JPWO2021174091A5

JPWO2021174091A5 -

Info

Publication number: JPWO2021174091A5
Application number: JP2022551273A
Authority: JP
Publication date: 2024-03-05

Claims

Formula (C):
[In the formula,
and
indicates the point of attachment within the oligonucleotide;
each T ¹ is independently O or S;
Each T ² is S ⁻ ;
T ³ is the base
{During the ceremony ,
indicates the point of attachment to the rest of the oligonucleotide};
Z is O or S;
U ^5' is -H or halogen;
R ^5' is -H or methoxy;
R ^c1 is -H or methoxy;
R ^g1 , R ^g2 , R ^g3 , and R ^g4 are H;
R ^3' is methoxy;
R ¹ is -(CH ₂ ) ₃ -OH;
R ² is -H or methyl; and n is an integer from 0 to 2]
or a pharmaceutically acceptable salt thereof.

Formula (D):
[In the formula,
and
indicates the point of attachment within the oligonucleotide;
each T ¹ is independently O or S;
Each T ² is S ⁻ ;
T ³ is the base
{During the ceremony,
indicates the connection point to L,
indicates the point of attachment to the rest of the oligonucleotide};
L is the base
{In the formula, m is an integer from 0 to 50,
indicates the point of attachment of the oligonucleotide to the rest of the oligonucleotide via ^T3 };
Z is O or S;
U ^5' is -H or halogen;
R ^5' is -H or methoxy;
R ^c1 is -H or methoxy;
R ^g1 , R ^g2 , R ^g3 , and R ^g4 are H;
R ^3' is methoxy;
R ¹ is -(CH ₂ ) ₃ -OH;
R ² is -H or methyl; and n is an integer from 0 to 2]
or a pharmaceutically acceptable salt thereof.

A conjugate comprising a monoclonal antibody or antigen-binding fragment thereof and one or more immunomodulatory oligonucleotides according to claim 1 or 2, wherein the immunomodulatory oligonucleotide binds to the monoclonal antibody or antigen-binding fragment thereof. Conjugate.

the monoclonal antibody or antigen-binding fragment thereof is linked to one or more Q tag peptides (Q) containing at least one glutamine residue,
Each of the one or more immunomodulatory oligonucleotides has the formula (A):
[In the formula,
indicates the point of attachment of each Q to the antibody or its antigen-binding fragment (Ab)]
is linked to the Q-tag peptide through an amide bond with the glutamine residue of the Q-tag peptide and a linker (L), as shown in
4. The conjugate of claim 3.

(a) one or more Q-tags are naturally occurring; or;
(b) the one or more Q-tags independently comprise a peptide sequence having from 5 to 15 amino acid residues;
Optionally,
(i) the peptide sequence of each Q-tag is independently selected from the group consisting of SEQ ID NO: 39-55; or (ii) the peptide sequence of each Q-tag is the peptide sequence RPQGF (SEQ ID NO: 47); optionally, each Q-tag peptide sequence independently comprises RPQGF (SEQ ID NO: 47), RPQGFPP (SEQ ID NO: 48), or RPQGFGPP (SEQ ID NO: 49).
5. The conjugate of claim 4.

5. The conjugate according to claim 4, wherein the peptide sequence (Q) of one or more Q tags comprises the amino acid sequence RPQGF (SEQ ID NO: 47).

the antibody or fragment thereof is a Fab, F(ab')2, Fab'-SH, Fv, scFv, single domain, single heavy chain or single light chain antibody or antibody fragment; 7. A conjugate according to any one of claims 3 to 6, wherein the fragment is a humanized, human, or chimeric antibody or fragment thereof.

