Anti-CD3epsilon antibodies
The present disclosure provides isolated monoclonal anti-CD3epsilon antibodies or antigen-binding fragments thereof comprising one or more heavy chain CDR sequences selected from the group consisting of: SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, and 47, and/or one or more kappa light chain CDR sequences selected from the group consisting of: SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46 and 48, isolated polynucleotides encoding the same, pharmaceutical compositions comprising the same, and the use thereof.
1 . An isolated antibody or antigen-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein the antibody or antigen-binding fragment selected from the group consisting of:
a) a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains of SEQ ID NO:117, and a kappa light chain variable region that comprises CDR1, CDR2 and CDR3 domains of SEQ ID NO: 119;
b) a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains of SEQ ID NO:81, and a kappa light chain variable region that comprises CDR1, CDR2 and CDR3 domains of SEQ ID NO: 83;
c) a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains of SEQ ID NO:85, and a kappa light chain variable region that comprises CDR1, CDR2 and CDR3 domains of SEQ ID NO: 87;
d) a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains of SEQ ID NO:89, and a kappa light chain variable region that comprises CDR1, CDR2 and CDR3 domains of SEQ ID NO: 91;
e) a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains of SEQ ID NO:93, and a kappa light chain variable region that comprises CDR1, CDR2 and CDR3 domains of SEQ ID NO: 95;
f) a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains of SEQ ID NO:97, and a kappa light chain variable region that comprises CDR1, CDR2 and CDR3 domains of SEQ ID NO: 99;
g) a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains of SEQ ID NO:101, and a kappa light chain variable region that comprises CDR1, CDR2 and CDR3 domains of SEQ ID NO: 103;
h) a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains of SEQ ID NO:105, and a kappa light chain variable region that comprises CDR1, CDR2 and CDR3 domains of SEQ ID NO: 107;
i) a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains of SEQ ID NO:109, and a kappa light chain variable region that comprises CDR1, CDR2 and CDR3 domains of SEQ ID NO: 111; or
j) a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains of SEQ ID NO:113, and a kappa light chain variable region that comprises CDR1, CDR2 and CDR3 domains of SEQ ID NO: 115.
2 . The antibody or an antigen-binding fragment thereof of claim 1 , comprising:
a) a heavy chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 7, CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and CDR3 comprising the amino acid sequence of SEQ ID NO: 11; and a kappa light chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 8, CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and CDR3 comprising the amino acid sequence of SEQ ID NO: 12;
b) a heavy chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 1, CDR2 comprising the amino acid sequence of SEQ ID NO: 3, and CDR3 comprising the amino acid sequence of SEQ ID NO: 5; and a kappa light chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 2, CDR2 comprising the amino acid sequence of SEQ ID NO: 4, and CDR3 comprising the amino acid sequence of SEQ ID NO: 6;
c) a heavy chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 13, CDR2 comprising the amino acid sequence of SEQ ID NO: 15, and CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and a kappa light chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 14, CDR2 comprising the amino acid sequence of SEQ ID NO: 16, and CDR3 comprising the amino acid sequence of SEQ ID NO: 18;
d) a heavy chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 19, CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and CDR3 comprising the amino acid sequence of SEQ ID NO: 23; and a kappa light chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 20, CDR2 comprising the amino acid sequence of SEQ ID NO: 22, and CDR3 comprising the amino acid sequence of SEQ ID NO: 24;
e) a heavy chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 25, CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and CDR3 comprising the amino acid sequence of SEQ ID NO: 29; and a kappa light chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 26, CDR2 comprising the amino acid sequence of SEQ ID NO: 28, and CDR3 comprising the amino acid sequence of SEQ ID NO: 30;
f) a heavy chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 31, CDR2 comprising the amino acid sequence of SEQ ID NO: 33, and CDR3 comprising the amino acid sequence of SEQ ID NO: 35; and a kappa light chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 32, CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and CDR3 comprising the amino acid sequence of SEQ ID NO: 36;
g) a heavy chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 37, CDR2 comprising the amino acid sequence of SEQ ID NO: 39, and CDR3 comprising the amino acid sequence of SEQ ID NO: 41; and a kappa light chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 38, CDR2 comprising the amino acid sequence of SEQ ID NO: 40, and CDR3 comprising the amino acid sequence of SEQ ID NO: 42; or
h) a heavy chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 43, CDR2 comprising the amino acid sequence of SEQ ID NO: 45, and CDR3 comprising the amino acid sequence of SEQ ID NO: 47; and a kappa light chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 44, CDR2 comprising the amino acid sequence of SEQ ID NO: 46, and CDR3 comprising the amino acid sequence of SEQ ID NO: 48.
