IP Library › Patent Application 18819116
Patent Application
App. No. 18/819,116

TARGETED IMMUNOTOLERANCE WITH A PD-1 AGONIST

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Patent No.
US None
App. No.
18/819,116
Abstract

Methods and polypeptides for conferring site-specific or local immune privilege.

Claims (72)

1 . A compound comprising a first component and a second component, wherein:

the first component is a protein of a formula of:

V H -H c -Linker-C 1 , wherein:

V H is the variable heavy chain domain of an anti-PD-1 antibody;

H c is a domain of a heavy chain of antibody comprising the CH1-CH2-CH3 domain and not the V H ,

the Linker is a peptide linker,

and C 1 is an anti-MAdCAM antibody;

the second component is a protein of a formula of:

V L -L c , wherein:

V L is the variable light chain domain of the anti-PD-1 antibody; and

L c is a domain of a light chain of antibody comprising the CL domain and not the V L , and

the variable heavy chain domain and variable light chain domain of the anti-PD-1 antibody, respectively, comprises

a heavy chain variable region comprising a first CDR of SEQ ID NO: 639, a second CDR of SEQ ID NO: 69, and a third CDR of SEQ ID NO: 640 and a light chain variable region comprising a first CDR of SEQ ID NO: 641, a second CDR of SEQ ID NO: 362, and a third CDR of SEQ ID NO: 642,

a heavy chain variable region comprising a first CDR of SEQ ID NO: 757, a second CDR of SEQ ID NO: 758, and a third CDR of SEQ ID NO: 759 and a light chain variable region comprising a first CDR of SEQ ID NO: 760, a second CDR of SEQ ID NO: 378, and a third CDR of SEQ ID NO: 761,

a heavy chain variable region comprising a first CDR of SEQ ID NO: 706, a second CDR of SEQ ID NO: 707, and a third CDR of SEQ ID NO: 708 and a light chain variable region comprising a first CDR of SEQ ID NO: 709, a second CDR of SEQ ID NO: 362, and a third CDR of SEQ ID NO: 421,

a heavy chain variable region comprising a first CDR of SEQ ID NO: 712, a second CDR of SEQ ID NO: 713, and a third CDR of SEQ ID NO: 714 and a light chain variable region comprising a first CDR of SEQ ID NO: 715, a second CDR of SEQ ID NO: 716, and a third CDR of SEQ ID NO: 717,

a heavy chain variable region comprising a first CDR of SEQ ID NO: 726, a second CDR of SEQ ID NO: 727, and a third CDR of SEQ ID NO: 728 and a light chain variable region comprising a first CDR of SEQ ID NO: 729, a second CDR of SEQ ID NO: 420, and a third CDR of SEQ ID NO: 730, or

a heavy chain variable region comprising a first CDR of SEQ ID NO: 757, a second CDR of SEQ ID NO: 758, and a third CDR of SEQ ID NO: 759 and a light chain variable region comprising a first CDR of SEQ ID NO: 760, a second CDR of SEQ ID NO: 378, and a third CDR of SEQ ID NO: 761.

2 . The compound of claim 1 , wherein the peptide linker is a glycine/serine linker.

3 . The compound of claim 1 , wherein the anti-MAdCAM antibody is an scFV antibody,

wherein the scFV antibody has a formula of:

VH SC -L SC -VL SC , wherein:

VH SC comprises a variable heavy chain domain that binds to MAdCAM in conjunction with the VL SC ;

L SC is a peptide linker; and

VL SC comprises a variable light chain domain that binds to MAdCAM in conjunction with the VH SC .

