Antibody variant combinations and uses thereof
The invention relates to combination therapy involving two or more antibodies, wherein the Fc regions of the two antibodies have been modified such that hetero-oligomerization between the antibodies is strongly favored over self-oligomerization when antibodies are bound to their corresponding target antigens and such that hetero-oligomerization-independent effector functions of one or both antibodies are eliminated or strongly reduced. The invention also relates to antibodies, compositions, and kits suitable for use in the combination therapy of the invention.
1 . A method of treating cancer, the method comprising administering an effective amount of a first antibody comprising a first Fc region of a human IgG and a first antigen-binding region capable of binding to a first antigen and a second antibody comprising a second Fc region of a human IgG and a second antigen-binding region capable of binding to a second antigen,
wherein said first Fc region comprises:
a. a substitution at position E430, a substitution at position E345, or a combination of the substitutions K248E and T437R, and
b. a K439E or S440K substitution,
and said second Fc region comprises
c. a substitution at position E430, a substitution at position E345, or a combination of the substitutions K248E and T437R, and
d. a K439E or S440K substitution,
wherein the first Fc region has a K439E substitution and the second Fc region has an S440K substitution, or the first Fc region has an S440K substitution and the second Fc region has a K439E substitution,
wherein the first antibody and/or the second antibody does not comprise N-linked glycosylation at position N297, and
wherein the amino acid positions correspond to human IgG1 according to the Eu numbering system.
2 . The method of claim 1 , wherein the first Fc region and/or second Fc region comprises an amino acid substitution at position N297 or at position T299, wherein the substitution at position T299 is not T299S.
3 . The method of claim 1 , wherein
a. the first Fc region comprises a K439E substitution and a Y436N substitution and the second Fc region comprises a S440K substitution and a Q438R substitution, or
b. the first Fc region comprises a K439E substitution and a Q438R substitution and the second Fc region comprises a S440K substitution and a Y436N substitution, or
c. the first Fc region comprises a S440K substitution and a Y436N substitution and the second Fc region comprises a K439E substitution and a Q438R substitution, or
d. the first Fc region comprises a S440K substitution and a Q438R substitution and the second Fc region comprises a K439E substitution and a Y436N substitution.
4 . The method of claim 1 , wherein the first Fc region and the second Fc region comprise a substitution selected from the group consisting of: E345K, E430G, E345R, E430Y, E345Q, E345Y, E430S, E430T, and E430F, and/or the combination of the substitutions K248E and T437R.
5 . The method of claim 1 , wherein the first Fc region and the second Fc region comprise:
a. a substitution selected from the group consisting of: E345K, E430G, E345R, and E430Y,
b. a substitution selected from the group consisting of: E430G and E345K,
c. a substitution selected from the group consisting of: E345R and E430Y, or
d. a combination of the substitutions K248E and T437R.
6 . The method of claim 1 , wherein the first Fc region and/or the second Fc region comprise one or more substitution(s) selected from the group consisting of: E333S, K326A, E333A, and K326W.
7 . The method of claim 1 , wherein the first antibody and/or second antibody is human, humanized or chimeric.
8 . The method of claim 1 , wherein the first antibody and/or second antibody is a monoclonal antibody.
9 . The method of claim 1 , wherein the first antibody and/or second antibody is a human IgG1, IgG2, IgG3 or IgG4 subclass.
10 . The method of claim 1 , wherein:
a. the first and second antigens are both cell surface-expressed molecules,
b. the first and second antigens are co-expressed in cells or tissues that are target cells or target tissue for the disease or disorder to be treated,
c. the first and second antigens are not identical,
d. the first antibody and second antibody in combination deplete a cell population co-expressing the first and second antigen,
e. the first antibody and second antibody in combination induces cell death in a cell population co-expressing the first and second antigen, and/or
f. the first antibody and second antibody in combination induces cell death in a cell population co-expressing the first and second antigen.
11 . The method of claim 10 , wherein the cell population is a tumor cell population.
12 . The method of claim 10 , wherein the cell population is a leukocyte, lymphocyte, B cell, T cell, regulatory T cell, NK cell, myeloid derived suppressor cell, or tumor associated macrophage cell population.
