NZ623425B2 - Anti il-36r antibodies - Google Patents
Anti il-36r antibodies Download PDFInfo
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- NZ623425B2 NZ623425B2 NZ623425A NZ62342512A NZ623425B2 NZ 623425 B2 NZ623425 B2 NZ 623425B2 NZ 623425 A NZ623425 A NZ 623425A NZ 62342512 A NZ62342512 A NZ 62342512A NZ 623425 B2 NZ623425 B2 NZ 623425B2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/715—Assays involving receptors, cell surface antigens or cell surface determinants for cytokines; for lymphokines; for interferons
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
- G01N33/6869—Interleukin
Abstract
Disclosed are antibodies for anti Interleukin (IL) 36R. Including therapeutic and diagnostic methods.
Description
WO 74569
Anti IL-36R Antibodies
Sequence Listing
The instant application contains a Sequence Listing which has been ted in ASCII
format via EFS-Web and is hereby orated by reference in its entirety. Said ASCII
copy, created on November 12, 2012, is named 09-0583WO.txt and is 147,390 bytes in
size.
Technical Field of the Invention
This invention generally relates to anti-IL-36R antibodies for diagnostic and therapeutic
use. The antibodies can be used in pharmaceutical compositions and kits sing
such compounds. The antibodies are useful in s for the treatment of various
diseases or disorders, for example immunological, inflammatory, autoimmune, fibrotic
and respiratory diseases in humans.
Background of the Invention
The IL-1 family of cytokines is composed of 11 different ligands, , IL-1or (also
termed IL-1F1), IL-1B (IL-1F2), IL-1 receptor antagonist (IL-1Ra or IL-1F3), IL-18 (IL-
1F4), IL-1F5 to IL-1F10, and IL-1F11 (or IL-33). IL-1or and IL-1B are known to induce
pro-inflammatory activities on g to type I IL-1 receptor (IL-1Rl) and recruitment of
the common co-receptor IL-1 receptor accessory protein (IL-1RAcP), whereas IL-1Ra
acts as a competitive inhibitor of IL-1 binding to IL-1Rl, thus ng nflammatory
activity. Numerous studies reported that IL-18 is a pro-inflammatory cytokine that is an
inducer of IFN-v, whereas IL-33 was described as an immunoregulatory cytokine
ed in particular in the control of Th2 ses. New members of the IL-1 family,
including IL-1F5, IL-1F6, IL-1F8, and IL-1F9, were identified through searches in DNA
databases for homologs of IL-1. In humans and mice, all the genes encoding these
cytokines map to less than 300 kb of chromosome 2q, where they are flanked by the
IL1A, IL1B, and IL1RN genes. IL-1 F6, IL-1 F8, and IL-1 F9 share 21% to 37% amino acid
sequence homology with lL-1 and lL-1Ra, whereas lL-1F5 displays 52% amino acid
sequence homology with lL-1Ra, suggesting that lL-1F5 might ent an
endogenous receptor antagonist.
lL-1 F6, lL-1F8, and lL-1F9 bind to lL-1Rrp2, a receptor of the lL-1 R family, and use lL-
1RAcP as a co-receptor to stimulate intracellular signals r to those induced by IL-
1, whereas lL-1F5 was shown to inhibit lL-1F9—induced NF-KB activation in Jurkat T
cells that over-express lL-1Rrp2. Like lL-1B, all these lL-1 homologs lack a leader
peptide and cannot be released through the conventional secretory pathway, although
studies suggest that release of lL-1Rrp2 agonists may be controlled by mechanisms
ent from those regulating lL-1B secretion. To acknowledge the specific biologic
effects of these cytokines and to recognize that they all bind to the same receptor, it has
recently been proposed to amend the nomenclature of lL-1 homologs. Thus, lL-1Rrp2 is
now termed lL-36R and its ligands are named lL-36d (IL-1 F6), lL-3BB 8), and IL-
36y (lL-1F9). In addition, lL-1F5, which has been shown to exert receptor antagonist
activities, has been renamed lL-36Ra.
Messenger RNAs for lL-36d, lL-3BB, and lL-36y are highly expressed in several tissues,
particularly in internal epithelial s, which are exposed to pathogens and in skin.
Interestingly, expression of lL-36Ra and lL-36d is significantly up-regulated in IL-
1B/TNF-d—stimulated human nocytes, and lL-36Ra and lL-36y mRNA are highly
increased in lesional psoriasis skin. Moreover, lL-36y n production is enhanced in
human keratinocytes after TNF-d and lFN-y stimulation. Elevated lL-36d mRNA and
protein sion was reported also in chronic kidney disease.
Transgenic mice overexpressing lL-36d in nocytes exhibit inflammatory skin
lesions sharing some features with psoriasis. This phenotype was more severe when
transgenic mice were crossed with lL-36Ra—deficient mice, ting a regulatory
function of lL-36Ra in vivo. The inflammatory skin condition in keratinocyte-specific lL-
36d transgenic is even more similar to human psoriasis if the mice are treated with 12-
O-tetradecanoylphorbol tate, resembling the human disease histologically,
molecularly, and in its se to therapeutics. Moreover, human psoriatic lesional skin
transplanted onto immunodeficient mice is normalized when the mice are treated with
anti–IL-36R dy, arguing that the IL-36 axis is required to maintain the lesional phenotype
in human psoriatic skin. Taken together, these data indicate that IL-36R s, including IL-
36α, IL-36β, and , exert proinflammatory effects in vitro and in vivo and that IL-36Ra
acts as a natural antagonist, thus mimicking the IL-1/IL-1Ra system.
There is therefore ce that IL-36R ligands are involved in a number of disease conditions,
and there is a need for new therapeutic agents targeting this y, in particular for use in the
treatment of inflammatory diseases.
Summary of the invention
The present invention addresses the above need by providing biotherapeutics, in particular
antibodies, which bind to IL-36R. In one aspect, the antibodies of the present invention block
IL36 ligand-mediated signaling (α, β and/or γ). In one aspect the antibodies of the present
invention are useful, for example for the treatment of epithelial-mediated inflammation/fibrosis
in diseases such as sis, inflammatory bowel disease, scleroderma, COPD, and chronic
kidney disease.
According to a first aspect, the present invention provides an anti-interleukin-36R (anti-IL-36R)
antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment
thereof comprises:
a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26
(L-CDR1); the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105, 106 or
140 (L-CDR2); the amino acid ce of SEQ ID NO: 44 (L-CDR3); and
b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:
53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111
2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).
In one aspect, the present invention provides an anti-IL-36R antibody having one or more of the
properties below.
In one aspect, an anti-IL-36R antibody of the t invention has high molecular/cellular
binding potency. In one aspect, an anti-IL-36R antibody of the present invention binds to human
IL-36R at a KD < 0.1 nM. In a further aspect, an anti-IL-36R antibody of the present invention,
in particular a humanized anti-IL-36R antibody, binds to human IL-36R at a KD < 50 pM. In one
aspect, an anti-IL-36R dy of the present invention binds to IL-36R expressing cells at an
EC90 <5 nM.
In another , an anti-IL-36R antibody of the present invention has high cell-based
functional ng potency. In one aspect, an anti-IL-36R dy of the present
AH26(10651560_1):RTK
2012/064933
invention blocks all three lL-36R agonistic ligands (or, B, y) at an I090 55 nM, in disease-
relevant cell lines and primary cells.
In one aspect, an anti-lL-36R antibody of the present invention has the
molecular/cellular binding potency and the cell-based functional blocking potency set
forth above.
In a further aspect, an anti-lL-36R antibody of the present invention has high selectivity
for example greater than 1000-fold selectivity against human lL-1R1 or lL-36R negative
cell lines. In a further aspect, an anti-lL-36R antibody of the present ion does not
bind to human lL-1 R1 or lL-36R negative cell lines.
In embodiment one, the present invention provides an anti-lL-36R antibody or antigen-
binding fragment thereof, which binds to human lL-36R at a KD equal to or< 0.1 nM.
ln embodiment two, the present invention provides an anti-lL-36R antibody or antigen-
binding fragment thereof according to embodiment one, wherein the said antibody or
antigen-binding fragment is a monoclonal dy or n-binding fragment f.
In embodiment three, the present invention es an anti-lL-36R antibody or antigen-
binding fragment thereof according to embodiment one or two, wherein the said
antibody or antigen-binding fragment is a zed antibody or antigen-binding
fragment thereof.
In embodiment four, the present invention provides an anti-lL-36R antibody or antigen-
binding fragment thereof ing to embodiment three, which binds to human lL-36R
at a KD equal to or< 50 pM.
ln embodiment five, the t invention provides an anti-lL-36R antibody or antigen-
binding fragment f according to any one of ment one to four, which does
not bind to human lL-1R1.
In embodiment six, the present invention provides an anti-IL-36R antibody or antigen-
binding fragment thereof according to embodiment one, wherein the antibody or
antigen-binding fragment thereof comprises:
a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26
(L-CDR1); the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105106 or 140
(L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and
b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53
(H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (HCDR2
); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).
In embodiment seven, the present invention provides an anti-IL-36R antibody or
antigen-binding fragment thereof ing to ment six, wherein the antibody or
antigen-binding fragment fragment thereof comprises:
a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26
(L-CDR1); the amino acid sequence of SEQ ID NO: 102 (L-CDR2); the amino acid
ce of SEQ ID NO: 44 (L-CDR3); and
b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53
(H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (HCDR2
); the amino acid ce of SEQ ID NO: 72 (H-CDR3).
In embodiment eight, the present invention provides an anti-IL-36R dy or n-
binding fragment thereof according to embodiment six, wherein the antibody or antigenbinding
fragment nt thereof comprises:
a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26
(L-CDR1); the amino acid sequence of SEQ ID NO: 103 (L-CDR2); the amino acid
ce of SEQ ID NO: 44 (L-CDR3); and
b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53
(H-CDR1); the amino acid ce of SEQ ID NO: 62, 108, 109, 110 or 111 (HCDR2
); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).
In embodiment nine, the t invention provides an anti-IL-36R antibody or antigen-
binding fragment thereof according to embodiment six, wherein the antibody or antigenbinding
fragment fragment thereof comprises:
a) a light chain le region comprising the amino acid sequence of SEQ ID NO: 26
(L-CDR1); the amino acid sequence of SEQ ID NO: 104 (L-CDR2); the amino acid
sequence of SEQ ID NO: 44 (L-CDR3); and
b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53
(H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (HCDR2
); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).
In embodiment ten, the present invention provides an anti-IL-36R antibody or antigen-
binding fragment thereof ing to embodiment six, n the dy or antigen-
binding fragment fragment thereof comprises:
a) a light chain variable region sing the amino acid sequence of SEQ ID NO: 26
(L-CDR1); the amino acid sequence of SEQ ID NO: 105 (L-CDR2); the amino acid
sequence of SEQ ID NO: 44 (L-CDR3); and
b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53
(H-CDR1); the amino acid ce of SEQ ID NO: 62, 108, 109, 110 or 111 (HCDR2
); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).
In embodiment eleven, the present invention provides an anti-IL-36R antibody or
antigen-binding fragment f ing to embodiment six, wherein the antibody or
antigen-binding fragment fragment thereof comprises:
a) a light chain variable region sing the amino acid sequence of SEQ ID NO: 26
(L-CDR1); the amino acid sequence of SEQ ID NO: 106 (L-CDR2); the amino acid
sequence of SEQ ID NO: 44 (L-CDR3); and
b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53
(H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (HCDR2
); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).