the antibody or fragment thereof specifically binds to human CD22;
Optionally, the antibody comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain, wherein:
(a) the VH domain comprises CDR-H1, CDR-H2, and CDR-H3 sequences derived from a VH domain sequence selected from the group consisting of SEQ ID NOs: 64-67, and/or the VL domain comprises sequences No.: comprising CDR-L1, CDR-L2, and CDR-L3 sequences derived from a VL domain sequence selected from the group consisting of 68 to 91;
(b) the VH domain comprises CDR-H1 comprising the sequence of SEQ ID NO: 113, CDR-H2 comprising the sequence of SEQ ID NO: 115, and CDR-H3 comprising the sequence of SEQ ID NO: 116, or CDR-H1 containing the sequence No.: 114, CDR-H2 containing the sequence SEQ ID NO: 189, and CDR-H3 containing the sequence SEQ ID NO: 116, and/or the VL domain contains SEQ ID NO: 117 CDR-L1 comprising the sequence of SEQ ID NO: 119, CDR-L2 comprising the sequence of SEQ ID NO: 119, and CDR-L3 comprising the sequence of SEQ ID NO: 120, or CDR-L1 comprising the sequence of SEQ ID NO: 118, or (c) an amino acid sequence in which the VH domain is selected from the group consisting of SEQ ID NO: 64-67; and/or the VL domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-91.
A conjugate according to any one of claims 3 to 7.

the antibody or fragment thereof specifically binds to human Her2;
Optionally, the antibody comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain, wherein:
(a) The VH domain comprises CDR-H1, CDR-H2, and CDR-H3 sequences derived from the VH domain sequence of SEQ ID NO: 168, and/or the VL domain is derived from the VL domain sequence of SEQ ID NO: 169. CDR-L1, CDR-L2, and CDR-L3 sequences;
(b) the VH domain comprises the sequence SEQ ID NO: 168 and/or the VL domain comprises the sequence SEQ ID NO: 169;
(c) the VH domain comprises CDR-H1, CDR-H2, and CDR-H3 sequences derived from the VH domain sequence of SEQ ID NO: 170, and/or the VL domain is derived from the VL domain sequence of SEQ ID NO: 171 or (d) the VH domain comprises the sequence of SEQ ID NO: 170 and/or the VL domain comprises the sequence of SEQ ID NO: 171. ,
A conjugate according to any one of claims 3 to 7.

the antibody comprises an Fc region;
Optionally, the Fc region is a human IgG1 Fc region, a human IgG2 Fc region, or a human IgG4 Fc region;
Optionally, the Fc region is a wild type human IgG1 Fc region, a wild type human IgG2 Fc region, or a wild type human IgG4 Fc region;
Optionally,
(a) the Fc region is a human IgG1 Fc region, in amino acid position numbering according to the EU index, comprising L234A, L235A, and/or G237A substitutions, optionally further comprising a N297A substitution; The conjugate has the following formula
[Wherein L is a linker moiety bonded to Q295 of the Fc region via an amide bond]
further comprising an immunomodulatory oligonucleotide P attached to Fc region residue Q295 as shown in;
(b) the Fc region is a human IgG2 Fc region comprising A330S and/or P331S substitutions, optionally further comprising a N297A substitution, in amino acid position numbering according to the EU index, and optionally the conjugate is , the following expression
[Wherein L is a linker moiety bonded to Q295 of the Fc region via an amide bond]
further comprising an immunomodulatory oligonucleotide P attached to Fc region residue Q295 as shown in;
(c) the Fc region is a human IgG4 Fc region comprising S228P and/or L235E substitutions, optionally further comprising a N297A substitution, in amino acid position numbering according to the EU index, and optionally the conjugate is , the following expression
[Wherein L is a linker moiety bonded to Q295 of the Fc region via an amide bond]
further comprising an immunomodulatory oligonucleotide P attached to Fc region residue Q295 as shown in;
Optionally, the antibody comprises an antibody heavy chain constant domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 92-107 and 178.
A conjugate according to any one of claims 3 to 9.

Any of claims 3 to 10, wherein the antibody comprises a human lambda or human kappa light chain, and optionally, the antibody comprises an antibody light chain constant domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 108-110. The conjugate according to item 1.

