Anti human interleukin-1 receptor accessory protein (IL1 RAP) antibodies and uses thereof
The present disclosure provides an antibody or an antigen-binding fragment thereof with binding specificity for human interleukin-1 receptor accessory protein (IL1 RAP) wherein the antibody or antigen-binding fragment is capable of inhibiting the binding of antibody ‘CAN04’ to human IL1 RAP. The disclosure further provides the use of such antibodies or an antigen-binding fragments in the treatment and/or diagnosis of IL-1 associated diseases and conditions, including cancers such as acute myeloid leukemia and melanoma.
1. An isolated antibody polypeptide with binding specificity for human interleukin-1 receptor accessory protein (IL1RAP) comprising:
a. A heavy chain variable region (VH) comprising:
(i) heavy chain CDR1 comprising:
GYAFTSS (amino acids 26-32 of SEQ ID NO:9);
(ii) Heavy chain CDR2 comprising:
YPGDGN (SEQ ID NO: 4; and
(iii) Heavy chain CDR3 comprising:
GYLDPMDY (SEQ ID NO: 5); and a light chain variable region (VL) comprising:
(i) Light chain CDR 1 comprising:
ASQGINNYLN (amino acids 25-34 of SEQ ID NO:16),
(ii) Light chain CDR2 comprising:
YTSGLHA (SEQ ID NO: 13); and
(iii) Light chain CDR3 comprising:
QQYSILPWT (SEQ ID NO: 14);
b. A heavy chain variable region (VH) comprising (i) heavy chain CDR1 comprising GYAFTSS (amino acids 26-32 of SEQ ID NO:9); (ii) heavy chain CDR2 comprising YPGDGN (SEQ ID NO: 4); and (iii) heavy chain CDR3 comprising GYLDPMDY (SEQ ID NO: 5); and a light chain variable region (VL) comprising (i) light chain CDR 1 comprising SASQGINNYLN (SEQ ID NO:12); light chain CDR2 comprising YTSGLHA (SEQ ID NO: 13); and (iii) light chain CDR3 comprising QQYSILPWT (SEQ ID NO: 14);
c. A heavy chain variable region (VH) comprising (i) heavy chain CDR1 comprising GYAFSSS (SEQ ID NO:3); (ii) heavy chain CDR2 comprising YPGDGN (SEQ ID NO: 4); and (iii) heavy chain CDR3 comprising GYLDPMDY (SEQ ID NO: 5); and a light chain variable region (VL) comprising (i) light chain CDR 1 comprising SASQGINNYLN (SEQ ID NO:12); light chain CDR2 comprising YTSGLHA (SEQ ID NO: 13); and (iii) light chain CDR3 comprising QQYSILPWT (SEQ ID NO: 14);
d. A heavy chain variable region (VH) comprising (i) heavy chain CDR1 comprising GYAFSSS (SEQ ID NO:3); (ii) heavy chain CDR2 comprising YPGDGN (SEQ ID NO: 4); and (iii) heavy chain CDR3 comprising GYLDPMDY (SEQ ID NO: 5); and a light chain variable region (VL) comprising (i) light chain CDR1 comprising ASQGINNYLN (amino acids 25-34 of SEQ ID NO:16); light chain CDR2 comprising YTSGLHA (SEQ ID NO: 13); and (iii) light chain CDR3 comprising QQYSILPWT (SEQ ID NO: 14);
e. A heavy chain variable region (VH) comprising (i) heavy chain CDR1 comprising GYTFTSS (amino acids 26-32 of SEQ ID NO:10); (ii) heavy chain CDR2 comprising YPGDGQ (amino acids 52-57 of SEQ ID NO:10); and (iii) heavy chain CDR3 comprising GYLDPMDY (SEQ ID NO: 5); and a light chain variable region (VL) comprising (i) light chain CDR 1 comprising SASQGINNYLN (SEQ ID NO:12); light chain CDR2 comprising YTSGLHA (SEQ ID NO: 13); and (iii) light chain CDR3 comprising QQYSILPWT (SEQ ID NO: 14); or
f. A heavy chain variable region (VH) comprising (i) heavy chain CDR1 comprising GYTFTSS (amino acids 26-32 of SEQ ID NO:10); (ii) heavy chain CDR2 comprising YPGDGQ (amino acids 52-57 of SEQ ID NO:10); and (iii) heavy chain CDR3 comprising GYLDPMDY (SEQ ID NO: 5); and a light chain variable region (VL) comprising (i) light chain CDR 1 comprising ASQGINNYLN (amino acids 25-34 of SEQ ID NO:16); light chain CDR2 comprising YTSGLHA (SEQ ID NO: 13); and (iii) light chain CDR3 comprising QQYSILPWT (SEQ ID NO: 14).
2. The antibody polypeptide of claim 1 wherein the antibody exhibits one or more of the following properties:
a) a binding affinity (K D ) for human IL1RAP of 200 pM or greater;
b) cross-reactivity with IL1RAP from Macaca fascicularis;
c) an inhibitory action on IL1 signalling;
d) capability of inducing ADCC in one or more cancer cell lines; and
e) capability of internalisation upon binding to one or more cancer cell lines.
3. The antibody polypeptide of claim 1 , wherein the antibody is an Fv fragment or an Fab fragment.
4. The antibody polypeptide of claim 1 comprising a heavy chain variable region comprising or consisting of the amino acids of SEQ ID NO: 9.
5. The antibody polypeptide of claim 1 comprising a light chain variable region comprising or consisting of the amino acids of SEQ ID NOs: 16.
6. The antibody polypeptide of claim 1 comprising a heavy chain variable region comprising or consisting of amino acids of SEQ ID NO: 9, and a light chain variable region comprising or consisting of the amino acids of SEQ ID NOs: 16.
7. The antibody polypeptide of claim 1 comprising:
a) a heavy chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 8 and a light chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 15;
b) a heavy chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 9 and a light chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 15;
c) a heavy chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 10 and a light chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 15;
d) a heavy chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 11 and a light chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 15;
e) a heavy chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 8 and a light chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 16;
f) a heavy chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 9 and a light chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 16;
g) a heavy chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 10 and a light chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 16;
h) a heavy chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 11 and a light chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 16;
i) a heavy chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 8 and a light chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 17;
j) a heavy chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 9 and a light chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 17;
k) a heavy chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 10 and a light chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 17; or
l) a heavy chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 11 and a light chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 17.
8. The antibody polypeptide of claim 1 comprising a heavy and light chain constant region, or part thereof.
9. The antibody polypeptide of claim 1 comprising an Fc region.
10. The antibody polypeptide of claim 1 further comprising a cytotoxic moiety.
11. The antibody polypeptide of claim 1 further comprising a detectable moiety.
12. An isolated nucleic acid molecule encoding the antibody polypeptide of claim 7 .
13. A pharmaceutical composition comprising the antibody polypeptide of claim 1 and a pharmaceutically-acceptable diluent, carrier or excipient.
14. An in vitro method for the detection of cancer cells expressing IL1RAP in a subject, the method comprising:
(a) obtaining cells from a subject to be tested; and
(b) detecting whether IL1RAP is present in the cells by contacting the cells with the antibody polypeptide of claim 1 , wherein detection of binding of the antibody to the cells indicates detection of cancer cells.