In embodiment twelve, the present invention provides an anti-IL-36R antibody or
antigen-binding fragment thereof according to embodiment six, wherein the antibody or
antigen-binding fragment fragment thereof comprises:
a) a light chain le region comprising the amino acid sequence of SEQ ID NO: 26
(L-CDR1); the amino acid sequence of SEQ ID NO: 140 (L-CDR2); the amino acid
sequence of SEQ ID NO: 44 (L-CDR3); and
b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53
(H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (HCDR2
); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).
In embodiment thirteen, the present invention provides an anti-IL-36R dy or
antigen-binding fragment thereof according to embodiment one, wherein the antibody or
antigen-binding fragment fragment thereof comprises alight chain variable region
comprising the amino acid sequence of any one of SEQ ID NO: 76, 77, 78, 79, 80, 81,
82 or 83; and a heavy chain variable region comprising the amino acid sequence of any
one of SEQ ID NO: 87, 88, 89, 90, 91, 92, 93, 94 or 95.
In embodiment fourteen, the present invention es an L-36R antibody or
antigen-binding fragment thereof according to embodiment thirteen, wherein the
antibody or antigen-binding fragment fragment thereof comprises alight chain le
region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain
variable region sing the amino acid sequence of SEQ ID NO: 87;or
alight chain variable region comprising the amino acid sequence of SEQ ID NO: 77;
and a heavy chain le region sing the amino acid sequence of SEQ ID NO:
88; or
alight chain variable region sing the amino acid sequence of SEQ ID NO: 77;
and a heavy chain variable region sing the amino acid sequence of SEQ ID NO:
In embodiment fifteen, the present invention provides an in the antibody or antigen-
binding fragment fragment thereof comprises alight chain variable region comprising
the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region
comprising the amino acid sequence of SEQ ID NO: 87;or
a light chain variable region comprising the amino acid ce of SEQ ID NO: 80;
and a heavy chain variable region comprising the amino acid ce of SEQ ID NO:
88; or
alight chain variable region comprising the amino acid sequence of SEQ ID NO: 80;
and a heavy chain le region comprising the amino acid sequence of SEQ ID NO:
In embodiment sixteen, the present invention es an anti-IL-36R antibody or
antigen-binding fragment thereof ing to embodiment one, wherein the antibody or
antigen-binding fragment fragment thereof comprises:
a light chain variable region comprising the amino acid sequence of SEQ ID NO: 27 (L-
CDRf); the amino acid sequence of SEQ ID NO: 36 (L-CDR2); the amino acid
sequence of SEQ ID NO: 45 (L-CDR3); and a heavy chain variable region sing
the amino acid sequence of SEQ ID NO: 107 (H-CDRt); the amino acid sequence of
SEQ ID NO: 63 (H-CDR2); the amino acid sequence of SEQ ID NO: 73 (H-CDR3); or
alight chain variable region comprising the amino acid sequence of SEQ ID NO: 27 (L-
CDRf); the amino acid sequence of SEQ ID NO: 36 (L-CDR2); the amino acid
sequence of SEQ ID NO: 45 (L-CDR3); and a heavy chain variable region comprising
the amino acid sequence of SEQ ID NO: 107 (H-CDRt); the amino acid sequence of
SEQ ID NO: 64 (H-CDR2); the amino acid sequence of SEQ ID NO: 73 (H-CDR3); or or
alight chain le region sing the amino acid sequence of SEQ ID NO: 27 (L-
CDRf); the amino acid sequence of SEQ ID NO: 36 (L-CDR2); the amino acid
sequence of SEQ ID NO: 45 (L-CDR3); and a heavy chain variable region comprising
the amino acid sequence of SEQ ID NO: 54 (H-CDRt); the amino acid sequence of
SEQ ID NO: 63 or 64 (H-CDR2); the amino acid sequence of SEQ ID NO: 73 (H-
CDR3).
In embodiment seventeen, the present ion provides an anti-IL-36R antibody or
antigen-binding nt thereof according to embodiment one, wherein the antibody or
antigen-binding fragment fragment thereof comprises alight chain variable region
comprising the amino acid sequence of any one of SEQ ID NO: 84, 85 or 86; and a
heavy chain variable region comprising the amino acid sequence of any one of SEQ ID
NO: 96, 97, 98, 99, 100 or 101.
In embodiment eighteen, the present invention provides an anti-IL-36R antibody or
antigen-binding fragment thereof according to embodinet seventeen, wherein the
antibody or antigen-binding fragment fragment thereof ses alight chain variable
region sing the amino acid sequence of SEQ ID NO: 85; and a heavy chain
variable region comprising the amino acid sequence of SEQ ID NO: 100; or
alight chain variable region comprising the amino acid sequence of SEQ ID NO: 85;
and a heavy chain variable region comprising the amino acid sequence of SEQ ID
NO:101.
In embodiment nineteen, the t invention provides an anti-IL-36R antibody or
antigen-binding nt thereof according to embodiment seventeen, wherein the
antibody or antigen-binding fragment fragment thereof ses alight chain le
region sing the amino acid sequence of SEQ ID NO: 86; and a heavy chain
variable region comprising the amino acid sequence of SEQ ID NO: 100; or
alight chain variable region comprising the amino acid sequence of SEQ ID NO: 86;
and a heavy chain variable region comprising the amino acid sequence of SEQ ID
NO:101.
In embodiment twenty, the present invention es an anti-IL-36R antibody, wherein
the antibody comprises alight chain comprising the amino acid sequence of any one of
SEQ ID NO:114,115,116,117,118,119,12O or 121; and a heavy chain comprising
the amino acid sequence of any one of SEQ ID NO: 125, 126, 127, 128, 129, 130, 131,
132 or 133.
In embodiment twenty one, the present invention provides an L-36R antibody
according to embodiment twenty, wherein the antibody comprises a light chain
sing the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising
the amino acid sequence of SEQ ID NO: 125.
In embodiment twenty two, the present invention provides an anti-IL-36R antibody
according to embodiment twenty, n the antibody comprises a light chain
comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising
the amino acid sequence of SEQ ID NO: 126.
In embodiment twenty three, the present invention es an anti-IL-36R antibody
according to embodiment twenty, wherein the antibody comprises a light chain
comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising
the amino acid sequence of SEQ ID NO: 127.
In embodiment twenty four, the present ion provides an L-36R antibody
according to embodiment twenty, n the antibody comprises a light chain
comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising
the amino acid sequence of SEQ ID NO: 125.
In embodiment twenty five, the present invention provides an anti-IL-36R antibody
according to embodiment twenty, wherein the antibody ses a light chain
comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising
the amino acid sequence of SEQ ID NO: 126.
In embodiment twenty six, the present invention provides an anti-IL-36R antibody
according to embodiment twenty, wherein the dy comprises a light chain
comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising
the amino acid sequence of SEQ ID NO: 127.
In embodiment twenty seven, the present invention es an anti-IL-36R antibody,
wherein the antibody comprises a light chain comprising the amino acid sequence of
any one of SEQ ID NO: 122, 123 or 124; and a heavy chain comprising the amino acid
sequence of any one of SEQ ID NO: 134, 135, 136, 137, 138 or 139.
In embodiment twenty eight, the t invention provides an anti-IL-36R antibody
according to embodiment twenty seven, wherein the antibody comprises a light chain
comprising the amino acid sequence of SEQ ID NO: 123; and a heavy chain comprising
the amino acid sequence of SEQ ID NO: 138.
In embodiment twenty nine, the present invention provides an anti-IL-36R antibody
according to embodiment twenty seven, wherein the antibody comprises a light chain
sing the amino acid sequence of SEQ ID NO: 123; and a heavy chain comprising
the amino acid sequence of SEQ ID NO: 139.
In embodiment thirty, the present invention provides an anti-IL-36R dy according
to twenty seven, wherein the antibody comprises a light chain comprising the amino
acid sequence of SEQ ID NO: 124; and a heavy chain comprising the amino acid
ce of SEQ ID NO: 138.
In embodiment thirty one, the present invention provides an anti-IL-36R dy or
antigen-binding fragment thereof according to embodiment one, wherein the antibody or
antigen-binding nt fragment thereof comprises:
a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26
(L-CDR1); the amino acid ce of SEQ ID NO: 103 2); the amino acid
sequence of SEQ ID NO: 44 (L-CDR3); and
b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53
(H-CDR1); the amino acid sequence of SEQ ID NO: 62 (H-CDR2); the amino acid
sequence of SEQ ID NO: 72 (H-CDR3).
In embodiment thirty two, the present invention es an anti-IL-36R antibody or
antigen-binding fragment thereof according to embodiment one, n the antibody or
antigen-binding fragment fragment thereof comprises:
a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26
(L-CDRt); the amino acid sequence of SEQ ID NO: 104(L-CDR2); the amino acid
sequence of SEQ ID NO: 44 (L-CDR3); and
b) a heavy chain variable region comprising the amino acid ce of SEQ ID NO: 53
(H-CDRt); the amino acid sequence of SEQ ID NO: 62 (H-CDR2); the amino acid
sequence of SEQ ID NO: 72 (H-CDR3).
In embodiment thirty three, the present invention provides an anti-IL-36R antibody or
antigen-binding fragment f ing to embodiment one, wherein the antibody or
n-binding nt fragment thereof comprises:
a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 27
(L-CDRt); the amino acid sequence of SEQ ID NO: 36(L-CDR2); the amino acid
sequence of SEQ ID NO: 45 (L-CDR3); and
b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:
107 t); the amino acid sequence of SEQ ID NO: 63 (H-CDR2); the amino acid
sequence of SEQ ID NO: 73 (H-CDR3).
In embodiment thirty four, the present invention provides an anti-IL-36R antibody or
antigen-binding fragment thereof according to embodiment one, wherein the antibody or
antigen-binding nt fragment f comprises:
a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 27
(L-CDRt); the amino acid sequence of SEQ ID NO: 36(L-CDR2); the amino acid
sequence of SEQ ID NO: 45 (L-CDR3); and
b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:
107 (H-CDRt); the amino acid sequence of SEQ ID NO: 64 (H-CDR2); the amino acid
sequence of SEQ ID NO: 73 (H-CDR3).
In one embodiment, an antibody or antigen-binding fragment thereof according to any
one of embodiments one to thirty-four is a onal antibody. In one embodiment, an
antibody or antigen-binding fragment thereof ing to any one of ments one
to -four is a humanized antibody. In one embodiment, an antibody or antigen-
binding fragment thereof according to any one of embodiments one to thirty-four is a
monoclonal humanized antibody.
