Anti-CD93 constructs and uses thereof
The present application provides anti-CD93 constructs that bind to CD93 (e.g., anti-CD93 antibodies), nucleic acid molecules encoding an amino acid sequence of the anti-CD93, vectors comprising the nucleic acid molecules, host cells containing the vectors, methods of preparing the anti-CD93 construct, pharmaceutical compositions containing the anti-CD93 construct, and methods of using the anti-CD93 construct or compositions.
1 . An anti-CD93 construct comprising an antibody moiety comprising a heavy chain variable region (V H ) and a light chain variable region (V L ), wherein:
a) the V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, and the V L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22;
b) the V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 304, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 305, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, and the V L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22;
c) the V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, and the V L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 301, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22;
d) the V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 304, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 305, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, and the V L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 301, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22;
e) the V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, and the V L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 302, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22;
f) the V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 304, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 305, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, and the V L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 302, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22;
g) the V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, and the V L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 303, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22;
h) the V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 304, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 305, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, and the V L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 303, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22;
i) the V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, and the V L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 306, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22;
j) the V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 304, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 305, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, and the V L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 306, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22;
k) the V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 177, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 178, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 179, and the V L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 353, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 181, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182;
l. The V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 177, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 178, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 179, and the V L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 353, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 354, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182;
m) the V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 177, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 178, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 179, and the V L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 180, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 181, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182; or
n) the V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 177, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 178, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 179, and the V L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 180, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 354, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182.
2 . The anti-CD93 construct of claim 1 , wherein:
a) the V H comprises an amino acid sequence of any of SEQ ID NOs: 29 and 307-312, or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V L comprises an amino acid sequence of any of SEQ ID NOs: 30 and 313-318, or a variant comprising an amino acid sequence having at least about 80% sequence identity, or
b) the V H comprises an amino acid sequence of any of SEQ ID NOs: 189 and 347-349, or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V L comprises an amino acid sequence of any of SEQ ID NOs: 190 and 350-352, or a variant comprising an amino acid sequence having at least about 80% sequence identity.
3 . The anti-CD93 construct of claim 1 , wherein the V H comprises the HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, the HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and the HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, and the V L comprises the LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, the LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and the LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.
4 . The anti-CD93 construct of claim 2 , wherein the V H comprises the amino acid sequence of SEQ ID NO: 310, and the V L comprises the amino acid sequence of SEQ ID NO: 318.
5 . The anti-CD93 construct of claim 1 , wherein the antibody moiety is an antibody or antigen-binding fragment thereof selected from the group consisting of a full-length antibody, a bispecific antibody, a single-chain Fv (scFv) fragment, a Fab fragment, a Fab′ fragment, a F(ab′)2, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv) 2 , a Fv-Fc fusion, a scFv-Fc fusion, a scFv-Fv fusion, a diabody, a tribody, and a tetrabody.
6 . The anti-CD93 construct of claim 1 , wherein the antibody moiety is a full-length antibody.
7 . The anti-CD93 construct of claim 5 , wherein the antibody moiety comprises the V H comprising the amino acid sequence of SEQ ID NO: 310, and the V L comprising the amino acid sequence of SEQ ID NO: 318, wherein the anti-CD93 construct is a bispecific antibody comprising an IgG1 Fc fragment.
8 . The anti-CD93 construct of claim 6 , wherein the antibody moiety comprises the V H comprising the amino acid sequence of SEQ ID NO: 310, and the V L comprising the amino acid sequence of SEQ ID NO: 318, wherein the anti-CD93 construct is a full-length antibody comprising an IgG1 Fc fragment.
9 . The anti-CD93 construct of claim 1 , wherein the antibody moiety has an Fc fragment selected from the group consisting of Fc fragments from IgG, IgA, IgD, IgE, IgM, and combinations and hybrids thereof.
10 . The anti-CD93 construct of claim 9 , wherein the Fc fragment is selected from the group consisting of Fc fragments from IgG1, IgG2, IgG3, IgG4, and combinations and hybrids thereof.
11 . The anti-CD93 construct of claim 9 , wherein the Fc fragment has a reduced effector function as compared to the corresponding wildtype Fc fragment.
12 . The anti-CD93 construct of claim 9 , wherein the Fc fragment has an enhanced effector function as compared to the corresponding wildtype Fc fragment.
13 . The anti-CD93 construct of claim 1 , wherein the antibody moiety blocks the binding of CD93 to IGFBP7.
14 . The anti-CD93 construct of claim 1 , wherein the antibody moiety blocks the binding of CD93 to MMRN2.
15 . The anti-CD93 construct of claim 1 , wherein the CD93 is a human CD93.
16 . An immunoconjugate comprising the anti-CD93 construct of claim 1 , linked to a therapeutic agent or a label.
17 . A pharmaceutical composition comprising the anti-CD93 construct of claim 1 , and a pharmaceutical acceptable carrier.
18 . An isolated nucleic acid encoding the anti-CD93 construct of claim 1 .
19 . A vector comprising the isolated nucleic acid of claim 18 .
20 . An isolated host cell comprising the isolated nucleic acid of claim 18 .
21 . A method of treating a CD93-positive cancer in an individual, comprising administering to the individual an effective amount of the pharmaceutical composition of claim 17 .
22 . The method of claim 21 , wherein the CD93-positive cancer is associated with an abnormal vascular structure.
23 . The method of claim 21 , wherein the CD93-positive cancer is a solid tumor.
24 . The method of claim 21 , wherein the antibody moiety comprises the V H comprising the amino acid sequence of SEQ ID NO: 310, and the V L comprising the amino acid sequence of SEQ ID NO: 318.
25 . The method of claim 21 , wherein the antibody moiety comprises the V H comprising the amino acid sequence of SEQ ID NO: 310, and the V L comprising the amino acid sequence of SEQ ID NO: 318, wherein the anti-CD93 construct is a full-length antibody comprising an IgG1 Fc fragment.