Prevention or mitigation of T-cell engaging agent-related adverse effects
The present invention relates to the prevention or mitigation of adverse effects related to T cell engaging agents, such as cytokine release syndrome. Specifically, the invention relates to the prevention or mitigation of such side effects using an inhibitor of JAK and/or mTOR.
1 . A method for preventing or mitigating an adverse effect related to the administration of a T cell bispecific antibody to an individual, comprising administering (a) a T cell bispecific antibody and (b) an inhibitor that inhibits mTOR signaling to the individual, wherein the adverse effect is prevented or mitigated, wherein the T cell bispecific antibody binds to CD3 and a target cell antigen, and wherein the method does not comprise administering a CAR-T cell, and wherein administering the inhibitor that inhibits mTOR signaling causes inhibition of an adverse effect related to administering the T cell bispecific antibody.
2 . The method of claim 1 , wherein the inhibitor that inhibits mTOR signaling comprises sirolimus, temsirolimus, or everolimus.
3 . The method of claim 1 , wherein the administration of the inhibitor does not cause inhibition of a desired effect related to administering the T cell bispecific antibody.
4 . The method of claim 1 , wherein the inhibition is a complete inhibition, a clinically meaningful inhibition, or a statistically significant inhibition.
5 . The method of claim 1 , wherein the adverse effect is:
(i) cytokine release syndrome (CRS);
(ii) fever;
(iii) hypotension;
(iv) hypoxia; or
(v) an elevated serum level of a cytokine.
6 . The method of claim 5 , wherein the adverse effect is an elevated serum level of a cytokine, wherein the cytokine is IL-6, IFN-γ, IL-10, TNF-α, GM-CSF, MCP-1, or IL-1β.
7 . The method of claim 1 , wherein the inhibitor is administered to the individual when the adverse effect clinically manifests.
8 . The method of claim 1 , wherein the inhibitor is administered before, concurrent with, or after administering the T cell bispecific antibody and is administered
(i) intermittently or continuously;
(ii) orally; or
(iii) parenterally.
9 . The method of claim 8 , wherein the inhibitor is administered parenterally, wherein the parenteral administration is intravenous administration.
10 . The method of claim 1 , wherein the T cell bispecific antibody is administered to the individual multiple times, and wherein the inhibitor is administered prior to, concurrent with, or subsequently to the first administration of the T cell bispecific antibody.
11 . The method of claim 1 , wherein the T cell bispecific antibody is administered intravenously and is a first administration of the T cell bispecific antibody.
12 . The method of claim 1 , wherein the target cell antigen is carcinoembryonic antigen (CEA), CD20, HLA-A2/MAGE-A4, or CD19.
13 . The method of claim 12 , wherein the target cell antigen is CEA, wherein the T cell bispecific antibody comprises:
(i) a first antigen binding moiety that binds to CD3 and comprises:
a heavy chain variable region comprising:
a heavy chain CDR (HCDR) 1 of SEQ ID NO: 4,
a HCDR2 of SEQ ID NO: 5, and
a HCDR3 of SEQ ID NO: 6; and
a light chain variable region comprising:
a light chain CDR (LCDR) 1 of SEQ ID NO: 7,
a LCDR2 of SEQ ID NO: 8, and
a LCDR3 of SEQ ID NO: 9;
and
(ii) a second antigen binding moiety that binds to CEA and comprises:
a heavy chain variable region comprising:
a heavy chain CDR (HCDR) 1 of SEQ ID NO: 12,
a HCDR2 of SEQ ID NO: 13, and
a HCDR3 of SEQ ID NO: 14; and
a light chain variable region comprising:
a light chain CDR (LCDR) 1 of SEQ ID NO: 15,
a LCDR2 of SEQ ID NO: 16, and
a LCDR3 of SEQ ID NO: 17.
14 . The method of claim 13 , wherein the T cell bispecific antibody further comprises a third antigen binding moiety that binds to CEA, an Fc domain composed of a first and a second subunit, or both the third antigen binding moiety and the Fc domain.
