Multispecific antibodies having specificity for IL-4R and IL-31, encoding nucleic acids thereof and methods of treating
The present invention relates to a multispecific antibody comprising one or two binding domains, which specifically bind to IL-4R (IL4R-BDs), and one or two binding domains, which specifically bind to IL-31 (IL31-BDs), wherein the multispecific antibody comprises an immunoglobulin Fc region. The present invention further relates to nucleic acids encoding said multispecific antibody, vector(s) comprising said nucleic acids, host cell(s) comprising said nucleic acids or said vector(s), and a method of producing said multispecific antibody. Additionally, the present invention relates to pharmaceutical compositions comprising said multispecific antibody and methods of use thereof.
1 . A multispecific antibody comprising:
a) one or two binding domains, which specifically bind to IL-4R (IL4R-BD), and
b) one or two binding domains, which specifically bind to IL-31 (IL31-BD),
wherein
the multispecific antibody comprises an immunoglobulin Fc region;
each of said IL4R-BDs comprise
an HCDR1 sequence of SEQ ID NO: 1,
HCDR2 sequence of SEQ ID NO: 2,
an HCDR3 sequence of SEQ ID NO: 3,
an LCDR1 sequence of SEQ ID NO: 7,
an LCDR2 sequence of SEQ ID NO: 8, and
an LCDR3 sequence of SEQ ID NO: 9; and
each of said IL31-BDs comprises
an HCDR1 sequence of SEQ ID NO: 12,
an HCDR2 sequence of SEQ ID NO: 13,
an HCDR3 sequence of SEQ ID NO: 14,
an LCDR1 sequence of SEQ ID NO: 17,
an LCDR2 sequence of SEQ ID NO: 19, and
an LCDR3 sequence of SEQ ID NO: 20.
2 . The multispecific antibody of claim 1 , wherein the format of said multispecific antibody is selected from bivalent bispecific IgG formats, trivalent bispecific IgG formats and tetravalent bispecific IgG formats.
3 . The multispecific antibody of claim 1 , wherein the format of said multispecific antibody is a Morrison format.
4 . The multispecific antibody of claim 1 , wherein said multispecific antibody comprises two IL4R-BDs and two IL31-BDs.
5 . The multispecific antibody of claim 3 , wherein the IL4R-BDs are located in a Fab of the Morrison format, and the IL31-BDs are located in an scFv of the Morrison format.
6 . The multispecific antibody of claim 3 , wherein the format of the multispecific antibody is selected from a Morrison-L and a Morrison-H format.
7 . The multispecific antibody of claim 1 , wherein said IL4R-BDs comprise
a) a heavy chain variable domain comprising an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 percent identical to SEQ ID NO: 4 and
a light chain variable domain comprising an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 percent identical to SEQ ID NO: 11; or
b) a heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 4 and a light chain variable domain comprising an amino acid sequence of SEQ ID NO: 11.
8 . The multispecific antibody of claim 1 , wherein said IL31-BDs comprise
a) a heavy chain variable domain comprising an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 percent identical to SEQ ID NO: 16 and
a light chain variable domain comprising an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 percent identical to SEQ ID NO: 21; or
b) a heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 16 and a light chain variable domain comprising an amino acid sequence of SEQ ID NO: 21.
9 . The multispecific antibody of claim 1 , wherein the immunoglobulin Fc region is selected from IgG subclasses IgG1 and IgG4.
10 . The multispecific antibody of claim 9 , wherein the immunoglobulin Fc region is selected from IgG subclass IgG4.
11 . The multispecific antibody of claim 2 , wherein the format of said multispecific antibody is selected from KiH-based IgGs; DVD-1g; CODV-IgG and Morrison (IgG CH3-scFv fusion (Morrison-H) or IgG CL-scFv fusion (Morrison-L)).
12 . The multispecific antibody of claim 6 , wherein the format of the multispecific antibody is the Morrison-H format.
13 . The multispecific antibody of claim 1 , comprising a Morrison antibody having a heavy chain comprising an amino acid sequence of SEQ ID NO: 38 and a light chain comprising an amino acid sequence of SEQ ID NO: 37.