13 . The method of claim 1 , wherein the antigen-binding region of the first or second antibody is capable of binding to an antigen selected from the group consisting of: DR4, DRS, CD20, CD37, CD52, HLA-DR, CD3, CDS, 4-1BB, PD1, and FAS.
14 . The method of claim 1 , wherein the antigen-binding region of the first or second antibody comprises:
a. a VH region comprising a CDR1 sequence as set forth in SEQ ID NO:9, a CDR2 sequence as set forth in SEQ ID NO:10 and a CDR3 sequence as set forth in SEQ ID NO:11, and a VL region comprising a CDR1 sequence as set forth in SEQ ID NO:13, a CDR2 sequence as set forth in: DAS and a CDR3 sequence as set forth in SEQ ID NO:14,
b. a VH region comprising a CDR1 sequence as set forth in SEQ ID NO:43, a CDR2 sequence as set forth in SEQ ID NO:44 and a CDR3 sequence as set forth in SEQ ID NO:45, and a VL region comprising a CDR1 sequence as set forth in SEQ ID NO:47, a CDR2 sequence as set forth in: VAT and a CDR3 sequence as set forth in SEQ ID NO:48,
c. a VH region comprising a CDR1 sequence as set forth in SEQ ID NO:2, a CDR2 sequence as set forth in SEQ ID NO:3 and a CDR3 sequence as set forth in SEQ ID NO:4, and a VL region comprising a CDR1 sequence as set forth in SEQ ID NO:6, a CDR2 sequence as set forth in:
NTN, and a CDR3 sequence as set forth in SEQ ID NO:7,
d. a VH region comprising a CDR1 sequence as set forth in SEQ ID NO: 118, a CDR2 sequence as set forth in SEQ ID NO:119, and a CDR3 sequence as set forth in SEQ ID NO:120 and a VL region comprising a CDR1 sequence as set forth in SEQ ID NO:122, a CDR2 sequence as set forth in SEQ ID NO: 123 and a CDR3 sequence as set forth in SEQ ID NO:124,
e. a VH region comprising a CDR1 sequence as set forth in SEQ ID NO:104, a CDR2 sequence as set forth in SEQ ID NO:105 and a CDR3 sequence as set forth in SEQ ID NO:106, and a VL region comprising a CDR1 sequence as set forth in SEQ ID NO:108, a CDR2 sequence as set forth in: YNN and a CDR3 sequence as set forth in SEQ ID NO:109,
f. a VH region comprising a CDR1 sequence as set forth in SEQ ID NO:111, a CDR2 sequence as set forth in SEQ ID NO: 112 and a CDR3 sequence as set forth in SEQ ID NO: 113, and a VL region comprising a CDR1 sequence as set forth in SEQ ID NO:115, a CDR2 sequence as set forth in: DAS and a CDR3 sequence as set forth SEQ ID NO:116,
g. a VH region comprising a CDR1 sequence as set forth in SEQ ID NO:90, a CDR2 sequence as set forth in SEQ ID NO:91 and a CDR3 sequence as set forth in SEQ ID NO:92, and a VL region comprising a CDR1 sequence as set forth in SEQ ID NO:94, a CDR2 sequence as set forth in: FAS, and a CDR3 sequence as set forth in SEQ ID NO:95, or
h. a VH region comprising a CDR1 sequence as set forth in SEQ ID NO:97, a CDR2 sequence as set forth in SEQ ID NO:98 and a CDR3 sequence as set forth in SEQ ID NO:99, and a VL region comprising a CDR1 sequence as set forth in SEQ ID NO:101, a CDR2 sequence as set forth in: RTS, and a CDR3 sequence as set forth in SEQ ID NO:102.
15 . The method according to claim 1 , wherein the method comprises administering an additional therapeutic agent.
16 . The method of claim 1 , wherein said method depletes a cell population expressing said first antigen and said second antigen.
17 . The method according to claim 1 , wherein the first antigen and/or second antigen is a member of the TNFR-SF.