15 . The method of claim 14 , wherein the third antigen binding moiety that binds to CEA comprises:
a heavy chain variable region comprising:
a heavy chain CDR (HCDR) 1 of SEQ ID NO: 12,
a HCDR2 of SEQ ID NO: 13, and
a HCDR3 of SEQ ID NO: 14; and
a light chain variable region comprising:
a light chain CDR (LCDR) 1 of SEQ ID NO: 15,
a LCDR2 of SEQ ID NO: 16, and
a LCDR3 of SEQ ID NO: 17;
wherein the first antigen binding moiety is a crossover Fab molecule wherein either the variable or the constant regions of the Fab light chain and the Fab heavy chain are exchanged; and
wherein the second and third antigen binding moieties are each a Fab molecule, and the second antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen binding moiety, and the first antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain, and wherein the third antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit of the Fc domain.
16 . The method of claim 13 , wherein
(i) the first antigen binding moiety comprises a heavy chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to an amino acid sequence of SEQ ID NO: 10 and a light chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to an amino acid sequence of SEQ ID NO: 11, or
(ii) the second antigen binding moiety comprises a heavy chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18 and a light chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19.
17 . The method of claim 14 , wherein the Fc domain comprises at least one of (i) a modification promoting the association of the first and the second subunit of the Fc domain or (ii) one or more amino acid substitutions that reduces binding to an Fc receptor or effector function.
18 . The method of claim 12 , wherein the target cell antigen is CD20, wherein the T cell bispecific antibody comprises:
(i) a first antigen binding moiety that binds to CD3 and comprises:
a heavy chain variable region comprising:
a heavy chain CDR (HCDR) 1 of SEQ ID NO: 4,
a HCDR2 of SEQ ID NO: 5, and
a HCDR3 of SEQ ID NO: 6; and
a light chain variable region comprising:
a light chain CDR (LCDR) 1 of SEQ ID NO: 7,
a LCDR2 of SEQ ID NO: 8, and
aLCDR3 of SEQ ID NO: 9;
and
(ii) a second antigen binding moiety that binds to CD20 and comprises:
a heavy chain variable region comprising:
a heavy chain CDR (HCDR) 1 of SEQ ID NO: 24,
a HCDR2 of SEQ ID NO: 25, and
a HCDR3 of SEQ ID NO: 26; and
a light chain variable region comprising:
a light chain CDR (LCDR) 1 of SEQ ID NO: 27,
a LCDR2 of SEQ ID NO: 28 and
a LCDR3 of SEQ ID NO: 29.
19 . The method of claim 18 , wherein the T cell bispecific antibody further comprises a third antigen binding moiety that binds to CD20, an Fc domain composed of a first and a second subunit, or both the third antigen binding moiety and the Fc domain.
20 . The method of claim 19 , wherein the third antigen binding moiety that binds to CD20 comprises:
a heavy chain variable region comprising:
a heavy chain CDR (HCDR) 1 of SEQ ID NO: 24,
a HCDR2 of SEQ ID NO: 25, and
a HCDR3 of SEQ ID NO: 26; and
a light chain variable region comprising:
a light chain CDR (LCDR) 1 of SEQ ID NO: 27,
a LCDR2 of SEQ ID NO: 28 and
a LCDR3 of SEQ ID NO: 29,
wherein the first antigen binding moiety is a crossover Fab molecule wherein either the variable or the constant regions of the Fab light chain and the Fab heavy chain are exchanged; and
wherein the second and third antigen binding moieties are each a Fab molecule, and the second antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen binding moiety, and the first antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain, and wherein the third antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit of the Fc domain.
21 . The method of claim 18 , wherein the T cell bispecific antibody comprises:
(i) the first antigen binding moiety comprises a heavy chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 10 and a light chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 11, or
(ii) the second antigen binding moiety comprises a heavy chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 30 and a light chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 31.
22 . The method of claim 20 , wherein
(i) the first antigen binding moiety is a crossover Fab molecule wherein the variable regions of the Fab light chain and the Fab heavy chain are exchanged, and
(ii) the second binding moiety is a conventional Fab molecule wherein in the constant domain CL the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) and the amino acid at position 123 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) and in the constant domain CH1 the amino acid at position 147 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index); or
(iii) the third binding moiety is a conventional Fab molecule wherein in the constant domain CL the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) and the amino acid at position 123 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) and in the constant domain CH1 the amino acid at position 147 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index).
