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 human subject for engraftment, the method comprising selectively depleting or ablating endogenous hematopoietic stem cells (HSCs) or a progenitor cell population in a target tissue of an immunocompetent human subject comprising administering to the subject an effective amount of an antibody, or antigen-binding fragment thereof, coupled to a toxin,
wherein:
the antibody or antigen-binding fragment binds to CD117 cell surface protein;
the method does not induce anemia in the subject; and
the toxin is internalized by an endogenous HSCs or progenitor cell population, thereby depleting or ablating the endogenous HSCs or progenitor cell population in the target tissue.
2. The method of claim 1 , wherein the antibody or antigen-binding fragment is indirectly coupled to the toxin.
3. The method of claim 1 , wherein the antibody or antigen-binding fragment is coupled to a streptavidin-toxin chimera.
4. The method of claim 1 , wherein the antibody or antigen-binding fragment is biotinylated.
5. The method of claim 1 , wherein the method does not deplete or ablate the subject's endogenous neutrophils.
6. The method of claim 1 , wherein the method does not deplete or ablate the subject's endogenous platelets.
7. The method of claim 1 , wherein the antibody is clone 2B8 or clone A3C6E2.
8. The method of claim 1 , wherein the antibody is bispecific.
9. The method of claim 1 , wherein the toxin is selected from the group consisting of saporin, diphtheria toxin, pseudomonas exotoxin A, a Ricin A chain derivative, a small molecule toxin, and combinations thereof.
10. The method of claim 1 , wherein the toxin comprises an RNA polymerase II and/or III inhibitor.
11. The method of claim 1 , wherein the toxin comprises an amatoxin.
12. The method of claim 11 , 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.
13. The method of claim 1 , wherein the target tissue is bone marrow.
14. The method of claim 1 , wherein the antibody is biotinylated.
15. The method of claim 1 , wherein the antibody is coupled to a streptavidin-toxin chimera.