.21, clone VIM3b, clone EMK08, clone TMP4, clone KPL-1, clone 3a6, clone HD83 and clone MEM-216.
22. The method of claim 1 , wherein the antibody comprises a complementarity determining region that is the same as the complementarity determining region for one or more antibodies selected from the group consisting of L243, clone TS2/4, clone TS1/18, clone 581, clone 4H11, clone A2A9/6, clone CD43-10G7, clone BHPT-1, clone orb12060, clone 2D1, clone CC2C6, clone TS2/9, clone CY1G4, clone OKT9, clone CD84.1.21, clone VIM3b, clone EMK08, clone TMP4, clone KPL-1, clone 3a6, clone HD83 and clone MEM-216.
23. The method of claim 1 , wherein the antibody is bispecific.
24. A method of conditioning a subject for engraftment, the method comprising selectively depleting or ablating an endogenous hematopoietic stem cell (HSC) or progenitor cell population in a target tissue of an immunocompetent subject comprising administering to the subject an effective amount of an antibody coupled to a toxin, wherein the toxin is internalized by an endogenous HSC or progenitor cell population, thereby depleting or ablating the endogenous hematopoietic stem cell or progenitor cell population in the target tissue, wherein the method does not induce anemia in the subject, wherein the antibody binds to CD45, and wherein the toxin comprises an amatoxin.
25. The method of claim 24 , wherein the amatoxin is selected from the group consisting of α-amanitin, β-amanitin, γ-amanitin, £-amanitin, amanin, amaninamide, amanullin, amanullinic acid and any functional fragments, derivatives or analogs thereof.