Cyclodextrin protein drug conjugates

1. A compound, or a pharmaceutically acceptable salt thereof,

wherein the compound

(i) is according to formula (Ib1), (Ib2), or (Ic1):

(ii) is according to a formula selected from:

wherein BA is an antibody or an antigen binding fragment thereof;

LL is a trivalent linker;

SP is, independently in each instance, absent or is a spacer;

n is an integer from 1 to 30; and

PA is a payload moiety; or

a regioisomer and/or stereoisomer thereof; or

(iii) is according to Formula (Ie):

wherein:

BA is an antibody or an antigen binding fragment thereof;

RG is, independently in each instance, a reactive group residue;

SP 2 is, independently in each instance, absent or a spacer group residue;

AA 2 is a di-peptide residue;

PEG is a polyethylene glycol residue;

PAB is

 wherein the

 indicates the atom through which the PAB is bonded to the adjacent groups in the formula;

CD is a cyclodextrin residue,

subscript n is an integer from 1 to 30;

subscript m is an integer from 0 to 5;

subscript p is 0 or 1; and

PA is a payload moiety.

2. The compound of claim 1 , according to formula (Ib1) or (Ib2):

or a regioisomer and/or stereoisomer thereof.

3. The compound of claim 1 , according to formula (Ib3), (Ib4), (Ib5), or (Ib6):

or a regioisomer and/or stereoisomer thereof.

4. The compound of claim 1 , according to formula (Ic1):

or a regioisomer and/or stereoisomer thereof.

5. The compound of claim 1 , according to Formula (Ie):

6. The compound of claim 1 , according to Formula (Ie1):

wherein:

BA is an antibody or an antigen binding fragment thereof;

RG is a reactive group residue;

SP 2 is, independently in each instance, absent or a spacer group residue;

AA 2 is a di-peptide residue;

PEG is a polyethylene glycol residue;

PAB is

wherein the

indicates the atom through which the PAB is bonded to the adjacent groups in the formula;

CD is a cyclodextrin residue;

subscript n is an integer from 1 to 30;

subscript m is an integer from 0 to 5;

subscript p is 0 or 1; and

PA is a payload moiety.

7. The compound of claim 1 , according to Formula (Ie2):

wherein:

BA is an antibody or an antigen binding fragment thereof;

RG is a reactive group residue;

SP 2 is, independently in each instance, absent or a spacer group residue;

AA 2 is a di-peptide residue;

PEG is a polyethylene glycol residue;

PAB is

wherein the

indicates the atom through which the PAB is bonded to the adjacent groups in the formula;

CD is a cyclodextrin residue;

subscript n is an integer from 1 to 30;

subscript m is an integer from 0 to 5;

subscript p is 0 or 1; and

PA is a payload moiety.

8. The compound of claim 1 , wherein CD is, independently in each instance, selected from the group consisting of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.

9. The compound of claim 1 , wherein CD is, independently in each instance, selected from the group consisting of

wherein the

indicates the atom through which the CD is bonded to the adjacent groups in the formula.

10. The compound of claim 1 , wherein RG is, independently in each instance, a click chemistry residue.

11. The compound of claim 1 , wherein RG, independently in each instance, comprises a triazole or a fused triazole.

12. The compound of claim 1 , wherein RG is, independently in each instance, selected from the group consisting of

wherein the

indicates the atom through which the RG is bonded to the adjacent groups in the formula.

13. The compound of claim 1 , wherein -LL- is according to the Formula (LL1):

wherein R AA1 , R AA2 , and R AA3 are each, independently, amino acid side chains, at least one of which is bonded directly or indirectly to -SP-RG-SP-CD, wherein one or both SP may be absent.

14. The compound of claim 13 , wherein R AA1 is a lysine side chain bonded directly or indirectly to CD and R AA2 and R AA3 are either valine and citrulline or valine and alanine side chains, respectively.

15. The compound of claim 13 , wherein

16. The compound of claim 1 , wherein the spacer group is, independently in each instance, selected from the group consisting of C 1-6 alkylene, —NH—, —C(O)—, (—CH 2 —CH 2 —O) e , —NH—CH 2 —CH 2 —(—O—CH 2 —CH 2 ) e —C(O)—, —C(O)—(CH 2 ) u —C(O)—, —C(O)—NH—(CH 2 ) v —, and combinations thereof, wherein subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8.