In embodiment thirty five, the present ion provides an anti-IL-36R antibody or
antigen-binding fragment f, wherein the antibody or n-binding fragment
fragment thereof comprises:
a light chain variable region comprising the amino acid sequence of SEQ ID NO: 21 (L-
CDR1); the amino acid sequence of SEQ ID NO: 30 (L-CDR2); the amino acid
ce of SEQ ID NO: 39 (L-CDR3); and a heavy chain variable region comprising
the amino acid sequence of SEQ ID NO: 48 (H-CDR1); the amino acid sequence of
SEQ ID NO: 57 (H-CDR2); the amino acid sequence of SEQ ID NO: 67 (H-CDR3); or
a light chain variable region comprising the amino acid sequence of SEQ ID NO: 22 (L-
CDR1); the amino acid ce of SEQ ID NO: 31 (L-CDR2); the amino acid
sequence of SEQ ID NO: 40 (L-CDR3); and a heavy chain le region comprising
the amino acid sequence of SEQ ID NO: 49 (H-CDR1); the amino acid sequence of
SEQ ID NO: 58 (H-CDR2); the amino acid sequence of SEQ ID NO: 68 (H-CDR3); or
a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23 (L-
CDR1); the amino acid sequence of SEQ ID NO: 32 (L-CDR2); the amino acid
sequence of SEQ ID NO: 41 (L-CDR3); and a heavy chain variable region comprising
the amino acid sequence of SEQ ID NO: 50 (H-CDR1); the amino acid sequence of
SEQ ID NO: 59 (H-CDR2); the amino acid sequence of SEQ ID NO: 69 (H-CDR3); or
a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24 (L-
CDR1); the amino acid sequence of SEQ ID NO: 33 (L-CDR2); the amino acid
sequence of SEQ ID NO: 42 (L-CDR3); and a heavy chain variable region comprising
the amino acid sequence of SEQ ID NO: 51 (H-CDR1); the amino acid sequence of
SEQ ID NO: 60 (H-CDR2); the amino acid sequence of SEQ ID NO: 70 (H-CDR3); or
2012/064933
a light chain le region comprising the amino acid sequence of SEQ ID NO: 25 (L-
CDRt); the amino acid sequence of SEQ ID NO: 34 (L-CDR2); the amino acid
sequence of SEQ ID NO: 43 3); and a heavy chain variable region comprising
the amino acid sequence of SEQ ID NO: 52 (H-CDRt); the amino acid sequence of
SEQ ID NO: 61 (H-CDR2); the amino acid sequence of SEQ ID NO: 71 3); or
a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-
CDRt); the amino acid sequence of SEQ ID NO: 35 (L-CDR2); the amino acid
sequence of SEQ ID NO: 44 (L-CDR3); and a heavy chain variable region comprising
the amino acid sequence of SEQ ID NO: 53 (H-CDRt); the amino acid sequence of
SEQ ID NO: 62 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 3); or
a light chain variable region comprising the amino acid sequence of SEQ ID NO: 27 (L-
CDRt); the amino acid sequence of SEQ ID NO: 36 (L-CDR2); the amino acid
sequence of SEQ ID NO: 45 (L-CDR3); and a heavy chain variable region comprising
the amino acid sequence of SEQ ID NO: 54 (H-CDRt); the amino acid sequence of
SEQ ID NO: 63 (H-CDR2); the amino acid sequence of SEQ ID NO: 73 (H-CDR3); or
a light chain variable region comprising the amino acid sequence of SEQ ID NO: 27 (L-
CDRt); the amino acid sequence of SEQ ID NO: 36 (L-CDR2); the amino acid
sequence of SEQ ID NO: 45 (L-CDR3); and a heavy chain variable region comprising
the amino acid sequence of SEQ ID NO: 54 (H-CDRt); the amino acid sequence of
SEQ ID NO: 64 (H-CDR2); the amino acid sequence of SEQ ID NO: 73 (H-CDR3); or
a light chain variable region comprising the amino acid sequence of SEQ ID NO: 28 (L-
CDRt); the amino acid sequence of SEQ ID NO: 37 (L-CDR2); the amino acid
ce of SEQ ID NO: 46 (L-CDR3); and a heavy chain le region comprising
the amino acid sequence of SEQ ID NO: 55 t); the amino acid sequence of
SEQ ID NO: 65 (H-CDR2); the amino acid sequence of SEQ ID NO: 74 (H-CDR3); or
a light chain variable region comprising the amino acid ce of SEQ ID NO: 29 (L-
CDRt ); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); the amino acid
sequence of SEQ ID NO: 47 (L-CDR3); and a heavy chain variable region comprising
the amino acid sequence of SEQ ID NO: 56 (H-CDRt); the amino acid sequence of
SEQ ID NO: 66 (H-CDR2); the amino acid sequence of SEQ ID NO: 75 (H-CDR3).
In ment thirty six, the present invention provides an L-36R antibody or
antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment
nt thereof comprises a light chain variable region comprising the amino acid
sequence of SEQ ID NO: 1; and a heavy chain variable region comprising the amino
acid sequence of SEQ ID NO: 11; or
a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2; and
a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 12;
a light chain variable region comprising the amino acid sequence of SEQ ID NO: 3; and
a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13;
a light chain variable region comprising the amino acid sequence of SEQ ID NO: 4; and
a heavy chain variable region comprising the amino acid ce of SEQ ID NO: 14;
a light chain variable region comprising the amino acid sequence of SEQ ID NO: 5; and
a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 15;
a light chain variable region sing the amino acid sequence of SEQ ID NO: 6; and
a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 16;
a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and
a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 17;
a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; and
a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 18;
a light chain variable region comprising the amino acid ce of SEQ ID NO: 9; and
a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19;
a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10;
and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:
In a further ment thirty seven, the present invention provides a pharmaceutical
composition comprising an antibody or antigen-binding fragment according to any one
of the previous ments and a pharmaceutically acceptable carrier.
In a further embodiment thirty eight the present invention provides an antibody or
antigen-binding fragment or pharmaceutical composition according to any one of the
previous embodiments, for use in ne.
In a further embodiment thirty nine the t invention provides an antibody or
antigen-binding fragment or pharmaceutical composition according to any one of the
embodiments 1-37, wherein the use is the treatment of an inflammatory disease, of an
autoimmune disease, of a respiratory disease, of a metabolic disorder, of an lial
mediated inflammatory disorder, fibrosis or of cancer.
In a further ment forty the present invention provides an antibody or antigen-
binding fragment or pharmaceutical composition ing to any one of the
embodiments 1-37, wherein the use is for the treatment of psoriasis, inflammatory
bowel disease, psoriatic tis, multiple sclerosis, rheumatoid arthritis, COPD, chronic
asthma or ankylosing litis.
In a further embodiment forty one, the present invention provides an antibody or
antigen-binding fragment or pharmaceutical composition according to any one of the
embodiments 1-37, wherein the use is for the treatment of inflammatory bowel disease.
In a still further embodiment forty two, the present invention es an antibody or
n-binding fragment or pharmaceutical composition according to ment 41,
wherein the the disease is Crohns disease.
In another embodiment forty three, the present invention provides a method of treating a
disease comprising administering the antibody or n-binding fragment or
pharmaceutical ition according to any one of the embodiments 1-37, to a patient
in need thereof, wherein the disease is selected from an inflammatory e, an
autoimmune disease, a respiratory disease, a metabolic disorder, an epithelial mediated
inflammatory disorder, fibrosis and cancer.
In another embodiment forty four, the present invention provides a method according to
embodiment 43 wherein the disease is selected from psoriasis, inflammatory bowel
disease, psoriatic tis, multiple sclerosis, rheumatoid arthritis, COPD, chronic
asthma and ankylosing litis.
In a still further embodiment forty five, the present invention provides a method for
treating Crohns disease.
Further embodiments of the invention encompass:
- An isolated polynucleotide comprising a ce encoding an anti-lL-36R
antibody or antigen-binding fragment according to the invention, preferably a DNA or
RNA sequence;
- an isolated polynucleotide according to the invention, encoding a sequence as
defined by one or more of SEQ ID NOs. 1 to 140;
- a vector comprising a cleotide according to the invention, preferably an
expression vector, more preferred a vector comprising the polynucleotide according to
the invention in functional association with an expression control ce;
- a host cell comprising a polynucleotide according to the invention and/or a vector
according to the invention;
- a method for the production of an anti-lL-36R dy or antigen-binding
fragment according to the invention, preferably a inant production method
comprising the use of a polynucleotide according to the invention, and/or of a vector
according to the invention and/or of a host cell according to the invention;
- such a method preferably comprises the steps (a) cultivating the host cell under
conditions allowing the expression of the anti-lL-36R antibody or antigen-binding
fragment and (b) recovering the anti-lL-36R antibody or antigen-binding fragment;
- a diagnostic kit or diagnostic method comprising an anti-lL-36R antibody or
antigen-binding fragment according to the invention, or the use thereof;
- a Diagnostic kit or diagnostic method according the invention, for the diagnosis of
an matory disease, an autoimmune e, a respiratory disease, a metabolic
disorder, an epithelial mediated inflammatory disorder, fibrosis, cancer, psoriasis,
inflammatory bowel disease, psoriatic arthritis, multiple sclerosis, toid arthritis,
COPD, chronic , ankylosing litis, or Crohns disease.
Brief Description of the Figures
Figure 1: lL-36 antagonist ligands (lL-36RA/IL1 F5, lL-38/ILF10) inhibit the signaling
cascade.
Figure 2: Gene chip es demonstrate lL-36R ligands are upregulated in
psoriatic skin (IL-36 RA, lL-36 or and lL-36 y).
Figure 3: sion profile using human skin sections.
Formalin-fixed paraffin embedded with antibody titrations using antibody
33D10
Figure 4: Method to Evaluate Epidermal thickness of human skin sections
Description of the invention
This invention s to anti-lL-36R antibodies. In one aspect, the antibodies of the
t ion are for diagnostic and therapeutic use, for example in humans.
The present invention provides antibodies that bind to lL-36R, in particular human lL-
36R. The present invention also relates to humanized antibodies that bind lL-36R. ln
specific ments, the sequence of these humanized antibodies has been identified
based on the sequences of certain lead mouse antibodies.
Without wishing to be bound by this theory it is believed that anti-lL-36R antibodies or
antigen-binding fragments thereof bind to human lL-36R and thus interfer with the
binding of lL-36 agonists, and in doing so block at least partially the signaling cascade
from the lL-36R to inflammatory mediators. This is illustrated by Figure 1.
In one aspect, the antibodies of the present invention are for use in models of human
disease. lL-36R is also known as lL-1RL2 and lL-1Rrp2. It has been reported that
agonistic lL-36 ligands (or, B, or y) initiate the signaling cascade by engaging the lL-36
receptor which then forms a heterodimer with the lL-1 receptor accessory n (lL-
1RAcP). lL-36 antagonist ligands (lL-36RA/IL1 F5, ILF10) t the ing
cascade (see figure 1).
In one , the present ion provides an anti-lL-36R antibody having one or
more of the properties below.
In one , an anti-lL-36R antibody of the present invention has high
molecular/cellular binding potency. In one aspect, an anti-lL-36R antibody of the present
invention binds to human lL-36R at a KD< 0.1 nM. In a further , an anti-lL-36R
antibody of the present invention, in particular a humanized anti-lL-36R antibody, binds
to human lL-36R at a KD < 50 pM. In one aspect, an anti-lL-36R antibody of the present
invention binds to lL-36R expressing cells at an E090 <5 nM.
In another aspect, an anti-lL-36R antibody of the present invention has high cell-based
functional blocking potency. In one aspect, an anti-lL-36R dy of the present
ion blocks all three lL-36R agonistic ligands (or, B, y) at an |Cgo 55 nM, in disease-
relevant cell lines and primary cells.
In one aspect, an anti-lL-36R antibody of the t invention has the
molecular/cellular binding potency and the cell-based functional blocking potency set
forth above.