4 . A compound comprising a first component,

wherein the first component is a protein of a formula of:

PD1VH-ConstantDomain-LinkerA-MAdCAMscFv,

wherein the PD1VH is a PD-1 heavy chain variable domain of an anti-PD-1 antibody;

the ConstantDomain is an IgG1 constant domain, or any other constant domain such as IgG2, IgG3, or IgG4;

Linker A is a G/S or a G/A linker,

MAdCAMscFv is of the following formula:

MAdCAMVH-LinkerB-MAdCAMVK,

wherein MAdCAMVH is a MAdCAM heavy chain variable domain;

Linker B is a G/S or a G/A linker; and

MAdCAMVK is a light chain variable domain, and wherein

the PD1VH comprises a first CDR of SEQ ID NO: 639, a second CDR of SEQ ID NO: 69, and a third CDR of SEQ ID NO: 640,

the PD1VH comprises a first CDR of SEQ ID NO: 757, a second CDR of SEQ ID NO: 758, and a third CDR of SEQ ID NO: 759,

the PD1VH comprises a first CDR of SEQ ID NO: 706, a second CDR of SEQ ID NO: 707, and a third CDR of SEQ ID NO: 708,

the PD1VH comprises a first CDR of SEQ ID NO: 712, a second CDR of SEQ ID NO: 713, and a third CDR of SEQ ID NO: 714, or

the PD1VH comprises a first CDR of SEQ ID NO: 726, a second CDR of SEQ ID NO: 727, and a third CDR of SEQ ID NO: 728.

5 . An antibody that binds to PD-1, wherein the antibody comprises

a heavy chain variable region comprising a first CDR of SEQ ID NO: 639, a second CDR of SEQ ID NO: 69, and a third CDR of SEQ ID NO: 640 and a light chain variable region comprising a first CDR of SEQ ID NO: 641, a second CDR of SEQ ID NO: 362, and a third CDR of SEQ ID NO: 642;

a heavy chain variable region comprising a first CDR of SEQ ID NO: 757, a second CDR of SEQ ID NO: 758, and a third CDR of SEQ ID NO: 759 and a light chain variable region comprising a first CDR of SEQ ID NO: 760, a second CDR of SEQ ID NO: 378, and a third CDR of SEQ ID NO: 761;

a heavy chain variable region comprising a first CDR of SEQ ID NO: 706, a second CDR of SEQ ID NO: 707, and a third CDR of SEQ ID NO: 708 and a light chain variable region comprising a first CDR of SEQ ID NO: 709, a second CDR of SEQ ID NO: 362, and a third CDR of SEQ ID NO: 421;

a heavy chain variable region comprising a first CDR of SEQ ID NO: 712, a second CDR of SEQ ID NO: 713, and a third CDR of SEQ ID NO: 714 and a light chain variable region comprising a first CDR of SEQ ID NO: 715, a second CDR of SEQ ID NO: 716, and a third CDR of SEQ ID NO: 717;

a heavy chain variable region comprising a first CDR of SEQ ID NO: 726, a second CDR of SEQ ID NO: 727, and a third CDR of SEQ ID NO: 728 and a light chain variable region comprising a first CDR of SEQ ID NO: 729, a second CDR of SEQ ID NO: 420, and a third CDR of SEQ ID NO: 730; or

a heavy chain variable region comprising a first CDR of SEQ ID NO: 757, a second CDR of SEQ ID NO: 758, and a third CDR of SEQ ID NO: 759 and a light chain variable region comprising a first CDR of SEQ ID NO: 760, a second CDR of SEQ ID NO: 378, and a third CDR of SEQ ID NO: 761.

6 . The antibody of claim 5 , wherein the antibody that binds to PD-1 is associated, either directly or indirectly, to another moiety.

7 . A pharmaceutical composition comprising the compound of claim 1 .

8 . A method of treating a subject with a disorder, comprising administering the compound of claim 1 to the subject to treat the disorder, wherein the disorder is inflammatory bowel disease, Crohn's disease, ulcerative colitis, auto-immune hepatitis, primary sclerosing cholangitis, Type 1 diabetes, or graft versus host disease (GVHD).

9 . A nucleic acid encoding the first component and/or the second component of claim 1 .

10 . A cell comprising the nucleic acid of claim 9 .

