JPWO2020159754A5

JPWO2020159754A5 -

Info

Publication number: JPWO2020159754A5
Application number: JP2021544141A
Authority: JP
Publication date: 2023-02-01

Claims

An isolated antibody that specifically binds to an epitope of human CD44 v7/8, wherein the epitope comprises the amino acid sequence of QAGRRMDMDSSSHSIT (SEQ ID NO: 13), and optionally the peptide PISHPMGRGHQAGRR (sequence No. 12) or said isolated antibody that does not bind to peptide SHSITLQPTANPNTG (SEQ ID NO: 14).

(a) the antibody is
(i) a heavy chain variable region ( _VH ) comprising heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2) and heavy chain complementarity determining region 3 (HC CDR3); and (ii) a light chain variable region (V _L ) comprising light chain CDR1 (LC CDR1), light chain CDR2 (LC CDR2), and light chain CDR3 (LC CDR3);
including
wherein HC CDR1, HC CDR2 and HC CDR3 are collectively at least 85% identical to HC CDR1, HC CDR2 and HC CDR3 of HIS029; and/or LC CDR1, LC CDR2 and LC CDR3 is collectively at least 85% identical to LC CDR1, LC CDR2, and LC CDR3 of HIS029, optionally _VH comprises the same HC CDR1, HC CDR2, and HC CDR3 as HIS029; and/or , _VL contains the same LC CDR1, LC CDR2, and LC CDR3 as HIS029; or (b) the antibody is
(i) a heavy chain variable region ( _VH ) comprising heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2) and heavy chain complementarity determining region 3 (HC CDR3); and (ii) a light chain variable region (V _L ) comprising light chain CDR1 (LC CDR1), light chain CDR2 (LC CDR2), and light chain CDR3 (LC CDR3);
including
wherein the HC CDR1, HC CDR2 and HC CDR3 collectively contain up to 8 amino acid residue variations compared to the HC CDR1, HC CDR2 and HC CDR3 of the reference antibody; and/or _VL comprises LC CDR1, LC CDR2, and LC CDRs that collectively contain up to 8 amino acid residue variations compared to LC CDR1, LC CDR2, and LC CDRs of the reference antibody;
2. The isolated antibody of claim 1.

The _VH of the isolated antibody is at least 85% identical to the _VH of HIS029 and/or the _VL of the isolated antibody is at least 85% identical to the _VL of HIS029, optionally , the same V _H as HIS029 and/or the same V _L as HIS029.

the antibody
(a) a full-length antibody or an antigen-binding fragment thereof, optionally wherein the antibody is an IgG molecule,
(b) is a single chain antibody (scFv), and/or (c) is a human, humanized, or chimeric antibody, optionally wherein the antibody has a V _H shown in SEQ ID NO: 10 and/or a SEQ ID NO: A humanized antibody comprising the V _L shown in 11,
The antibody according to any one of claims 1-3.

a nucleic acid or set of nucleic acids collectively encoding an anti-CD44 v7/8 antibody according to any one of claims 1 to 4, or a vector or set of vectors comprising said nucleic acid(s), such as expression vector(s); or a host cell containing said vector or set of vectors.

i. an antibody according to any one of claims 1-4; and ii. at least one therapeutic agent;
wherein the antibody is covalently conjugated to at least one therapeutic agent
Antibody-drug conjugate (ADC).

7. The antibody-drug conjugate of claim 6, wherein the antibody and therapeutic agent are conjugated via a linker, optionally the linker is a cleavable or non-cleavable linker.

The linker
(a) a protease-sensitive linker comprising a protease-sensitive linker, pH-sensitive linker, or glutathione-sensitive linker, optionally comprising a peptide sequence of 2-5 amino acids, eg, 2-5 amino acids, naturally occurring non-naturally occurring amino acid residues, or combinations thereof, examples including valine-citrulline; or
(b) an uncleavable linker comprising an optionally substituted alkane or thioether; and/or (c) comprising a functional group that forms a covalent bond with the antibody and the linker, optionally wherein the functional group is a maleimide group. , an iodoacetamide group, a vinyl sulfone group, an acrylate group, an acrylamide group, an acrylonitrile group, or a methacrylate group; and/or
(d) further formula I:

During the ceremony,
R ₁ is optionally substituted C1-6 alkyl, optionally substituted phenyl, optionally substituted C2-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene , or an optionally substituted triazole; and X is O, S, or N.
containing a molecular spacer represented by
The antibody-drug conjugate of claim 7.

The antibody-drug conjugate of any one of claims 6-8, wherein at least one therapeutic agent is a cytotoxic agent, optionally the cytotoxic agent is monomethylauristatin E.

(i) an extracellular domain comprising an antigen-binding fragment that specifically binds to CD44 v7/8;
(ii) a transmembrane domain; and (iii) one or more intracellular signaling domains.

(a) the antigen-binding fragment is a single chain antibody fragment (scFv), optionally wherein the scFv comprises a heavy chain variable domain and a light chain variable domain according to claim 2 or 3; b) the antigen-binding fragment specifically binds to an epitope of human CD44 v7/8, wherein the epitope comprises the amino acid sequence of QAGRRMDMDSSHSIT (SEQ ID NO: 13); optionally, the antigen-binding fragment comprises the peptide PISHPMGRGHQAGRR ( SEQ ID NO: 12) or peptide SHSITLQPTANPNTG (SEQ ID NO: 14); and/or (c) the transmembrane domain of (ii) comprises a transmembrane domain derived from a CD28 or CD8 receptor; and/or (d ) one or more domains (iii) comprise a signaling domain from CD3ζ, a co-stimulatory domain, or a combination thereof; optionally (iii) is 4-1BB, CD7, CD27, CD28, CD40, OX40; comprising a co-stimulatory domain that is from the ICOS, GITR, HVEM, TIM1, or LFA-1 receptor;
11. The chimeric antigen receptor of claim 10.

a nucleic acid comprising a nucleotide sequence encoding a chimeric antigen receptor according to claims 10 or 11; or a vector comprising said nucleic acid; or a host cell, e.g. cells, such as T cells.

(i) an antibody according to any one of claims 1 to 4, a nucleic acid according to claims 5 or 12, a set of nucleic acids or host cells, or any one of claims 6 to 9. A pharmaceutical composition comprising an antibody-drug conjugate; and (ii) a pharmaceutically acceptable carrier.

14. A pharmaceutical composition according to claim 13 for use in a method of inhibiting cells expressing CD44 v7/8 comprising administering an effective amount of the pharmaceutical composition to a subject in need thereof, optionally, the subject has or is suspected of having cancer, e.g., a cancer selected from the group consisting of head and neck cancer, cervical cancer, and breast cancer .

A method of detecting the presence of cells expressing surface CD44 v7/8, comprising:
i. contacting a sample suspected of having cells expressing surface CD44 v7/8 with an antibody according to any one of claims 1 to 4, wherein the antibody is conjugated with a labeling agent, and ,
ii. detecting the presence of cells expressing surface CD44 v7/8 in the sample based on binding of the antibody to cells in the sample.