23 . The method of claim 19 , wherein the Fc domain comprises at least one of (i) a modification promoting the association of the first and the second subunit of the Fc domain or (ii) one or more amino acid substitutions that reduces binding to an Fc receptor or effector function.
24 . The method of claim 12 , wherein the target cell antigen is HLA-A2/MAGE-A4, wherein the T cell bispecific antibody comprises:
(i) a first antigen binding moiety that binds to CD3 and comprises:
a heavy chain variable region comprising:
a heavy chain CDR (HCDR) 1 of SEQ ID NO: 37,
a HCDR2 of SEQ ID NO: 38, and
a HCDR3 of SEQ ID NO: 39; and
a light chain variable region comprising:
a light chain CDR (LCDR) 1 of SEQ ID NO: 40,
a LCDR2 of SEQ ID NO: 41 and
a LCDR3 of SEQ ID NO: 42;
and
(ii) a second antigen binding moiety that binds to HLA-A2/MAGE-A4 and comprises:
a heavy chain variable region comprising:
a heavy chain CDR (HCDR) 1 of SEQ ID NO: 45,
a HCDR2 of SEQ ID NO: 46, and
a HCDR3 of SEQ ID NO: 47; and
a light chain variable region comprising:
a light chain CDR (LCDR) 1 of SEQ ID NO: 48,
a LCDR2 of SEQ ID NO: 49 and
a LCDR3 of SEQ ID NO: 50.
25 . The method of claim 24 , wherein the T cell bispecific antibody further comprises a third antigen binding moiety that binds to HLA-A2/MAGE-A4, an Fc domain composed of a first and a second subunit, or both the third antigen binding moiety and the Fc domain.
26 . The method of claim 25 , wherein the third antigen binding moiety that binds to HLA-A2/MAGE-A4 comprises:
a heavy chain variable region comprising:
a heavy chain CDR (HCDR) 1 of SEQ ID NO: 45,
a HCDR2 of SEQ ID NO: 46, and
a HCDR3 of SEQ ID NO: 47; and
a light chain variable region comprising:
a light chain CDR (LCDR) 1 of SEQ ID NO: 48,
a LCDR2 of SEQ ID NO: 49 and
a LCDR3 of SEQ ID NO: 50,
wherein the first antigen binding moiety is a crossover Fab molecule wherein either the variable or the constant regions of the Fab light chain and the Fab heavy chain are exchanged; and
wherein the second and third antigen binding moieties are each a Fab molecule, and the second antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen binding moiety, and the first antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain, and wherein the third antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit of the Fc domain.
27 . The method of claim 24 , wherein the T cell bispecific antibody comprises:
(i) first antigen binding moiety of the T cell bispecific antibody comprises a heavy chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 43 and a light chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 44, or
(ii) the second antigen binding moiety of the T cell bispecific antibody comprises a heavy chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 51 and a light chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 52.
28 . The method of claim 26 , wherein
(i) the first antigen binding moiety is a crossover Fab molecule wherein the variable regions of the Fab light chain and the Fab heavy chain are exchanged, and
(ii) the second binding moiety is a conventional Fab molecule wherein in the constant domain CL the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) and the amino acid at position 123 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) and in the constant domain CH1 the amino acid at position 147 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index); or
(iii) the third binding moiety is a conventional Fab molecule wherein in the constant domain CL the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) and the amino acid at position 123 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) and in the constant domain CH1 the amino acid at position 147 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index).
29 . The method of claim 25 , wherein the Fc domain comprises at least one of (i) a modification promoting the association of the first and the second subunit of the Fc domain or (ii) one or more amino acid substitutions that reduces binding to an Fc receptor or effector function.
