CLEC12a Binding Polypeptides and Uses Thereof
Provided herein are VHH-containing polypeptides that bind CLEC12a. Uses of the VHH-containing polypeptides are also provided.
1 . A polypeptide comprising at least one VHH domain that binds CLEC12a and that comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 47; a CDR2 comprising the amino acid sequence of SEQ ID NO: 48; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 49.
2 .- 8 . (canceled)
9 . The polypeptide of claim 1 , wherein at least one VHH domain is humanized.
10 . The polypeptide claim 1 , wherein at least one VHH domain comprises an amino acid sequence, at least 90% identical to the amino acid sequence of SEQ ID NO: 31 99.
11 . The polypeptide of claim 1 , wherein at least one VHH domain comprises the amino acid sequence of SEQ ID NO: 31, or 99.
12 . (canceled)
13 . (canceled)
14 . The polypeptide of claim 1 , comprising one, two, or three VHH domains.
15 . (canceled)
16 . The polypeptide of claim 1 , wherein the polypeptide comprises at least one binding domain that binds an antigen other than CLEC12a.
17 . The polypeptide of claim 16 , wherein the polypeptide comprises at least one binding domain that binds CD3, T-cell receptor (TCR) α, TCRβ, CD28, CD16, CD32A, CD64, CD89, NKp46, or NKG2D.
18 .- 21 . (canceled)
22 . The polypeptide of claim 1 , wherein the polypeptide comprises an Fc region.
23 . The polypeptide of claim 22 , wherein the Fc region comprises an amino acid sequence selected from SEQ ID NOs: 50 to 85.
24 . The polypeptide of claim 22 , which forms a dimer under physiological conditions.
25 . (canceled)
26 . (canceled)
27 . An immunoconjugate comprising the polypeptide of claim 1 and a cytotoxic agent.
28 . The immunoconjugate of claim 27 , wherein the cytotoxic agent is selected from a calicheamicin, an auristatin, a dolastatin, a tubulicin, a maytansinoid, a cryptophycin, a duocarmycin, an esperamicin, a pyrrolobenzodiazepine, and an enediyne antibiotic.
29 . A pharmaceutical composition comprising the polypeptide of claim 1 , and a pharmaceutically acceptable carrier.
30 . An isolated nucleic acid that encodes the polypeptide of claim 1 .
31 . A vector comprising the nucleic acid of claim 30 .
32 . (canceled)
33 . A host cell that expresses the polypeptide of claim 1 .
34 . A method of producing a polypeptide, comprising incubating the host cell of claim 33 under conditions suitable for expression of the polypeptide and isolating the polypeptide.
35 . (canceled)
36 . A method of treating cancer comprising administering to a subject with cancer a pharmaceutically effective amount of the polypeptide of claim 1 .
37 . The method of claim 36 , wherein the cancer is selected from lymphoma; Hodgkin's lymphoma; non-Hodgkin's lymphoma; B-cell lymphoma; low grade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; Waldenstrom's macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); Hairy cell leukemia; and chronic myeloblastic leukemia.
38 . (canceled)
39 . The method of claim 36 , further comprising administering an additional therapeutic agent.
40 . The method of claim 39 , wherein the additional therapeutic agent is an anti-cancer agent, wherein the anti-cancer therapy or agent is selected from a chemotherapeutic agent, an anti-cancer biologic, radiation therapy, CAR-T therapy, and an oncolytic virus.
41 . (canceled)
42 . (canceled)
43 . The polypeptide of claim 1 , wherein at least one VHH domain that binds CLEC12a comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 31 or 99.
44 . The polypeptide of claim 14 , wherein at least one VHH domain that binds CLEC12a comprises the amino acid sequence of SEQ ID NO: 31 or 99.
45 . The polypeptide of claim 16 , wherein at least one VHH domain that binds CLEC12a comprises the amino acid sequence of SEQ ID NO: 31 or 99.
46 . The method of claim 36 , wherein at least one VHH domain that binds CLEC12a comprises the amino acid sequence of SEQ ID NO: 31 or 99.
47 . The immunoconjugate of claim 27 , wherein at least one VHH domain that binds CLEC12a comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 31 or 99.
48 . The immunoconjugate of claim 27 , wherein at least one VHH domain that binds CLEC12a comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 31 or 99.
49 . A method of inhibiting or slowing the progression of cancer comprising administering to a subject with cancer a pharmaceutically effective amount of the immunoconjugate of claim 27 , wherein the cancer is selected from chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); Hairy cell leukemia; and chronic myeloblastic leukemia.
50 . The method of claim 49 , wherein the cytotoxic agent is selected from a calicheamicin, an auristatin, a dolastatin, a tubulicin, a maytansinoid, a cryptophycin, a duocarmycin, an esperamicin, a pyrrolobenzodiazepine, and an enediyne antibiotic.
51 . The method of claim 49 , wherein the polypeptide comprises at least one VHH domain that binds CLEC12a comprising the amino acid sequence of SEQ ID NO: 31 or 99.
52 . The method of claim 50 , wherein the polypeptide comprises at least one VHH domain that binds CLEC12a comprising the amino acid sequence of SEQ ID NO: 31 or 99.