3 . The antibody or antigen-binding fragment thereof of claim 1 , further comprising an immunoglobulin constant region, optionally a constant region of IgG, optionally a constant region of human IgG1.
4 . The antibody or an antigen-binding fragment thereof of claim 1 , which is a humanized antibody.
5 . The antibody or antigen-binding fragment thereof of claim 1 , which is a camelized single domain antibody, a diabody, a scFv, an scFv dimer, a BsFv, a dsFv, a (dsFv) 2 , a dsFv-dsFv′, an Fv fragment, a Fab, a Fab′, a F(ab′) 2 , a bispecific antibody, a ds diabody, a nanobody, a domain antibody, or a bivalent domain antibody.
6 . The antibody or an antigen-binding fragment thereof of claim 5 , wherein the antibody or an antigen-binding fragment thereof is bispecific and has a first specificity for CD3epsilon, and a second specificity.
7 . The antibody or an antigen-binding fragment thereof of claim 6 , wherein the second specificity is for a second antigen different from CD3epsilon wherein presence of the second antigen in proximity to a CD3epsilon-expressing T cells is desirable for the second antigen to be recognized by immune system.
8 . The antibody or antigen-binding fragment thereof of claim 1 linked to one or more conjugates, wherein the conjugate comprises a chemotherapeutic agent, a toxin, a radioactive isotope, a lanthanide, a luminescent label, a fluorescent label, or an enzyme-substrate label.
9 . The antibody or an antigen-binding fragment thereof of claim 1 , capable of specifically binding to CD3epsilon, and optionally wherein the CD3epsilon are derived from mouse, rat, monkey or human, and optionally wherein the CD3epsilon is a recombinant CD3epsilon or a CD3epsilon expressed on a cell surface.
10 . A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 1 , and a pharmaceutically acceptable carrier.
11 . An isolated polynucleotide encoding the antibody or an antigen-binding fragment thereof of claim 1 .
12 . A vector comprising the isolated polynucleotide of claim 11 .
13 . A host cell comprising the vector of claim 12 .
14 . A method of expressing the antibody or antigen-binding fragment thereof of claim 1 , comprising culturing a host cell comprising a vector comprising an isolated polynucleotide encoding the antibody or antigen-binding fragment thereof of claim 1 under the condition at which the vector is expressed.
15 . A method of treating a CD3 related disease or condition, comprising administering to the subject a therapeutically effective amount of the antibody or antigen-binding fragment thereof of claim 1 .
16 . The method of claim 15 , wherein the antibody or antigen-binding fragment thereof is bispecific and the disease or condition is cancer.
17 . A method of activating CD3epsilon-expressing T cells in vivo or in vitro, comprising contacting the CD3epsilon-expressing T cells with the antibody or antigen-binding fragment thereof of claim 1 .
18 . A method of promoting in vivo or in vitro processing of a second antigen by CD3epsilon-expressing T cell, comprising contacting the CD3epsilon-expressing T cells with the bispecific antibody or antigen-binding fragment thereof of claim 6 , wherein the bispecific antibody or antigen-binding fragment is capable of specifically binding to both the CD3epsilon-expressing T cells and a second antigen thereby bringing both in close proximity.
19 . A kit comprising the antibody or antigen-binding fragment thereof of claim 1 , useful in detecting CD3epsilon, optionally recombinant CD3epsilon, CD3epsilon expressed on cell surface, or CD3epsilon-expressing cells, or useful in diagnosing a CD3 related disease or condition in a subject.