17. The compound of claim 16 , wherein e is 4.

18. The compound of claim 17 , wherein subscript p is 1.

19. The compound of claim 1 , wherein subscript n is 2-4.

20. The compound of claim 1 , wherein the antibody or antigen-binding fragment thereof is selective for an antigen selected from the group consisting of AXL, BAFFR, BCMA, BCR-list components, BDCA2, BDCA4, BTLA, BTNL2, BTNL3, BTNL8, BTNL9, C10 or f54, CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR9, CCR10, CD11c, CD137, CD138, CD14, CD168, CD177, CD19, CD20, CD209, CD209L, CD22, CD226, CD248, CD25, CD27, CD274, CD276, CD28, CD30, CD300A, CD33, CD37, CD38, CD4, CD40, CD44, CD45, CD46, CD48, CD5, CD52, CD55, CD56, CD59, CD62E, CD68, CD69, CD70, CD74, CD79a, CD79b, CD8, CD80, CD86, CD90.2, CD96, CLEC12A, CLEC12B, CLEC7A, CLEC9A, CR1, CR3, CRTAM, CSF1R, CTLA4, CXCR1/2, CXCR4, CXCR5, DDR1, DDR2, DEC-205, DLL4, DR6, FAP, FCamR, FCMR, FcR's, Fire, GITR, HHLA2, HLA class II, HVEM, ICOSLG, IFNLR1, IL10R1, IL10R2, IL12R, IL13RA1, IL13RA2, IL15R, IL17RA, IL17RB, IL17RC, IL17RE, IL20R1, IL20R2, IL21R, IL22R1, IL22RA, IL23R, IL27R, IL29R, IL2Rg, IL31R, IL36R, IL3RA, IL4R, IL6R, IL5R, IL7R, IL9R, Integrins, LAG3, LIFR, MAG/Siglec-4, MMR, MSR1, NCR3LG1, NKG2D, NKp30, NKp46, PDCD1, PROKR1, PVR, PVRIG, PVRL2, PVRL3, RELT, SIGIRR, Siglec-1, Siglec-10, Siglec-5, Siglec-6, Siglec-7, Siglec-8, Siglec-9, SIRPA, SLAMF7, TACI, TCR-list components/assoc, PTCRA, TCRb, CD3z, CD3, TEK, TGFBR1, TGFBR2, TGFBR3, TIGIT, TLR2, TLR4, TROY, TSLPR, TYRO, VLDLR, VSIG4, and VTCN1.

21. The compound of claim 1 , wherein PA is a residue of a group selected from the group consisting of a dolastatin, an auristatin, a maytansinoid, a plant alkaloid, a taxane, a vinca alkaloid, a steroid, an LXR modulator, and combinations thereof.

22. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. The compound of claim 1 , wherein subscript m is 4.

24. The compound of claim 5 , wherein subscript m is 4.

25. The compound of claim 6 , wherein subscript m is 4.

26. The compound of claim 7 , wherein subscript m is 4.

27. A compound according to Formula (If):

wherein:

BA is an antibody or an antigen binding fragment thereof;

RG is, independently in each instance, a reactive linker residue;

SP 1 , SP 2 , and SP 3 are each, independently in each instance, absent or a spacer group residue;

AA 2 is a di-peptide residue;

PEG is a polyethylene glycol residue;

PAB is

wherein the

indicates the atom through which the PAB is bonded to the adjacent groups in the formula;

CD is a cyclodextrin residue;

subscript n is an integer from 1 to 30;

subscript m is an integer from 0 to 5;

subscript q is an integer from 0 to 5;

subscript p is 0 or 1; and

PA is a payload moiety.

28. The compound of claim 21 , wherein PA is selected from the group consisting of

wherein the

indicates the atom through which the PA is bonded to the adjacent groups in the formula.

29. The compound of claim 1 wherein the payload moiety is a drug moiety.

30. The compound of claim 1 wherein the payload moiety is a biologically active molecule.

31. The compound of claim 1 wherein the payload moiety is the residue of a group selected from the group consisting of dolastatins, auristatins, maytansinoids, plant alkaloids, taxanes, vinca alkaloids, steroids, LXR modulators, pyrrolobenzodiazepines, tubulysins, and camptothecins.

32. The compound of claim 1 wherein the payload moiety is the residue of a maytansinoid, steroid, LXR modulator, pyrrolobenzodiezepine, tubulysin, or camptothecin.

33. The compound of claim 1 wherein the payload moiety is a residue of an auristatin.

34. The compound of claim 1 wherein the payload moiety is a residue of a maytansinoid.

35. The compound of claim 1 wherein the payload moiety is a residue of a glucocorticoid.

36. The compound of claim 1 wherein the payload moiety is a residue of a liver X receptor modulator.

37. The compound of claim 1 , wherein the antibody or the antigen-binding fragment thereof is coupled to a primary amine compound by a transglutaminase-mediated coupling.

38. The compound of claim 1 , wherein the glutaminyl-modified antibody is an antibody modified with an azido-polyethylene glycol compound.

39. The compound of claim 1 , wherein the binding agent is an antibody conjugated to a reactive group compound at a glutamine residue, and LL is bonded to BA through said reactive group compound.