14 . A multispecific antibody comprising two IL-4R binding domains (IL4R-BD) and two IL-31 binding domains (IL31-BD), wherein
(a) each of said IL4R-BDs comprise an HCDR1 sequence of SEQ ID NO: 1, an HCDR2 sequences of SEQ ID NO: 2, an HCDR3 sequence of SEQ ID NO: 3, an LCDR1 sequence of SEQ ID NO: 7, an LCDR2 sequence of SEQ ID NO: 8, and an LCDR3 sequence of SEQ ID NO: 9; and
(b) each of said IL31-BDs comprises an HCDR1 sequence of SEQ ID NO: 12, an HCDR2 sequence of SEQ ID NO: 13, an HCDR3 sequence of SEQ ID NO: 14, an LCDR1 sequence of SEQ ID NO: 17, an LCDR2 sequence of SEQ ID NO: 19, and an LCDR3 sequence of SEQ ID NO: 20.
15 . A multispecific antibody comprising
(a) a first heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 4;
(b) a first light chain variable domain comprising an amino acid sequence of SEQ ID NO: 11;
(c) a second heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 16; and
(d) a second light chain variable domain comprising an amino acid sequence of SEQ ID NO: 21.
16 . A multispecific antibody comprising
(a) two heavy chains, each heavy chain comprising an amino acid sequence of SEQ ID NO: 38; and
(b) two light chains, each light chain comprising an amino acid sequence of SEQ ID NO: 37.
17 . A nucleic acid or two nucleic acids encoding the multispecific antibody of claim 1 .
18 . A vector or two vectors comprising the nucleic acid or the two nucleic acids of claim 17 .
19 . A host cell or host cells comprising the vector or the two vectors of claim 18 .
20 . A nucleic acid or two nucleic acids encoding the multispecific antibody of claim 14 .
21 . A vector or two vectors comprising the nucleic acid or the two nucleic acids of claim 20 .
22 . A host cell or host cells comprising the vector or the two vectors of claim 21 .
23 . A pharmaceutical composition comprising the multispecific antibody of claim 14 and a pharmaceutically acceptable carrier.
24 . A nucleic acid or two nucleic acids encoding the multispecific antibody of claim 15 .
25 . A vector or two vectors comprising the nucleic acid or the two nucleic acids of claim 24 .
26 . A host cell or host cells comprising the vector or the two vectors of claim 25 .
27 . A pharmaceutical composition comprising the multispecific antibody of claim 15 and a pharmaceutically acceptable carrier.
28 . A nucleic acid or two nucleic acids encoding the multispecific antibody of claim 16 .
29 . A vector or two vectors comprising the nucleic acid or the two nucleic acids of claim 28 .
30 . A host cell or host cells comprising the vector or the two vectors of claim 29 .
31 . A method for producing the multispecific antibody of claim 1 , comprising providing the nucleic acid or the two nucleic acids encoding the multispecific antibody of claim 1 , expressing said nucleic acid or said two nucleic acids, and collecting said multispecific antibody from an expression system.
32 . A pharmaceutical composition comprising the multispecific antibody of claim 1 and a pharmaceutically acceptable carrier.
33 . A pharmaceutical composition comprising the multispecific antibody of claim 13 and a pharmaceutically acceptable carrier.
34 . A pharmaceutical composition comprising the multispecific antibody of claim 16 and a pharmaceutically acceptable carrier.
35 . A method of treating a condition comprising the administration of the multispecific antibody of claim 16 to a subject in need thereof, wherein the condition is selected from the group consisting of pruritus-causing allergic diseases, pruritus-causing inflammatory diseases, pruritus-causing autoimmune diseases, atopic dermatitis, acute allergic contact dermatitis, chronic spontaneous urticaria, bullous pemphigoid, alopecia areata, dermatomyositis, prurigo nodularis, psoriasis or atopic asthma.
36 . A method of treating a condition comprising the administration of the antibody of claim 16 to a subject in need thereof, wherein the condition is selected from the group consisting of pruritus, atopic dermatitis, acute allergic contact dermatitis, chronic spontaneous urticaria, bullous pemphigoid, alopecia areata, dermatomyositis, prurigo nodularis, psoriasis and atopic asthmas.