In one aspect, an anti-lL-36R antibody of the present invention is a humanized antibody.
In one aspect, an anti-lL-36R antibody of the present invention is a monoclonal
antibody. In one , an anti-lL-36R antibody of the t invention is a full length
antibody. In one , an anti-lL-36R antibody of the present invention is a humanized
monoclonal antibody, for e a full length humanized monoclonal dy.
An antibody or antigen-binding nt thereof of the present invention recognizes
specific "IL-36R antigen epitope" or " lL-36R epitope". As used herein these terms refer
to a molecule (e.g., a peptide) or a nt of a molecule capable of immunoreactivity
with an anti-lL-36R antibody.
The epitopes are most commonly proteins, short oligopeptides, oligopeptide mimics
(i.e., organic compounds that mimic antibody g properties of the lL-36R antigen),
or combinations thereof. The minimum size of a peptide or polypeptide epitope for an
antibody is thought to be about four to five amino acids. Peptide or polypeptide
epitopes n for example at least seven amino acids or for example at least nine
amino acids or for example between about 15 to about 20 amino acids. Since an
antibody can recognize an antigenic peptide or polypeptide in its tertiary form, the amino
acids comprising an epitope need not be contiguous, and in some cases, may not even
be on the same peptide chain. Epitopes may be determined by various techniques
known in the art, such as X-ray crystallography, Hydrogen/Deuterium Exchange Mass
Spectrometry (HXMS), irected mutagenesis, alanine ng mutagenesis, and
peptide screening methods.
The generalized structure of antibodies or immunoglobulin is well known to those of skill
in the art. These les are heterotetrameric glycoproteins, typically of about
150,000 daltons, composed of two identical light (L) chains and two identical heavy (H)
chains and are typically referred to as full length antibodies. Each light chain is
covalently linked to a heavy chain by one disulfide bond to form a heterodimer, and the
heterotrameric molecule is formed through a covalent disulfide linkage between the two
identical heavy chains of the heterodimers. Although the light and heavy chains are
linked together by one disulfide bond, the number of disulfide es between the two
heavy chains varies by immunoglobulin isotype. Each heavy and light chain also has
regularly spaced intrachain disulfide bridges. Each heavy chain has at the amino-
terminus a variable domain (VH), followed by three or four constant domains (CH1, CH2,
CH3, and CH4), as well as a hinge region between CH1 and CH2. Each light chain has two
domains, an amino-terminal variable domain (VL) and a carboxy-terminal constant
domain (CL). The VL domain associates non-covalently with the VH , whereas the
CL domain is commonly covalently linked to the CH1 domain via a disulfide bond.
Particular amino acid es are believed to form an interface between the light and
heavy chain variable domains (Chothia et al., 1985, J. Mol. Biol. 186:651-663). Variable
domains are also referred herein as variable regions.
Certain domains within the variable domains differ ively between different
antibodies i.e., are "hypervariable." These hypervariable domains contain residues that
are ly involved in the binding and specificity of each particular dy for its
specific nic determinant. Hypervariability, both in the light chain and the heavy
chain variable s, is concentrated in three segments known as mentarity
determining s (CDRs) or hypervariable loops (HVLs). CDRs are defined by
sequence comparison in Kabat et al., 1991, In: Sequences of Proteins of Immunological
Interest, 5th Ed. Public Health Service, National Institutes of , da, Md.,
whereas HVLs (also referred herein as CDBs) are structurally defined according to the
three-dimensional structure of the variable domain, as described by Chothia and Lesk,
1987, J. Mol. Biol. 196: 901-917. These two methods result in slightly different
fications of a CDB. As defined by Kabat, CDR-L1 is positioned at about es
24-34, CDB-L2, at about residues 50-56, and CDR-L3, at about residues 89-97 in the
light chain variable domain; CDB-H1 is positioned at about residues 31-35, CDR-H2 at
about residues 50-65, and CDR-H3 at about residues 95-102 in the heavy chain
variable domain. The exact residue numbers that encompass a particular CDR will vary
depending on the sequence and size of the GDP. Those skilled in the art can routinely
determine which residues comprise a particular CDR given the variable region amino
acid sequence of the antibody. The CDR1, CDR2, CDR3 of the heavy and light chains
therefore define the unique and functional properties specific for a given antibody.
The three CDRs within each of the heavy and light chains are separated by framework
regions (FR), which n sequences that tend to be less variable. From the amino
us to the carboxy terminus of the heavy and light chain variable domains, the FRs
and CDRs are arranged in the order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
The largely B-sheet uration of the FRs brings the CDRs within each of the chains
into close proximity to each other as well as to the CDRs from the other chain. The
resulting conformation contributes to the antigen binding site (see Kabat et al., 1991,
NIH Publ. No. 91-3242, Vol. I, pages 647-669), although not all CDR residues are
necessarily directly ed in antigen binding.
FR residues and lg constant domains are not directly involved in antigen g, but
contribute to antigen binding and/or mediate antibody effector function. Some FR
residues are thought to have a significant effect on antigen binding in at least three
ways: by noncovalently binding directly to an epitope, by interacting with one or more
CDR residues, and by affecting the interface n the heavy and light chains. The
constant domains are not directly involved in antigen binding but mediate various lg
or ons, such as ipation of the antibody in antibody dependent cellular
cytotoxicity (ADCC), complement dependent cytotoxicity (CDC) and antibody dependent
cellular phagocytosis (ADCP).
The light chains of vertebrate immunoglobulins are assigned to one of two clearly
distinct s, kappa (K) and lambda (7»), based on the amino acid sequence of the
constant domain. By comparison, the heavy chains of mammalian immunoglobulins are
assigned to one of five major classes, according to the ce of the constant
domains: lgA, lgD, lgE, lgG, and lgM. lgG and lgA are further divided into subclasses
pes), e.g., lgG1, lng, lgG3, lgG4, lgA1, and lgAz. The heavy chain constant
domains that correspond to the different classes of immunoglobulins are called or, 6, s, y,
and u, respectively. The subunit structures and three-dimensional configurations of the
classes of native immunoglobulins are well known.
WO 74569
The terms, ody", "anti-lL-36R antibody", "humanized anti-lL-36R dy",
"humanized anti-lL-36R epitope antibody", and "variant humanized anti-lL-36R epitope
antibody" specifically encompass monoclonal antibodies (including full length
monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific
antibodies), and antibody fragments such as variable domains and other portions of
antibodies that exhibit a desired biological activity, e.g., lL-36R binding.The term
"monoclonal antibody" (mAb) refers to an antibody that is highly specific, being directed
against a single antigenic inant, an “epitope”. Therefore, the er
"monoclonal" is tive of antibodies directed to the identical epitope and is not to be
construed as requiring production of the antibody by any ular . It should be
understood that monoclonal antibodies can be made by any technique or methodology
known in the art; including e.g., the hybridoma method ( Kohler et al., 1975, Nature
256:495), or recombinant DNA methods known in the art (see, e.g., U.S. Pat. No.
4,816,567), or s of isolation of monoclonal inantly produced using phage
dy libraries, using techniques described in on et al., 1991, Nature 352: 624-
628, and Marks et al., 1991, J. Mol. Biol. 222: 581-597.
The term “monomer” refers to a homogenous form of an antibody. For example, for a
full-length antibody, monomer means a monomeric antibody having two identical heavy
chains and two identical light chains.
Chimeric antibodies consist of the heavy and light chain variable regions of an dy
from one species (e.g., a non-human mammal such as a mouse) and the heavy and
light chain constant regions of another species (e.g., human) antibody and can be
obtained by linking the DNA sequences encoding the variable regions of the antibody
from the first species (e.g., mouse) to the DNA sequences for the constant regions of
the antibody from the second (e.g. human) species and transforming a host with an
expression vector ning the linked sequences to allow it to produce a chimeric
antibody. Alternatively, the chimeric antibody also could be one in which one or more
regions or domains of the heavy and/or light chain is identical with, homologous to, or a
variant of the corresponding ce in a monoclonal antibody from another
immunoglobulin class or isotype, or from a consensus or germline sequence. Chimeric
antibodies can include fragments of such antibodies, provided that the antibody
2012/064933
fragment exhibits the desired biological activity of its parent dy, for example
binding to the same epitope (see, e.g., U.S. Pat. No. 4,816,567; and Morrison et al.,
1984, Proc. Natl. Acad. Sci. USA 81: 6851-6855).
The terms, "antibody fragment anti-lL-36R antibody fragment", "anti-lL-36R epitope
antibody fragment", "humanized anti-lL-36R antibody fragment", "humanized anti-IL-
36R epitope antibody fragment", "variant humanized anti-lL-36R epitope dy
fragment" refer to a portion of a full length anti-lL-36R antibody, in which a variable
region or a functional capability is retained, for e, specific lL-36R epitope binding.
es of antibody fragments include, but are not limited to, a Fab, Fab', F(ab')2, Fd,
Fv, scFv and scFv-Fc fragment, a diabody, a linear antibody, a single-chain antibody, a
minibody, a diabody formed from antibody fragments, and multispecific antibodies
formed from antibody fragments.
Full length antibodies can be treated with enzymes such as papain or pepsin to
generate useful dy fragments. Papain digestion is used to produces two cal
antigen-binding dy nts called "Fab" fragments, each with a single antigen-
binding site, and a residual "Fc" fragment. The Fab fragment also contains the constant
domain of the light chain and the CH1 domain of the heavy chain. Pepsin treatment
yields a F(ab')2 fragment that has two antigen-binding sites and is still capable of cross-
linking antigen.
Fab' fragments differ from Fab fragments by the presence of additional residues
including one or more cysteines from the antibody hinge region at the C-terminus of the
CH1 domain. F(ab')2 dy fragments are pairs of Fab' fragments linked by cysteine
residues in the hinge region. Other chemical couplings of antibody fragments are also
known.
"Fv" fragment contains a complete antigen-recognition and g site consisting of a
dimer of one heavy and one light chain variable domain in tight, non-covalent
association. In this configuration, the three CDRs of each le domain interact to
define an antigen-biding site on the surface of the VH-VL dimer. Collectively, the six
CDRs confer antigen-binding specificity to the antibody.
A "single-chain Fv" or "scFv" antibody fragment is a single chain Fv variant comprising
the VH and VL domains of an antibody where the domains are present in a single
polypeptide chain. The single chain Fv is capable of recognizing and g antigen.
The scFv polypeptide may optionally also contain a polypeptide linker positioned
n the VH and VL domains in order to facilitate formation of a desired three-
dimensional structure for antigen binding by the scFv (see, e.g., hun, 1994, In The
Pharmacology of monoclonal Antibodies, Vol. 113, Rosenburg and Moore eds.,
Springer-Verlag, New York, pp. 269-315).
A "diabody" refers to small antibody fragments with two antigen-binding sites, which
nts se a heavy chain variable domain (V.sub.H) connected to a light chain
variable domain (V.sub.L) in the same polypeptide chain (V.sub.H-V.sub.L or V.sub.L-
V.sub.H). Diabodies are described more fully in, e.g., Holliger et al. (1993) Proc. Natl.
Acad. Sci. USA 90: 6444-6448.
Other recognized antibody fragments include those that comprise a pair of tandem Fd
segments (VH-CH1-VH-CH1) to form a pair of antigen binding regions. These “linear
antibodies” can be bispecific or monospecific as described in, for example, Zapata et al.