(a) the antibody comprises two antibody heavy chains and two antibody light chains, one Q-tag is attached to one or both heavy chains of the antibody, and optionally the Q-tag is attached to one or both heavy chains of the antibody; fused to the C-terminus of or within the Fc domain;
(b) the antibody comprises two antibody heavy chains and two antibody light chains, and one Q-tag binds to one or both light chains of the antibody;
A conjugate according to any one of claims 4 to 11.

13. A conjugate according to any one of claims 3 to 12, having a DAR of 1 or 2.

Linker L includes a polyethylene glycol moiety, and/or
Linker L is
[wherein m is an integer ranging from about 0 to about 50,
indicates the point of attachment to T ³ , and
indicates the point of attachment to the rest of the conjugate],
An immunomodulatory oligonucleotide according to claim 2 or a conjugate according to any one of claims 4 to 13.

15. The immunomodulatory oligonucleotide or conjugate of claim 14, wherein m is an integer from about 20 to about 25, optionally, m is 24.

The oligonucleotide P comprises at least one pair of geminals T ¹ and T ² in which T ¹ is S and T ² is S ^- , optionally T ¹ is S and T ² is S ^- . at least one pair of geminals T ¹ and T ² is located at the 3′ position of nucleoside residue 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14;
An immunomodulatory oligonucleotide according to claim 1 or 2 or a conjugate according to any one of claims 4 to 15.

1 . The oligonucleotide P comprises at least two pairs of geminals T ¹ and T ² , T ¹ is S and T ² is S ^- ; optionally, U ^5' is bromo or H. or an immunomodulatory oligonucleotide according to claim 2 or a conjugate according to any one of claims 4 to 15.

Table 10:
2. The immunomodulatory oligonucleotide of claim 1, comprising an oligonucleotide selected from: or a pharmaceutically acceptable salt thereof.

The oligonucleotides are shown in Table 12:
The immunomodulatory oligonucleotide according to claim 2 or the conjugate according to any one of claims 3 to 13, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the oligonucleotide according to claim 2.

The antibody or antigen-binding fragment thereof (Ab) comprises an anti-CD22 antibody, the Ab comprises two antibody light chains, two antibody heavy chains, and two Q tag peptides (Q) having at least one glutamine residue. One Q-tag peptide is linked to the C-terminus of each of the two antibody heavy chains, and each heavy chain of the Ab has a heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 65, and SEQ ID NO: 68. , 73, and 87;
Linker L is
[In the formula, m is 24,
indicates the point of attachment to oligonucleotide P, and
indicates the point of attachment of the Q tag to the glutamine residue]
and oligonucleotide P has the structure:
,
Or
[
and
indicates the point of attachment within the oligonucleotide,
indicates the point of attachment to linker L]
5. The conjugate according to claim 4, or a pharmaceutically acceptable salt thereof.

(a) Each heavy chain of the Ab comprises a heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 65, and each light chain of the Ab comprises a light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 68. ) contains domains;
(b) Each heavy chain of the Ab comprises a heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 65, and each light chain of the Ab comprises a light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 73. ) domain; or (c) each heavy chain of the Ab comprises a heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 65, and each light chain of the Ab comprises the amino acid sequence of SEQ ID NO: 87. comprising a light chain variable (VL) domain comprising;
21. The conjugate of claim 20.

22. A conjugate according to claim 20 or 21, wherein each of the two Q-tag peptides comprises the amino acid sequence RPQGFGPP (SEQ ID NO: 49).

(a) Each heavy chain of the Ab comprising Q comprises the amino acid sequence of SEQ ID NO: 179, and each light chain of the Ab comprises the amino acid sequence of SEQ ID NO: 181;
(b) each heavy chain of the Ab comprising Q comprises the amino acid sequence of SEQ ID NO: 179 and each light chain of the Ab comprises the amino acid sequence of SEQ ID NO: 182;
(c) each heavy chain of the Ab comprising Q comprises the amino acid sequence of SEQ ID NO: 180 and each light chain of the Ab comprises the amino acid sequence of SEQ ID NO: 181; or (d) each of the Abs comprising Q The heavy chain comprises the amino acid sequence of SEQ ID NO: 180, and each light chain of the Ab comprises the amino acid sequence of SEQ ID NO: 182.
21. The conjugate of claim 20.

