Superkine
Contemplated compositions and methods comprise chimeric molecule complexes that advantageously provide activating signaling to immune competent cells when bound to ALL cells. Furthermore, chimeric molecule complexes include an Fc portion to extend serum half live time and facilitate purification.
1. A chimeric molecule complex, comprising:
a first fusion protein comprising an Fc domain, an IL15 receptor alpha chain, and a first affinity domain, wherein the first affinity domain specifically binds to a CD molecule selected from CD19, CD20, and CD22; and
a second fusion protein comprising an IL15 domain and a second affinity domain, wherein the second affinity domain specifically binds to a CD molecule selected from CD19, CD20, and CD22; and
wherein the first and second fusion proteins form a complex via the IL15 domain and the IL15 receptor alpha chain, and wherein (i) the IL15 receptor alpha chain and the first affinity domain are coupled to each other via a first binding domain, (ii) the IL15 domain and the second affinity domain are coupled to each other via a second binding domain, or (iii) the IL15 receptor alpha chain and the first affinity domain are coupled to each other via a first binding domain and the IL15 domain and the second affinity domain are coupled to each other via a second binding domain.
2. The molecule complex of claim 1 , wherein at least one of the first affinity domain or second affinity domain comprise an scFv.
3. The molecule complex of claim 1 , wherein at least one of the first binding domain and the second binding domain comprises at least a portion of one or more of biotin, Protein A, Protein B, and an RNA fragment.
4. The molecule complex of claim 1 , wherein at least one of the first and second fusion proteins further comprises an affinity domain that binds to CD3.
5. The molecule complex of claim 1 , wherein the Fc domain of the first fusion protein comprises at least a portion of one or more of an IgG, IgM, IgA, IgD, and IgE antibody.
6. The molecule complex of claim 1 , forming at least a dimer with at least a second chimeric molecule complex.
7. The molecule complex of claim 6 , wherein the second chimeric molecule complex comprises:
a third fusion protein comprising an Fc domain, an IL15 receptor alpha chain, and a third affinity domain, wherein the third affinity domain specifically binds to a CD molecule selected from CD19, CD20, and CD22; and
a fourth fusion protein comprising an IL15 domain and a fourth affinity domain, wherein the fourth affinity domain specifically binds to a CD molecule selected from CD19, CD20, and CD22; and
wherein the third and fourth fusion proteins form a complex via the IL15 domain and the IL15 receptor alpha chain.
8. The molecule complex of claim 7 , wherein the third and the fourth affinity domains do not each bind the same CD molecule.
9. The molecule complex of claim 7 , wherein at least one of the third and the fourth affinity domain does not bind the same CD molecule with respect to the first and the second affinity domain.
10. The molecule complex of claim 7 , wherein at least one of the first, second, third, and fourth affinity domains comprise an scFv.
11. The molecule complex of claim 1 , wherein the IL15 receptor alpha chain and the first affinity domain form a single polypeptide.
12. The molecule complex of claim 1 , wherein at least one Fc domain of the first and third fusion protein is coupled to an albumin.
13. The molecule complex of claim 1 , wherein at least one of the first affinity domain and the second affinity domain is a BiKE or TriKE.
14. The molecule complex of claim 1 , wherein at least one of the first affinity domain and the second affinity domain comprises a scFv domain with CDR regions of a therapeutic antibody against one of CD19, CD20, and CD22.
15. The molecule complex of claim 14 wherein the therapeutic antibody is selected from the group consisting of blinatumomab, denintuzumab, rituximab, taplitumomab, afutuzumab, ofatumumab, obinutuzumab, lymphomun, ibritumomab, ocrelizumab, ocaratuzumab, ublituximab, veltuzumab, bectumomab, epratuzumab, inotuzumab, moxetumomab, and pinatuzumab.
16. The molecule complex of claim 1 , wherein (i) the IL15 domain comprises an IL15 N72D mutant, (ii) the IL15 receptor alpha chain comprises IL15Rα, or (iii) the IL15 domain comprises an IL15 N72D mutant and the IL15 receptor alpha chain comprises IL15Rα.
17. The molecule complex of claim 1 , wherein the IL15 domain and the second affinity domain form a single polypeptide.
18. The molecule complex of claim 11 , wherein the IL15 domain and the second affinity domain form a single polypeptide.