11 . A method of making the compound of claim 1 comprising culturing a cell comprising a nucleic acid molecule encoding the first component and/or second component to make the compound.

12 . The compound of claim 4 , wherein the compound comprises a second component that is a protein of a formula of PD1VL-ConstantDomainLight, wherein PD1VL is a light chain variable domain of the anti-PD-1 antibody and the ConstantDomainLight is an IgG K domain, wherein:

the PD1VH comprises a first CDR of SEQ ID NO: 639, a second CDR of SEQ ID NO: 69, and a third CDR of SEQ ID NO: 640, and the PD1VL comprises a first CDR of SEQ ID NO: 641, a second CDR of SEQ ID NO: 362, and a third CDR of SEQ ID NO: 642;

the PD1VH comprises a first CDR of SEQ ID NO: 757, a second CDR of SEQ ID NO: 758, and a third CDR of SEQ ID NO: 759, and the PD1VL comprises a first CDR of SEQ ID NO: 760, a second CDR of SEQ ID NO: 378, and a third CDR of SEQ ID NO: 761;

the PD1VH comprises a first CDR of SEQ ID NO: 706, a second CDR of SEQ ID NO: 707, and a third CDR of SEQ ID NO: 708, and the PD1VL comprises a first CDR of SEQ ID NO: 709, a second CDR of SEQ ID NO: 362, and a third CDR of SEQ ID NO: 421;

the PD1VH comprises a first CDR of SEQ ID NO: 712, a second CDR of SEQ ID NO: 713, and a third CDR of SEQ ID NO: 714, and the PD1VL comprises a first CDR of SEQ ID NO: 715, a second CDR of SEQ ID NO: 716, and a third CDR of SEQ ID NO: 717;

the PD1VH comprises a first CDR of SEQ ID NO: 726, a second CDR of SEQ ID NO: 727, and a third CDR of SEQ ID NO: 728, and the PD1VL comprises a first CDR of SEQ ID NO: 729, a second CDR of SEQ ID NO: 420, and a third CDR of SEQ ID NO: 730; or

the PD1VH comprises a first CDR of SEQ ID NO: 757, a second CDR of SEQ ID NO: 758, and a third CDR of SEQ ID NO: 759, and the PD1VL comprises a first CDR of SEQ ID NO: 760, a second CDR of SEQ ID NO: 378, and a third CDR of SEQ ID NO: 761.

13 . A pharmaceutical composition comprising the compound of claim 12 .

14 . A method of treating a subject with a disorder, comprising administering the compound of claim 12 to the subject to treat the disorder, wherein the disorder is inflammatory bowel disease, Crohn's disease, ulcerative colitis, auto-immune hepatitis, primary sclerosing cholangitis, Type 1 diabetes, or graft versus host disease (GVHD).

15 . A nucleic acid encoding the first component and/or the second component of claim 12 .

16 . A cell comprising the nucleic acid of claim 15 .

17 . A method of making the compound of claim 12 comprising culturing a cell comprising a nucleic acid molecule encoding the first component and/or the second component to make the compound.

18 . A pharmaceutical composition comprising the antibody of claim 5 .

19 . A method of treating a subject with a disorder, comprising administering the antibody of claim 5 to the subject to treat the disorder, wherein the disorder is inflammatory bowel disease, Crohn's disease, ulcerative colitis, auto-immune hepatitis, primary sclerosing cholangitis, Type 1 diabetes, or graft versus host disease (GVHD).

20 . A nucleic acid encoding the antibody of claim 5 .

21 . A cell comprising the nucleic acid of claim 20 .

22 . A method of making the compound of claim 4 comprising culturing a cell comprising a nucleic acid molecule encoding the first component and the second component to make the compound.

23 . The compound of claim 1 , wherein the anti-MAdCAM antibody comprises the CDRs of Clone ID: 6, Clone ID: 75, or Clone ID: 79 of MAdCAM Antibody Table 2.