1995, Protein Eng. 1057-1062.
A “humanized antibody” or a “humanized antibody fragment” is a specific type of
chimeric antibody which includes an immunoglobulin amino acid sequence variant, or
fragment f, which is capable of binding to a predetermined n and which,
comprises one or more FRs having substantially the amino acid sequence of a human
immunoglobulin and one or more CDRs having substantially the amino acid sequence
of a non-human immunoglobulin. This man amino acid sequence often referred
to as an "import" ce is typically taken from an "import" antibody domain,
particularly a variable domain. In general, a humanized antibody includes at least the
CDRs or HVLs of a non-human antibody, inserted n the PBS of a human heavy
or light chain variable domain. The t invention describes specific humanized anti-
lL-36R antibodies which contain CDRs derived from the mouse monoclonal antibodies
or humanized CDRs ed between the PBS of human ne sequence heavy and
light chain variable domains. It will be understood that certain mouse FR residues may
be important to the function of the zed antibodies and therefore certain of the
human germline sequence heavy and light chain variable domains residues are
modified to be the same as those of the corresponding mouse sequence.
In another aspect, a humanized anti-lL-36R antibody comprises substantially all of at
least one, and typically two, variable domains (such as contained, for example, in Fab,
Fab', F(ab')2, Fabc, and Fv fragments) in which all, or ntially all, of the CDRs
correspond to those of a non-human immunoglobulin, and specifically herein, all of the
CDRs are mouse or humanized sequences as detailed herein below and all, or
substantially all, of the FRs are those of a human immunoglobulin consensus or
germline sequence. In r aspect, a humanized anti- lL-36R antibody also es
at least a n of an immunoglobulin Fc region, typically that of a human
immunoglobulin. Ordinarily, the antibody will contain both the light chain as well as at
least the variable domain of a heavy chain. The antibody also may include one or more
of the CH1, hinge, CH2, CH3, and/or CH4 regions of the heavy chain, as appropriate.
A humanized anti-lL-36r antibody can be selected from any class of immunoglobulins,
including lgM, lgG, lgD, lgA and lgE, and any isotype, ing lgG1, lng, lgG3, lgG4,
lgA1 and lgA2. For example, the constant domain can be a complement fixing constant
domain where it is desired that the humanized antibody exhibit cytotoxic activity, and
the isotype is typically lgG1. Where such cytotoxic activity is not desirable, the nt
domain may be of another isotype, e.g., lng. An alternative humanized anti-lL-36R
antibody can comprise sequences from more than one immunoglobulin class or e,
and selecting particular constant domains to optimize desired or functions is within
the ry skill in the art. In specific embodiments, the present invention provides
dies that are lth antibodies and more particularly, are lth antibodies in which
there is a knock-out of effector functions.
The FRs and CDRs, or HVLs, of a humanized anti-lL-36R antibody need not
correspond precisely to the parental sequences. For e, one or more residues in
the import CDR, or HVL, or the consensus or germline FR sequence may be altered
(e.g., mutagenized) by substitution, insertion or deletion such that the resulting amino
acid residue is no longer identical to the original e in the corresponding position in
either parental sequence but the antibody nevertheless retains the function of binding to
IL-36R. Such alteration typically will not be extensive and will be conservative
alterations. Usually, at least 75% of the humanized antibody residues will correspond to
those of the parental consensus or germline FR and import CDR sequences, more often
at least 90%, and most frequently greater than 95%, or greater than 98% or r
than 99%.
lmmunoglobulin residues that affect the interface between heavy and light chain
variable regions ("the VL-VH interface") are those that affect the proximity or orientation
of the two chains with respect to one another. Certain residues that may be involved in
interchain interactions include VL residues 34, 36, 38, 44, 46, 87, 89, 91, 96, and 98 and
VH es 35, 37, 39, 45, 47, 91, 93, 95, 100, and 103 (utilizing the numbering system
set forth in Kabat et al., Sequences of Proteins of Immunological Interest (National
Institutes of Health, Bethesda, Md., 1987)). U.S. Pat. No. 6,407,213 also discusses that
es such as VL residues 43 and 85, and VH residues 43 and 60 also may be
involved in this interaction. While these residues are indicated for human IgG only, they
are applicable across species. Important antibody es that are reasonably
ed to be ed in interchain interactions are selected for substitution into the
consensus sequence.
The terms "consensus sequence" and "consensus antibody" refer to an amino acid
sequence which comprises the most frequently occurring amino acid residue at each
location in all immunoglobulins of any ular class, isotype, or subunit structure, e.g.,
a human immunoglobulin variable domain. The consensus sequence may be based on
immunoglobulins of a particular species or of many species. A "consensus" sequence,
structure, or antibody is understood to encompass a consensus human ce as
described in certain embodiments, and to refer to an amino acid sequence which
ses the most frequently occurring amino acid residues at each location in all
human immunoglobulins of any particular class, isotype, or subunit structure. Thus, the
sus sequence contains an amino acid sequence having at each position an
amino acid that is present in one or more known immunoglobulins, but which may not
exactly duplicate the entire amino acid sequence of any single immunoglobulin. The
le region consensus ce is not obtained from any naturally produced
antibody or globulin. Kabat et al., 1991, Sequences of Proteins of
Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health,
Bethesda, Md., and variants thereof.
Human germline sequences are found naturally in the human population. A combination
of those germline genes generates antibody diversity. ne antibody sequences for
the light chain of the antibody come from conserved human germline kappa or lambda
v-genes and j-genes. Similarly the heavy chain sequences come from germline v-, d-
and j-genes (LeFranc, M-P, and LeFranc, G, “The Immunoglobulin Facts Book”
Academic Press, 2001).
As used herein, "variant", "anti- IL-36R variant", "humanized anti- IL-36R variant", or
"variant humanized anti- IL-36R" each refers to a humanized anti-IL-36R dy
having at least a light chain variable murine CDR. Variants include those having one or
more amino acid changes in one or both light chain or heavy chain variable domains,
provided that the amino acid change does not substantially impair binding of the
antibody to IL-36R.
An "isolated" antibody is one that has been identified and separated and/or recovered
from a component of its natural environment. Contaminant components of the
antibody's natural environment are those materials that may interfere with diagnostic or
therapeutic uses of the dy, and can be enzymes, hormones, or other
proteinaceous or nonproteinaceous solutes. In one , the dy will be purified
to at least greater than 95% isolation by weight of antibody.
An isolated dy includes an antibody in situ within recombinant cells in which it is
produced, since at least one ent of the antibody's natural environment will not
be present. Ordinarily r, an isolated antibody will be prepared by at least one
purification step in which the recombinant cellular material is removed.
The term "antibody performance" refers to s that contribute to antibody recognition
of n or the iveness of an antibody in vivo. Changes in the amino acid
sequence of an antibody can affect antibody properties such as folding, and can
influence physical factors such as initial rate of antibody binding to antigen (ka),
dissociation constant of the antibody from n (kd), affinity constant of the antibody
for the antigen (Kd), conformation of the antibody, protein stability, and half life of the
antibody.
The term "epitope tagged" when used herein, refers to an anti-lL-36R antibody fused to
an "epitope tag". An "epitope tag" is a polypeptide having a sufficient number of amino
acids to provide an epitope for antibody production, yet is designed such that it does not
interfere with the d activity of the zed anti-lL-36R antibody. The e
tag is y sufficiently unique such that an antibody raised t the epitope tag
does not substantially cross-react with other epitopes. le tag polypeptides
generally contain at least 6 amino acid residues and usually contain about 8 to 50
amino acid residues, or about 9 to 30 residues. Examples of epitope tags and the
antibody that binds the epitope include the flu HA tag polypeptide and its antibody
12CA5 (Field et al., 1988 Mol. Cell. Biol. 8: 2159-2165; c-myc tag and 8F9, 3C7, 6E10,
G4, B7 and 9E10 antibodies thereto (Evan et al., 1985, Mol. Cell. Biol. 5(12):3610-3616;
and Herpes simplex virus glycoprotein D (gD) tag and its antibody (Paborsky et al.
1990, Protein Engineering 3(6): 3). In certain embodiments, the epitope tag is a
"salvage receptor binding e". As used herein, the term "salvage receptor binding
epitope" refers to an epitope of the Fc region of an lgG molecule (such as lgG1, lng,
lgGs, or lgG4) that is responsible for sing the in vivo serum half-life of the lgG
molecule.
In some embodiments, the antibodies of the present invention may be ated to a
cytotoxic agent. This is any substance that inhibits or prevents the function of cells
and/or causes destruction of cells. The term is intended to include radioactive isotopes
(such as l‘3‘, I125, Y90 and Re
, 186) , chemotherapeutic agents, and toxins such as
enzymatically active toxins of bacterial, fungal, plant, or animal origin, and fragments
thereof. Such cytotoxic agents can be coupled to the zed antibodies of the
t invention using standard procedures, and used, for example, to treat a patient
indicated for therapy with the antibody.
A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer.
There are numerous examples of chemotherapeutic agents that could be conjugated
with the therapeutic antibodies of the present invention. Examples of such
chemotherapeutic agents include ting agents such a thiotepa and
cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan;
aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines
and methylamelamines including altretamine, triethylenemelamine,
trietylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine;
acetogenins ially bullatacin and bullatacinone); camptothecin (including the
synthetic analogue can); bryostatin; callystatin; CC-1065 (including its adozelesin,
esin, and bizelesin synthetic analogues); cryptophycines (particularly cryptophycin
1 and phycin 8); dolastatin, auristatins, (including analogues monomethyl-
auristatin E and monomethyl-auristatin F); duocarmycin (including the synthetic
analogues, 9 and CBl-TMI); eleutherobin; pancratistatin; sarcodictyin;
spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine,
cholophosphamide, ustine, ifosfamide, mechlorethamine, mechlorethamine oxide
hydrochloride, melphalan, novembichin, phenesterine, prednimustine; trofosfamide,
uracil mustard; ureas such as carmustine, chlorozotocin, fotemustine, lomustine,
nimustine, stine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin,
especially calichemicin gamma1l and calicheamicin phil1, see for example, Agnew,
Chem. lntl. Ed. Engl., 33:183-186; dynemicin, including dynemicin A; bisphosphonates,
such as clodronate; esperamicin; as well as neocarzinostatin chromophore and d
chromoprotein enediyne antibiotic chromomophores), nomysins, actinomycin,
authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin,
carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6—diazooxo-L-
norleucine, doxorubicin (AdriamycinT'V') ding morpholino-doxorubicin,
cyanomorpholino-doxorubicin, 2—pyrrolino-doxorubicin, and deoxydoxorubicin),
epirubucin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C,
enolic acid, nogalamycin, olivomycins, peplomycin, omycin, puromycine,
quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ex, zinostatin,
zorubicin; anti-metabolites such a methotrexate and 5-fluorouracil (5-FU); folic acid
analogues such as denopterin, methotrexate, pteropterin, rexate; purine analogs
such as fludarabine, aptopurine, prine, thioguanine; pyrimidine analogs
such as ancitabine, azacitidine, 6—azauridine, carmofur, cytarabine, dideoxyuridine,
doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone
nate, epitiostanol, mepitiostane, testolactone; anti-adranals such as
aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid;
aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; ine;
bestrabucil; bisantrene; edatraxate; defofamine; lcine; diaziquone; elfomithine;
elliptinium e; an lone; etoglucid; gallium nitrate; hydroxyurea; lentinan;
Ionidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone,
mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; Iosoxantrone;
yllinic acid; 2—ethylhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sizofuran;
spirogermanium; tenuazonic acid; quone; 2,2',2"-trichlorotriethylamine;
trichothecenes ially T-2 toxin, verracurin A, roridin A and ine); urethan;
vindesine; dacarbazine; mannomustine; mitabronitol; mitolactol; pipobroman;
gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel
(TAXOL®, l-Myers Squibb Oncology, Princeton, NJ.) and doxetaxel
(TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine
(GemzarT'V'); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as
cisplatin and carboplatin; vinblastine; platinum; etoposide ); ifosfamide;
mitoxantrone; vincristine; vinorelbine NavelbineT'V'); novantrone; teniposide; edatrexate;
daunomycin; aminopterin; xeloda; ibandronate; OPT-11; topoisomerase inhibitor RFS
2000; difluoromethylornithine (DMFO); retinoids such as ic acid; capecitabine; and
pharmaceutically acceptable salts, acids, or derivatives of any of the above. Also
included in this tion are ormonal agents that act to regulate or inhibit
hormone action on tumors such as anti-estrogens and ive estrogen receptor
modulators (SERMs), including, for example, tamoxifen (including NolvadexT'V'),
raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018,
onapristone, and toremifene (FarestonTM); aromatase inhibitors that inhibit the enzyme
aromatase, which regulates estrogen production in the adrenal glands, such as, for
example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate (MegaceT'V'),
exemestane, formestane, fadrozole, vorozole (RivisorT'V'), letrozole (FemaraT'V'), and
anastrozole (ArimidexT'V'); and anti-androgens such as flutamide, mide,
bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids, or
tives of any of the above. Any one or more of these agents may be conjugated to
the humanized antibodies of the present invention to provide a useful therapeutic agent
for the treatment of various disorders.