30 . The method of claim 12 , wherein the target antigen is CD19, wherein the T cell bispecific antibody comprises:
(i) a first antigen binding moiety that binds to CD3 and comprises:
a heavy chain variable region comprising:
a heavy chain CDR (HCDR) 1 of SEQ ID NO: 61,
a HCDR2 of SEQ ID NO: 5, and
a HCDR3 of SEQ ID NO: 62;
or a heavy chain variable region comprising:
a HCDR1 of SEQ ID NO: 64,
a HCDR2 of SEQ ID NO: 5, and
a HCDR3 of SEQ ID NO: 65; and
a light chain variable region comprising:
a light chain CDR (LCDR) 1 of SEQ ID NO: 7,
a LCDR2 of SEQ ID NO: 8, and
a LCDR3 of SEQ ID NO: 9;
and
(ii) a second antigen binding moiety that binds to CD19 and comprises:
a heavy chain variable region comprising:
a heavy chain CDR (HCDR) 1 of SEQ ID NO: 67,
a HCDR2 of SEQ ID NO: 68, and
a HCDR3 of SEQ ID NO: 69; and
a light chain variable region comprising:
a light chain CDR (LCDR) 1 of SEQ ID NO: 70,
a LCDR2 of SEQ ID NO: 71, and
a LCDR3 of SEQ ID NO: 72.
31 . The method of claim 30 , wherein the T cell bispecific antibody further comprises a third antigen binding moiety that binds to CD19, an Fc domain composed of a first and a second subunit, or both the third antigen binding moiety and the Fc domain.
32 . The method of claim 31 , wherein the third antigen binding moiety that binds to CD19 comprises:
a heavy chain variable region comprising:
a heavy chain CDR (HCDR) 1 of SEQ ID NO: 67,
a HCDR2 of SEQ ID NO: 68, and
a HCDR3 of SEQ ID NO: 69; and
a light chain variable region comprising:
a light chain CDR (LCDR) 1 of SEQ ID NO: 70,
a LCDR2 of SEQ ID NO: 71, and
a LCDR3 of SEQ ID NO: 72,
wherein the first antigen binding moiety is a crossover Fab molecule wherein either the variable or the constant regions of the Fab light chain and the Fab heavy chain are exchanged; and
wherein the second and third antigen binding moieties are each a Fab molecule, and the second antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen binding moiety, and the first antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain, and wherein the third antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit of the Fc domain.
33 . The method of claim 30 , wherein
(i) the first antigen binding moiety comprises a heavy chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to an amino acid sequence of SEQ ID NO: 63 or SEQ ID NO: 66 and a light chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to an amino acid sequence of SEQ ID NO: 11, or
(ii) the second antigen binding moiety comprises a heavy chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 73 and a light chain variable region sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 74.
34 . The method of claim 32 , wherein
(i) the first antigen binding moiety is a crossover Fab molecule wherein the variable regions of the Fab light chain and the Fab heavy chain are exchanged, and
(ii) the second binding moiety is a conventional Fab molecule wherein in the constant domain CL the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) and the amino acid at position 123 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) and in the constant domain CH1 the amino acid at position 147 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index); or
(iii) the third binding moiety is a conventional Fab molecule wherein in the constant domain CL the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) and the amino acid at position 123 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) and in the constant domain CH1 the amino acid at position 147 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index).
35 . The method of claim 31 , wherein the Fc domain comprises at least one of (i) a modification promoting the association of the first and the second subunit of the Fc domain or (ii) one or more amino acid substitutions that reduces binding to an Fc receptor or effector function.
36 . The method of claim 1 , wherein the T cell bispecific antibody is cibisatamab or glofitamab.
37 . The method of claim 1 , wherein the administration of a T cell bispecific antibody to the individual treats a disease in the individual.
38 . The method of claim 37 , wherein the disease is cancer or an autoimmune disease.
39 . The method of claim 38 , wherein the cancer is:
(i) a carcinoembryonic antigen (CEA)-expressing cancer, or selected from the group consisting of colorectal cancer, lung cancer, pancreatic cancer, breast cancer, and gastric cancer;
(ii) a CD20-expressing cancer, a B-cell cancer, or selected from the group consisting of Non-Hodgkin lymphoma (NHL), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle-cell lymphoma (MCL) and marginal zone lymphoma (MZL);
(iii) a MAGE-A4 expressing cancer; or
(iv) a CD19-expressing cancer, a B-cell cancer, or selected from the group consisting of Non-Hodgkin lymphoma (NHL), acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL).
40 . The method of claim 38 , wherein the autoimmune disease is lupus.
41 . The method of claim 40 , wherein the autoimmune disease is systemic lupus erythematosus (SLE) or lupus nephritis (LN).