40. The compound of claim 39 , wherein the reactive group compound comprises a divalent polyethylene glycol group.

41. The compound of according to Formula (Id):

wherein:

BA is an antibody or antigen binding fragment thereof;

RG is a reactive group residue independently selected from

wherein the

 indicates the atom through which the RG is bonded to the adjacent groups in the formula;

SP 1 and SP 2 are each, independently in each instance, a spacer group residue, and wherein SP 1 comprises a trivalent linker when attached to —CD;

or SP 1 -CD or SP 2 are independently, in each instance, absent;

AA 1 is a trivalent linker comprising an amino acid residue;

AA 2 is a di-peptide residue;

PEG is a polyethylene glycol residue;

PAB is

 wherein the

 indicates the atom through which the PAB is bonded to the adjacent groups in the formula;

CD is, independently in each instance, absent, a cyclodextrin, or a modified cyclodextrin wherein the modified cyclodextrin is —SP 3 —RG-cyclodextrin; and, wherein at least one of CD is present;

SP 3 is, independently in each instance, absent or a spacer group residue selected from the group consisting of C 1-6 alkylene, —NH—, —C(O)—, (—CH 2 —CH 2 —O), —NH—CH 2 —CH 2 —(—O—CH 2 —CH 2 ) e —C(O)—, —C(O)—(CH 2 ) u —C(O)—, —C(O)—NH—(CH 2 ) y — and combinations thereof;

Cyclodextrin is selected from

wherein the

 indicates the atom through which the cyclodextrin is bonded to the adjacent groups in the formula;

subscript n is an integer from 1 to 30;

subscript m is an integer from 0 to 5;

subscript p is 0 or 1; and

PA is a payload moiety.

42. The compound of claim 41 , wherein

is selected from the group consisting of

or a pharmaceutically acceptable salt, or stereoisomeric form thereof, or a regioisomer thereof, or mixture of regioisomers thereof, wherein:

each

is a bond to the antibody or an antigen binding fragment thereof;

each

is a bond to the payload; and

R 9 is —CH 3 or —(CH 2 ) 3 N(H)C(O)NH 2 .

43. The compound of claim 42 , comprising a group selected from the group consisting of

or a pharmaceutically acceptable salt, or stereoisomeric form thereof, or a regioisomer thereof, or mixture of regioisomers thereof, wherein:

each

is a bond to the antibody or an antigen binding fragment thereof; and

each

is a bond to the payload.

44. The compound of claim 43 , wherein the compound is selected from:

or a stereoisomeric form, or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody or antigen-binding fragment thereof;

PA is a payload moiety; and

n is an integer from 1 to 30.

45. The compound of claim 43 , wherein the compound is selected from:

or a stereoisomeric form, or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody or antigen-binding fragment thereof; and n is an integer from 1 to 30.

46. The compound of claim 27 , wherein any one of subscript m and q is 4.

47. A compound wherein the compound

(i) is according to formula (IIb1), (IIb2), or (IIc2):

(ii) is according to a formula selected from:

wherein:

L is composed of LL, SP, and RG;

RG′ is a reactive group;

LL is a trivalent linker;

SP is, independently in each instance, absent or a spacer group;

RG is a reactive group residue; and

PA is a payload moiety; or

a regioisomer, stereoisomer, or mixture thereof;

or

is according to Formula (IIe):

wherein:

RG′ is a reactive group;

SP 2 is, independently in each instance, absent or a spacer group residue;

AA 1 is a trivalent linker comprising an amino acid residue;

AA 2 is a di-peptide residue;

PEG is a polyethylene glycol residue;

PAB is

 wherein the

 indicates the atom through which the PAB is bonded to the adjacent groups in the formula;

CD is, independently in each instance, absent or a cyclodextrin residue, wherein at least one CD is present;

subscript m is an integer from 0 to 5;

subscript p is 0 or 1; and

PA is a payload moiety.

48. The compound of claim 47 , according to formula (IIb1) or (IIb2):

wherein RG′ is a reactive group;

LL is a trivalent linker;

SP is, independently in each instance, absent or is a spacer; and

PA is a payload moiety; or

a regioisomer, stereoisomer, or mixture thereof.

49. The compound of claim 47 , according to formula (IIb3), (IIb4), (IIb5), or (IIb6):

wherein subscript e is an integer from 0 to 4;

or a regioisomer, stereoisomer, or mixture thereof.

50. The compound of claim 47 , according to formula (IIc1):

51. The compound of claim 47 , wherein the compound is:

or a stereoisomeric form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof.

52. The compound of claim 47 wherein the payload moiety is a drug moiety.

53. The compound of claim 47 wherein the payload moiety is a biologically active molecule.

54. The compound of claim 47 wherein the payload moiety is the residue of a group selected from the group consisting of dolastatins, auristatins, maytansinoids, plant alkaloids, taxanes, vinca alkaloids, steroids, LXR modulators, pyrrolobenzodiazepines, and SN-38.

55. The compound of claim 47 wherein the payload moiety is the residue of a maytansinoid, steroid, LXR modulator, pyrrolobenzodiezepine, or camptothecin.

56. The compound of claim 47 wherein the payload moiety is a residue of an auristatin.

57. The compound of claim 47 wherein the payload moiety is a residue of a maytansinoid.

58. The compound of claim 47 wherein the payload moiety is a residue of a glucocorticoid.

59. The compound of claim 47 wherein the payload moiety is a residue of a liver X receptor modulator.