The dies also may be ated to prodrugs. A "prodrug" is a precursor or
derivative form of a pharmaceutically active substance that is less cytotoxic to tumor
cells compared to the parent drug and is capable of being enzymatically activated or
converted into the more active form. See, for example, Wilman, 1986, ugs in
Cancer Chemotherapy", ln Biochemical Society Transactions, 14, pp. 375-382, 615th
Meeting Belfast and Stella et al., 1985, "Prodrugs: A Chemical Approach to Targeted
Drug Delivery, ln: "Directed Drug Delivery, Borchardt et al., (ed.), pp. 247-267, Humana
Press. Useful prodrugs include, but are not d to, phosphate-containing gs,
thiophosphate-containing prodrugs, sulfate-containing prodrugs peptide-containing
prodrugs, o acid-modified prodrugs, ylated prodrugs, B-lactam-containing
prodrugs, optionally tuted phenoxyacetamide-containing prodrugs, and optionally
substituted phenylacetamide-containing prodrugs, 5-fluorocytosine and other 5-
fluorouridine prodrugs that can be converted into the more active cytotoxic free drug.
Examples of cytotoxic drugs that can be derivatized into a prodrug form include, but are
not limited to, those chemotherapeutic agents described above.
For diagnostic as well as eutic monitoring es, the antibodies of the
invention also may be conjugated to a label, either a label alone or a label and an
additional second agent (prodrug, chemotherapeutic agent and the like). A label, as
distinguished from the other second agents refers to an agent that is a detectable
compound or composition and it may be conjugated directly or indirectly to a zed
antibody of the present invention. The label may itself be detectable (e.g., radioisotope
labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze
chemical alteration of a substrate compound or composition that is detectable. Labeled
humanized anti-lL-36R antibody can be prepared and used in various ations
including in vitro and in vivo diagnostics.
The antibodies of the present ion may be formulated as part of a liposomal
preparation in order to affect ry thereof in vivo. A "liposome" is a small vesicle
composed of various types of lipids, phospholipids, and/or surfactant. Liposomes are
useful for delivery to a mammal of a compound or formulation, such as a humanized
anti-lL-36R antibody disclosed herein, optionally, coupled to or in combination with one
or more pharmaceutically active agents and/or labels. The components of the liposome
are commonly arranged in a bilayer formation, similar to the lipid arrangement of
biological membranes.
Certain aspects of the present ion related to isolated c acids that encode
one or more domains of the humanized antibodies of the present invention. An
"isolated" nucleic acid molecule is a nucleic acid molecule that is identified and
separated from at least one contaminant nucleic acid molecule with which it is ordinarily
associated in the natural source of the antibody c acid. An isolated nucleic acid
molecule is distinguished from the nucleic acid molecule as it exists in natural cells.
In various aspects of the present invention one or more domains of the humanized
antibodies will be recombinantly expressed. Such recombinant expression may employ
one or more control sequences, i.e., polynucleotide sequences necessary for
expression of an operably linked coding sequence in a particular host organism. The
control sequences suitable for use in yotic cells e, for example, promoter,
operator, and ribosome binding site sequences. Eukaryotic control sequences include,
but are not limited to, promoters, polyadenylation signals, and enhancers. These control
sequences can be utilized for sion and production of humanized anti-lL-36R
antibody in yotic and eukaryotic host cells.
A c acid sequence is "operably linked" when it is placed into a functional
relationship with another nucleic acid sequence. For example, a nucleic acid
presequence or secretory leader is operably linked to a nucleic acid encoding a
ptide if it is expressed as a tein that participates in the secretion of the
polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects
the ription of the sequence; or a ribosome binding site is operably linked to a
coding sequence if it is positioned so as to tate translation. Generally, "operably
linked" means that the DNA sequences being linked are contiguous, and, in the case of
a secretory leader, uous and in g frame. However, enhancers are optionally
uous. Linking can be accomplished by ligation at convenient ction sites. If
such sites do not exist, synthetic oligonucleotide adaptors or linkers can be used.
As used herein, the sions "cell", "cell line", and "cell culture" are used
interchangeably and all such designations include the y thereof. Thus,
"transformants" and "transformed cells" include the primary subject cell and cultures
derived rom without regard for the number of transfers.
The term "mammal" for purposes of treatment refers to any animal classified as a
mammal, including humans, domesticated and farm animals, and zoo, sports, or pet
animals, such as dogs, horses, cats, cows, and the like. Preferably, the mammal is
human.
A "disorder", as used herein, is any condition that would t from treatment with a
zed anti-lL-36R antibody described herein. This includes chronic and acute
disorders or diseases including those pathological conditions that predispose the
mammal to the disorder in question. Non-limiting examples or disorders to be treated
herein include inflammatory, angiogenic, autoimmune and immunologic disorders,
respiratory disorders, cancer, hematological malignancies, benign and malignant
tumors, leukemias and lymphoid ancies.
The terms "cancer" and "cancerous" refer to or be the physiological condition in
mammals that is typically terized by lated cell growth. Examples of cancer
include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia.
An lL-36R-associated disorder includes diseases and disorders of the immune system,
such as autoimmune disorders and inflammatory disorders. Such conditions include, but
are not limited to, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE),
scleroderma, Sjogren's syndrome, multiple sclerosis, sis, psoriatic arthritis,
inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), pulmonary
inflammation, asthma, idiopathic ocytopenic purara (lTP) epithelial inflammatory
disorders, fibrosis and ankylosing spondylitis.
The term "intravenous infusion" refers to introduction of an agent into the vein of an
animal or human patient over a period of time greater than approximately 15 minutes,
lly between approximately 30 to 90 s.
The term venous bolus" or "intravenous push" refers to drug stration into a
vein of an animal or human such that the body receives the drug in approximately 15
minutes or less, generally 5 minutes or less.
The term "subcutaneous administration" refers to introduction of an agent under the skin
of an animal or human patient, preferable within a pocket between the skin and
ying tissue, by relatively slow, sustained delivery from a drug receptacle. Pinching
or drawing the skin up and away from underlying tissue may create the pocket.
The term "subcutaneous infusion" refers to introduction of a drug under the skin of an
animal or human patient, preferably within a pocket between the skin and underlying
tissue, by relatively slow, ned delivery from a drug receptacle for a period of time
including, but not limited to, 30 minutes or less, or 90 minutes or less. Optionally, the
infusion may be made by subcutaneous implantation of a drug delivery pump implanted
under the skin of the animal or human patient, wherein the pump delivers a
predetermined amount of drug for a predetermined period of time, such as 30 minutes,
90 minutes, or a time period spanning the length of the treatment regimen.
The term "subcutaneous bolus" refers to drug administration beneath the skin of an
animal or human patient, where bolus drug delivery is less than approximately 15
s; in another aspect, less than 5 minutes, and in still another aspect, less than 60
seconds. In yet even another aspect, administration is within a pocket between the skin
and underlying tissue, where the pocket may be created by ng or drawing the skin
up and away from underlying tissue.
The term "therapeutically ive amount" is used to refer to an amount of an active
agent that relieves or ameliorates one or more of the symptoms of the disorder being
treated. In r aspect, the therapeutically effective amount refers to a target serum
concentration that has been shown to be effective in, for e, slowing disease
progression. Efficacy can be measured in conventional ways, depending on the
condition to be treated.
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The terms "treatment" and "therapy" and the like, as used herein, are meant to include
therapeutic as well as prophylactic, or suppressive measures for a disease or disorder
leading to any clinically desirable or beneficial effect, including but not limited to
alleviation or relief of one or more symptoms, sion, slowing or cessation of
progression of the disease or disorder. Thus, for example, the term treatment includes
the stration of an agent prior to or following the onset of a m of a disease
or disorder thereby preventing or removing one or more signs of the disease or
disorder. As another example, the term includes the administration of an agent after
clinical manifestation of the disease to combat the symptoms of the disease. Further,
administration of an agent after onset and after clinical symptoms have developed
where administration affects al ters of the disease or disorder, such as the
degree of tissue injury or the amount or extent of metastasis, r or not the
treatment leads to amelioration of the disease, comprises "treatment" or "therapy" as
used herein. Moreover, as long as the itions of the invention either alone or in
combination with another therapeutic agent alleviate or ameliorate at least one symptom
of a disorder being treated as compared to that m in the absence of use of the
humanized L-36R antibody composition, the result should be considered an
effective ent of the ying disorder regardless of whether all the symptoms of
the disorder are alleviated or not.
The term "package insert" is used to refer to instructions customarily included in
commercial packages of therapeutic products, that contain information about the
indications, usage, administration, contraindications and/or warnings concerning the use
of such therapeutic products.
Antibodies
In one , described and disclosed herein are anti-lL-36R antibodies, in particular
humanized anti-lL-36R antibodies, and compositions and articles of manufacture
comprising one or more anti-lL-36R antibody, in particular one or more humanized anti-
lL-36R antibody of the present invention. Also described are binding agents that include
an antigen-binding fragment of an anti-lL-36 antibody, in particular a zed anti-IL-
36R antibody.