(a) Each of the two Q tag peptides contains the amino acid sequence RPQGFGPP (SEQ ID NO: 49), each heavy chain of the Ab containing Q contains the amino acid sequence of SEQ ID NO: 179, and each light chain of the Ab contains the amino acid sequence RPQGFGPP (SEQ ID NO: 49). , SEQ ID NO: 182, and oligonucleotide P has the structure:
including;
(b) Each of the two Q tag peptides contains the amino acid sequence RPQGFGPP (SEQ ID NO: 49), each heavy chain of the Ab containing Q contains the amino acid sequence of SEQ ID NO: 179, and each light chain of the Ab contains the amino acid sequence RPQGFGPP (SEQ ID NO: 49). , SEQ ID NO: 182, and oligonucleotide P has the structure:
including;
(c) Each of the two Q tag peptides contains the amino acid sequence RPQGFGPP (SEQ ID NO: 49), each heavy chain of the Ab containing Q contains the amino acid sequence of SEQ ID NO: 180, and each light chain of the Ab contains the amino acid sequence RPQGFGPP (SEQ ID NO: 49). , SEQ ID NO: 182, and oligonucleotide P has the structure:
including;
(d) Each of the two Q-tag peptides contains the amino acid sequence RPQGFGPP (SEQ ID NO: 49), each heavy chain of the Ab containing Q contains the amino acid sequence of SEQ ID NO: 180, and each light chain of the Ab contains the amino acid sequence RPQGFGPP (SEQ ID NO: 49). , SEQ ID NO: 182, and oligonucleotide P has the structure:
,
including;
(e) Each of the two Q tag peptides contains the amino acid sequence RPQGFGPP (SEQ ID NO: 49), each heavy chain of the Ab containing Q contains the amino acid sequence of SEQ ID NO: 180, and each light chain of the Ab contains the amino acid sequence RPQGFGPP (SEQ ID NO: 49). , SEQ ID NO: 181, and oligonucleotide P has the structure:
or (f) each of the two Q-tag peptides comprises the amino acid sequence RPQGFGPP (SEQ ID NO: 49), and each heavy chain of the Q-containing Ab comprises the amino acid sequence of SEQ ID NO: 180; Each light chain comprises the amino acid sequence of SEQ ID NO: 181, and oligonucleotide P has the structure:
21. The conjugate of claim 20, comprising:

25. A pharmaceutical composition comprising a conjugate according to any one of claims 3-13 or 20-24 and a pharmaceutically acceptable carrier.

26. A pharmaceutical composition according to claim 25 for use in the treatment of cancer in an individual.

20. A pharmaceutical composition comprising the immunomodulatory oligonucleotide of any one of claims 1, 2, 18, or 19 and a pharmaceutically acceptable carrier.

28. A pharmaceutical composition according to claim 27 for use in the treatment of cancer in an individual.

If the cancer is B-cell cancer, breast cancer, colorectal cancer, lung cancer, head and neck cancer, melanoma, lymphoma, leukemia, head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), renal cell cancer (RCC), gastric cancer, hepatocellular carcinoma (HCC), esophageal cancer, cervical cancer, cervical squamous cell carcinoma, Merkel cell carcinoma, endometrial cancer, ovarian cancer, pancreatic cancer, skin melanoma , sarcoma, small cell lung cancer (SCLC), cutaneous squamous cell carcinoma, or urothelial carcinoma.

27. A pharmaceutical composition for use according to claim 26, wherein the conjugate specifically binds to an antigen expressed by cancer or cancer-associated stroma.

27. A pharmaceutical composition for use according to claim 26, wherein an effective amount of an immune checkpoint inhibitor is further administered to the individual.

the cancer is refractory or resistant to the immune checkpoint inhibitor when administered in the absence of the conjugate; and the antibody or antigen-binding fragment thereof of the conjugate binds human CD22 , a pharmaceutical composition for use according to claim 26.

Pharmaceutical composition for use according to claim 31 or 32, wherein the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.