Modified anti-PD-L1 Antibody and Methods and Uses for Treating a Neurodegenerative Disease
The present specification discloses modified anti-PD-L1 antibodies that abolishes Fc-related effector function and enhances clearance rate while maintaining therapeutic efficacy for neurodegenerative disease modification. The present specification also discloses nucleic acid sequences and expression constructs encoding such modified anti-PD-L1 antibodies as well as methods of making such modified anti-PD-L1 antibodies. In addition, the present specification discloses methods of treatment and uses that employ an administration regime of the disclosed anti-PD-L1 antibodies that ensures the antibodies are present for only a specific period of time and then are sufficiently cleared from the body to ensure treatment efficacy is maintained.
1 . A modified anti-Programmed Death Ligand 1 (PD-L1) antibody, comprising
a heavy chain comprising a heavy chain variable region including a CDR1 of SEQ ID NO: 3 or SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 or SEQ ID NO: 6, and a CDR3 of SEQ ID NO: 7 or SEQ ID NO: 8, and a heavy chain constant region of SEQ ID NO: 108, and
a light chain comprising a light chain variable region including CDR1 of SEQ ID NO: 10 or SEQ ID NO: 11, a CDR2 of SEQ ID NO: 12 or SEQ ID NO: 13 and a CDR3 of SEQ ID NO: 14 or SEQ ID NO 15,
wherein the heavy chain constant domain comprises a lower hinge region, a CH2 domain and a CH3 domain,
wherein the modified anti-PD-L1 antibody has one or more amino acid modifications in the CH2 domain and/or the CH3 domain to enhance a clearance rate of the modified anti-PD-L1 antibody from the blood relative to an anti-PD-L1 antibody without the one or more amino acid modifications, and
wherein the modified anti-PD-L1 antibody having one or more amino acid modifications in the lower hinge region and/or the CH2 domain to abolished Fc-related effector function.
2 . The modified anti-PD-L1 antibody according to claim 1 , comprising a heavy chain constant domain of SEQ ID NO: 108 and wherein the one or more amino acid modifications to enhance a clearance rate of the modified anti-PD-L1 antibody is located at H315 and/or H440.
3 . The modified anti-PD-L1 antibody according to claim 2 , wherein the heavy chain constant domain is SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57.
4 . The modified anti-PD-L1 antibody according to claim 1 , wherein the heavy chain constant domain is SEQ ID NO: 108, and wherein the one or more amino acid modifications to abolish Fc-related effector function are located at L239, L240, and/or K327.
5 . The modified anti-PD-L1 antibody according to claim 4 , wherein the heavy chain constant domain is SEQ ID NO: 108, and wherein the one or more amino acid modifications to enhance a clearance rate of the modified anti-PD-L1 antibody is located at H315 and/or H440.
6 . The modified anti-PD-L1 antibody according to claim 5 , wherein the heavy chain constant domain is SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57.
7 . The modified anti-PD-L1 antibody according to claim 1 , wherein the heavy chain is SEQ ID NO: 38, and wherein the one or more amino acid modifications to enhance a clearance rate of the modified anti-PD-L1 antibody is located at H315 and/or H440.
8 . The modified anti-PD-L1 antibody according to claim 7 , wherein the heavy chain is SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44.
9 . The modified anti-PD-L1 antibody according to claim 1 , wherein the heavy chain is SEQ ID NO: 38, and wherein the one or more amino acid modifications to abolish Fc-related effector function are located at L239, L240, and/or K327.
10 . The modified anti-PD-L1 antibody according to claim 9 , wherein the heavy chain is SEQ ID NO: 38, and wherein the one or more amino acid modifications to enhance a clearance rate of the modified anti-PD-L1 antibody is located at H315 and/or H440.
11 . The modified anti-PD-L1 antibody according to claim 10 , wherein the heavy chain is SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44.
12 . The modified anti-PD-L1 antibody according to claim 1 , wherein the heavy chain variable region of SEQ ID NO: 2.
13 . The modified anti-PD-L1 antibody according to claim 1 , wherein the light chain variable region is SEQ ID NO: 9.
14 . The modified anti-PD-L1 antibody according to claim 1 , wherein the light chain further comprises a kappa light chain constant region.
15 . The modified anti-PD-L1 antibody according to claim 14 , wherein the kappa light chain constant region is SEQ ID NO: 16.
16 . The modified anti-PD-L1 antibody according to claim 1 , wherein the light chain is SEQ ID NO: 21.
17 . A pharmaceutical kit comprising a modified anti-PD-L1 antibody as defined in claim 1 .
18 . A pharmaceutical composition comprising a modified anti-PD-L1 antibody as defined in claim 1 .