Variable regions and CDRs of representative antibodies of the present invention are
disclosed below:
Anti-lL-36R Mouse Antibody Seguences
Variable regions and CDRs of representative mouse lead antibodies of the t
invention (mouse leads) are shown below:
Light Chain le Region (VK) Amino Acid Sequences
>33D10B12VK Protein (antibody 33D 1 0)
QIVLTQSPAIMSASLGERVTMTCTASSSVSSSYLHWYQKKPGSSPKLWVYSTSNLASGV
PVRFSGSGSGTSYSLTISSMEAEDAATYYCHQHHRSPVTFGSGTKLEMK (SEQ ID NO: 1)
>172C8B 12 VK protein ody 172C8)
SPASQSASLGESVTFTCLASQTIGTWLAWYQQRPGKSPQLLIYAATSLADGVPS
RFSGSGSGTQFSFNIRSLQAEDFASYYCQQVYTTPLTFGGGTKLEIK (SEQ ID NO: 2)
>67E7E8 VK protein (antibody 67E7)
DIQMTQSPASQSASLGESVTFTCLASQTIGTWLGWYQQKPGKSPQLLIYRSTTLADGVPS
RFSGSGSGTKFSFKISSLQAADFASYYCQQLYSAPYTFGGGTKLEIR (SEQ ID NO: 3)
>78C8D1 VK Protein (antibody 78C8)
DVLLTQTPLSLPVSLGDQASISCRSSQNIVHSNGNTYLQWYLQKPGQSPKLLIYKVSNRF
SGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPFTFGAGTKLELK (SEQ ID
NO: 4)
>81A1D1 VK Protein (antibody 81A1)
DIQMTQTTSSLSASLGDRVTISCRASQDIYKYLNWYQQKPDGTLKLLIYYTSGLHSGVPS
RFSGSGSGTDFSLTISNLEPEDIATYFCQQDSKFPWTFGGDTKLEIK (SEQ ID NO: 5)
>81B4E11 VK Protein (antibody 81B4)
QIVLTQSPAIMSASLGERVTMTCTASSSVSSSYFHWYQQKPGSSPKLWIYRTSNLASGVP
GSGTSYSLTISSMEAEDAATYYCHQFHRSPLTFGAGTKLELK (SEQ ID NO: 6)
>73C5C10 VK protein (antibody 73C5)
DIVMTQSQKFLSTSVGVRVSVTCKASQDVGTNVLWYQQKIGQSPKPLIYSASYRHSGVP
DRFTGSGSGTDFTLIISNVQSEDLAEYFCQQYSRYPLTFGPGTKLELK (SEQ ID NO: 7)
>73F6F8 VK protein (antibody 73F6)
DIVMTQSQKFLSTSVGVRVSVTCKASQDVGTNVLWYQQKIGQSPKALIYSASYRHSGVP
GSGTDFTLIITNVQSEDLAEYFCQQYSRYPLTFGPGTKLELK (SEQ ID NO: 8)
>76E10E8 VK protein (antibody 76E10)
DIVMTQSQKFMSATVGGRVNITCKASQNVGRAVAWYQQKPGQSPKLLTHSASNRYTG
GSGSGTDFTLTITNMQSEDLADYFCQQYSSYPLTFGAGTKLDLK (SEQ ID NO:
>89A12B8 VK protein (antibody 89A12)
DIQMTQSPASQSASLGESVTFSCLASQTIGTWLGWYQQKPGKSPQLLIYRATSLADGVPS
RFSGSGSGTNFSFKISSLQAEDLASYYCQQLYSGPYTFGGGTKLEIR (SEQ ID NO: 10)
Heavy Chain Variable Region (VH) Amino Acid Sequences
>33D10B12VH Protein (antibody 33D 1 0)
QVQLQQSGTELLKPGASVKLSCKASGNTVTSYWMHWVKQRPGQGLEWIGEILPSTGRT
NYNENFKGKAMLTVDKSSSTAYMQLSSLASEDSAVYYCTIVYFGNPWFAYWGQGTLV
TVSA (SEQ ID NO: 11)
>172C8B12 VH n (antibody 172C8)
SGPELVKPGASVKLSCKASGYTFTDNYMNWVRQSHGKSLEWIGRVNPSNGD
TKYNQNFKGKATLTVDKSLSTAYMQLNGLTSEDSAVYYCGRTKNFYSSYSYDDAMDY
WGQGTSVTVSS (SEQ ID NO: 12)
>67E7E8 VH protein (antibody 67E7)
EVQLQQSGAEFVRPGASVKFSCTASGFNIKDDYIHWVRQRPEQGLEWVGRIDPANGNT
QDKATITADTSSNTAYLQLSSLTSEDTAVYYCAKSFPNNYYSYDDAFAYWGQ
GTLVTVSA (SEQ ID NO: 13)
>78C8D1 VH Protein (antibody 78C8)
QVQLKESGPVLVAPSQSLSITCTVSGFSLTKFGVHWIRQTPGKGLEWLGVIWAGGPTNY
NSALMSRLTISKDISQSQVFLRIDSLQTDDTAMYYCAKQIYYSTLVDYWGQGTSVTVSS
(SEQ ID NO: 14)
>81A1D1 VH Protein (antibody 81A1)
QVQLKESGPGLVAPSQSLFITCTVSGFSLSSYEINWVRQVPGKGLEWLGVIWTGITTNYN
SALISRLSISKDNSKSLVFLKMNSLQTDDTAIYYCARGTGTGFYYAMDYWGQGTSVTVS
S (SEQ ID NO: 15)
>81B4E11 VH Protein (antibody 81B4)
QVQLQQPGADFVRPGASMRLSCKASGYSFTSSWIHWVKQRPGQGLEWIGEINPGNVRT
NYNENFRNKATLTVDKSSTTAYMQLRSLTSADSAVYYCTVVFYGEPYFPYWGQGTLVT
VSA (SEQ ID NO: 16)
>73C5C10 VH Protein (antibody 73C5)
QVQLKESGPGLVAPSQSLSITCTVSGFSLTNYAVHWVRQFPGKGLEWLGVIWSDGSTDF
NAPFKSRLSINKDNSKSQVFFKMNSLQIDDTAIYYCARKGGYSGSWFAYWGQGTLVTV
SA (SEQ ID NO: 17)
>73F6F8 VH protein ody 73F6)
QVQLKESGPGLVAPSQSLSITCTVSGFSLTNYAVHWVRQFPGKGLEWLGVIWSDGSTDY
NAPFKSRLSINKDNSKSQVFFKMNSLQTDDTAIYYCARKGGYSGSWFAYWGQGTLVTV
SA (SEQ ID NO: 18)
>76E10E8 VH n (antibody 76E10)
SGPVLVAPSQSLSITCTVSGFSLTNYGVHWVRQPPGKGLEWLGVIWPVGSTNY
NSALMSRLSIHKDNSKSQVFLRMNSLQTDDTAIYYCAKMDWDDFFDYWGQGTTLTVSS
(SEQ ID NO: 19)
>89A12B8 VH Protein (antibody 89A12)
EVQLQQSGAELVRPGASVRLSCTASGENIKDDYIHWVRQRPKQGLEWLGRIDPANGNT
KYDPRFQDKATITADTSSNTAYLHLSSLTSEDTAVYYCAKSFPDNYYSYDDAFAYWGQ
GTLVTVSA (SEQ ID NO: 20)
Light chain CDR-l (L-CDRl) Amino Acid Sequences
>33D10G1 L—CDR1
TASSSVSSSYLH (SEQ ID NO: 21)
>172C8B12 L-CDRl
LASQTIGTWLA (SEQ ID NO: 22)
>67E7E8 L-CDR1
LASQTIGTWLG (SEQ ID NO: 23)
>78C8D1 L-CDRl
RSSQNIVHSNGNTYLQ (SEQ ID NO: 24)
>81A1D1L—CDR1
YKYLN (SEQ ID NO: 25)
11 L—CDRI
TASSSVSSSYFH (SEQ ID NO: 26)
>73C5C10 L—CDRl
KASQDVGTNVL (SEQ ID NO: 27)
>73F6F8 L—CDRl
KASQDVGTNVL (SEQ ID NO: 27)
>76E10E8 L—CDRI
KASQNVGRAVA (SEQ ID NO: 28)
B8 L—CDRI
LASQTIGTWLG (SEQ ID NO: 29)
Light chain CDR-2 (L-CDR2) Amino Acid Sequences
>33D10B12 L—CDR2
STSNLAS (SEQ ID NO: 30)
>172C8B12 L—CDR2
AATSLAD ( SEQ ID NO: 31)
>67E7E8 L—CDR2
RSTTLAD (SEQ ID NO: 32)
>78C8D1 L—CDR2
KVSNRFS (SEQ ID NO: 33)
>81A1D1 L—CDR2
YTSGLHS (SEQ ID NO: 34)
>81B4E11 L—CDR2
RTSNLAS (SEQ ID NO: 35)
>73C5C10 L—CDR2
SASYRHS (SEQ ID NO: 36)
>73F6F8 L—CDR2
SASYRHS (SEQ ID NO: 36)
>76E10E8 L—CDR2
SASNRYT (SEQ ID NO: 37)
>89A12B8 L—CDR2
RATSLAD (SEQ ID NO: 38)
Light chain CDR-3 (L-CDR3) Amino Acid Sequences
>33D10B12 L—CDR3
HQHHRSPVT (SEQ ID NO: 39)
>172C8B12 L—CDR3
QQVYTTPLT (SEQ ID NO: 40)
>67E7E8 L—CDR3
QQLYSAPYT (SEQ ID NO: 41)
>78C8D1 L—CDR3
FQGSHVPFT (SEQ ID NO: 42)
1 L—CDR3
QQDSKFPWT (SEQ ID NO: 43)
>81B4E11 L—CDR3
HQFHRSPLT (SEQ ID NO: 44)
>73C5C10 L—CDR3
QQYSRYPLT (SEQ ID NO: 45)
>73F6F8 L—CDR3
QQYSRYPLT (SEQ ID NO: 45)
>76E10E8 L—CDR3
PLT (SEQ ID NO: 46)
>89A12B8 L—CDR3
QQLYSGPYT (SEQ ID NO: 47)
Heavy chain CDR-l (H-CDRl) Amino Acid Sequences
>33D10B12 H—CDRI
GNTVTSYWMH (SEQ ID NO: 48)
>172C8B 12 H-CDRI
GYTFTDNYMN (SEQ ID NO: 49)
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>67E7E8 H—CDR1
GFNIKDDYIH (SEQ ID NO: 50)
>78C8D1 H—CDR1
GFSLTKFGVH (SEQ ID NO: 51)
>81A1D1 H—CDR1
GFSLSSYEIN (SEQ ID NO: 52)
>81B4E11 H—CDR1
GYSFTSSWIH (SEQ ID NO: 53)
>73C5C10 H—CDRl
GFSLTNYAVH (SEQ ID NO: 54)
>73F6F8 H-CDR1
GFSLTNYAVH (SEQ ID NO: 54)
>76E10E8 H—CDR1
GFSLTNYGVH (SEQ ID NO: 55)
>89A12B8 H-CDR1
GFNIKDDYIH (SEQ ID NO: 56)
Heavy chain CDR-2 (H-CDR2) Amino Acid Sequences
>33D10B12 H-CDR2
EILPSTGRTNYNENFKG (SEQ ID NO: 57)
>172C8B 12 H—CDR2
GDTKYNQNFKG (SEQ ID NO: 58)
>67E7E8 H—CDR2
RIDPANGNTKYAPKFQD (SEQ ID NO: 59)
>78C8D1 H—CDR2
VIWAGGPTNYNSALMS (SEQ ID NO: 60)
1 H-CDR2
VIWTGITTNYNSALIS (SEQ ID NO: 61)
>81B4E11 H-CDR2
EINPGNVRTNYNENF (SEQ ID NO: 62)
>73C5C10 H—CDR2
STDFNAPFKS (SEQ ID NO: 63)
>73F6F8 H—CDR2
VIWSDGSTDYNAPFKS (SEQ ID NO: 64)
>76E10E8 H-CDR2
VIWPVGSTNYNSALMS (SEQ ID NO: 65)
>89A12B8 H-CDR2
RIDPANGNTKYDPRFQD (SEQ ID NO: 66)
Heavy chain CDR-3 (H-CDR3) Amino Acid Sequences
>33D10B12 H-CDR3
VYFGNPWFAY (SEQ ID NO: 67)
>172C8B 12 H-CDR3
TKNFYSSYSYDDAMDY (SEQ ID NO: 68)
8 H-CDR3
SFPNNYYSYDDAFAY (SEQ ID NO: 69)
>78C8D1 H-CDR3
LVDY (SEQ ID NO: 70)
>81A1D1 H—CDR3
GTGTGFYYAMDY (SEQ ID NO: 71)
>81B4E11 H—CDR3
VFYGEPYFPY (SEQ ID NO: 72)
>73C5C10 H—CDR3
KGGYSGSWFAY (SEQ ID NO: 73)
>73F6F8 H—CDR3
KGGYSGSWFAY (SEQ ID NO: 73)
>76E10E8 H—CDR3
MDWDDFFDY (SEQ ID NO: 74)
>89A12B8 H-CDR3
SFPDNYYSYDDAFAY (SEQ ID NO: 75)
Anti-lL-36R Mouse CDR Sequences
A summary of the CDR seguences of the lead mouse dies is shown below:
Antibody H-CDR Sequences L—CDR Sequences
33D10 GNTVTSYWMH (H—CDRI) TASSSVSSSYLH (L—CDRI)
SEQ ID No: 48 SEQ ID No: 21
EILPSTGRTNYNENFKG STSNLAS (L—CDR2) SEQ ID
2) SEQ ID No: 57 No: 30
VYFGNPWFAY (H—CDR3) HQHHRSPVT (L—CDR3)
SEQ ID No: 67 SEQ ID No: 39
172C8 GYTFTDNYMN (H—CDRI) LASQTIGTWLA (L—CDRI)
SEQ ID No: 49 SEQ ID No: 22
RVNPSNGDTKYNQNFKG AATSLAD (L—CDR2) SEQ
(H-CDR2) SEQ ID No: 58 ID No: 31
TKNFYSSYSYDDAMDY QQVYTTPLT (L—CDR3)
3) SEQ ID No: 68 SEQ ID No: 40
67E7 GFNIKDDYIH (H—CDRI) LASQTIGTWLG (L—CDRI)
SEQ ID No: 50 SEQ ID No: 23
RIDPANGNTKYAPKFQD RSTTLAD (L—CDR2) SEQ ID
(H-CDR2) SEQ ID No: 59 No: 32
YSYDDAFAY (H- QQLYSAPYT 3)
CDR3) SEQ ID NO: 69 SEQ ID No: 41
GFSLTKFGVH (H—CDRI) RSSQNIVHSNGNTYLQ (L—
SEQ ID No: 51 CDRl) SEQ ID No: 24
VIWAGGPTNYNSALMS KVSNRFS (L—CDR2) SEQ ID
(H-CDR2) SEQ ID No: 60 No: 33
QIYYSTLVDY (H—CDR3) FQGSHVPFT (L—CDR3) SEQ
ID No: 42
SEQ ID No: 70
YEIN (H—CDRI) RASQDIYKYLN I)
SEQ ID No: 52 SEQ ID No: 25
YTSGLHS (L—CDR2) SEQ ID
VIWTGITTNYNSALIS (H— No: 34
CDR2) SEQ ID No: 61 QQDSKFPWT 3)
SEQ ID No: 43
GTGTGFYYAMDY (H—
CDR3) SEQ ID No: 71
GYSFTSSWIH (H—CDRI) TASSSVSSSYFH (L—CDRI)
SEQ ID No: 53 SEQ ID No: 26
RTSNLAS (L—CDR2) SEQ ID
EINPGNVRTNYNENF (H- No: 35
CDR2) SEQ ID No: 62 HQFHRSPLT (L—CDR3) SEQ
ID No: 44
VFYGEPYFPY (H—CDR3)
SEQ ID No: 72
GFSLTNYAVH (H—CDRI) KASQDVGTNVL (L—CDRI)
SEQ ID No: 54 SEQ ID No: 27
VIWSDGSTDFNAPFKS (H- SASYRHS (L—CDR2) SEQ ID
CDR2) SEQ ID NO: 63 No: 36
KGGYSGSWFAY (H—CDR3) QQYSRYPLT (L—CDR3)
SEQ ID No: 73 SEQ ID No: 45
GFSLTNYAVH (H—CDRI) KASQDVGTNVL (L—CDRI)
SEQ ID No: 54 SEQ ID N0:27
VIWSDGSTDYNAPFKS (H- SASYRHS (L—CDR2) SEQ ID
CDR2) SEQ ID No: 64 No: 36
KGGYSGSWFAY (H—CDR3) PLT (L—CDR3)
SEQ ID No: 73 SEQ ID No: 45
YGVH I) KASQNVGRAVA (L-CDRI)
SEQ ID NO: 55 SEQ ID No: 28
VIWPVGSTNYNSALMS (H— SASNRYT (L—CDR2) SEQ
CDR2) SEQ ID No: 65 ID NO: 37
MDWDDFFDY (H—CDR3) QQYSSYPLT (L—CDR3) SEQ
“3 N03 46
SEQ ID No: 74
GFNIKDDYIH (H—CDRI) LASQTIGTWLG (L—CDRI)
SEQ ID NO: 56 SEQ ID No: 29
RIDPANGNTKYDPRFQD RATSLAD (L—CDR2) SEQ
(H-CDR2) SEQ ID No: 66 ID No: 38
QQLYSGPYT (L—CDR3)
SFPDNYYSYDDAFAY (H— SEQ ID No: 47
CDR3) SEQ ID No: 75
Anti-lL-36R Humanized Antibody Seguences
Human framework sequences were selected for the mouse leads based on the
framework homology, CDR structure, ved canonical residues, conserved
interface g residues and other parameters to produce humanized variable regions
(see Example 5).
Representative zed variable regions derived from antibodies 81 B4 and 7305 are
shown below.
Light Chain Variable Region (VK) Amino Acid Sequences
K32_3 VK protein
EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSTLASGIPD
RFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 76)
>81B4VK32_105 VK protein
EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSILASGVPD
RFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 77)
>81B4VK32_116 VK n
EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLASGVP
DRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 78)
>81B4VK32_127 VK n
EIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSRLASGVP
DRFSGSGSGTDFTLTISRLEPEDFAVYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 79)
>81B4VK32_13 8 VK protein
QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLASGVP
DRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGAGTKLEIK (SEQ ID NO: 80)
>81B4VK32_140 VK protein
QIVLTQSPGTLSLSPGERVTMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSQLASGIPD
RFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 81)
>81B4VK32_141 VK protein
SPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSKLASGVP
DRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 82)
>81B4VK32_147 VK protein
EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSHLASGIPG
RFSGSGSGTDFTLTISRLEPEDAAVYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 83)
>73C5VK39_2 VK n
EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIP
DRFSGSGSGTEFTLTISSLQSEDFAEYFCQQYSRYPLTFGQGTKLEIK (SEQ ID NO: 84)
>73C5VK39_7 VK protein
EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIP
DRFSGSGSGTEFTLTISSLQSEDFAVYYCQQYSRYPLTFGQGTKLEIK (SEQ ID NO: 85)
>73C5VK39_15 VK protein
EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIP
ARFSGSGSGTEFTLTISSLQSEDFAEYYCQQYSRYPLTFGQGTKLEIK (SEQ ID NO: 86)
Heavy Chain le Region (VH) Amino Acid Sequences
>81B4VH33_49 VH Protein
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGNVRT
NYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVT
VSS (SEQ ID NO: 87)
>81B4VH33_85T VH Protein
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGNVRT
RNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVT
VSS (SEQ ID NO: 88)
>81B4VH33_90 VH Protein
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVKQAPGQGLEWMGEINPGNVR
TNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLV
TVSS (SEQ ID NO: 89)
>81B4VH33_93 VH Protein
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEINPGNVR
TNYNENFRNRATLTRDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLV
TVSS (SEQ ID NO: 90)
>81B4VH50_22 VH Protein
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEILPGVVR
TNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLV
TVSS (SEQ ID NO: 91)
>81B4VH50_30 VH Protein
SGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGAVRT
NYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVT
VSS (SEQ ID NO: 92)
>81B4VH51_13 VH Protein
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGLVRT
NYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVT
VSS (SEQ ID NO: 93)
>81B4VH51_15 VH Protein
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGAVRT
NYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVT
VSS (SEQ ID NO: 94)
>81B4VH52_83 VH Protein
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGSVRT
NYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVT
VSS (SEQ ID NO: 95)
>73C5VH46_4 VH Protein
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYN
APFKSRVTINKDTSKSQVSFKMSSVQAADTAVYYCARKGGYSGSWFAYWGQGTLVTV
SS (SEQ ID NO: 96)
>73C5VH46_19 VH Protein
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYN
APFKSRVTISKDTSKNQVSLKMNSLTTDDTAVYYCARKGGYSGSWFAYWGQGTLVTV
SS (SEQ ID NO: 97)
>73C5VH46_40 VH Protein
SGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYN
APFKSRVTISKDNSKSQVSLKMNSVTVADTAVYYCARKGGYSGSWFAYWGQGTLVTV
SS (SEQ ID NO: 98)
>73C5VH47_65 VH Protein
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWVRQPPGKGLEWIGVIWSDGSTDY
NAPFKSRVTISKDTSKNQVSFKLSSVTVDDTAVYYCARKGGYSGSWFAYWGQGTLVTV
SS (SEQ ID NO: 99)
>73C5VH47_77 VH Protein
SGPGLVAPSETLSLTCTVSGFSLTDYAVHWIRQFPGKGLEWIGVIWSDGSTDF
RVTISKDTSKNQVSFKLSSVTTDDTAVYYCARKGGYSGSWFAYWGQGTLVTV
SS (SEQ ID NO: 100)
>73C5VH58_91 VH Protein
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYN
APFKSRVTISKDNSKSQVSFKMSSVTADDTAVYYCARKGGYSGSWFAYWGQGTLVTVS
s (SEQ ID NO: 101)
The CDR sequences from the humanized variable regions derived from antibodies
81 B4 and 7305 shown above are depicted below.
L-CDRI Amino Acid Seguences
>81B4VK32_3 L—CDR1
TASSSVSSSYFH (SEQ ID NO: 26)
>81B4VK32_105 L-CDR1
TASSSVSSSYFH (SEQ ID NO: 26)
K32_116 L-CDR1
TASSSVSSSYFH (SEQ ID NO: 26)
>81B4VK32_127 L-CDR1
TASSSVSSSYFH (SEQ ID NO: 26)
K32_138 L-CDR1
TASSSVSSSYFH (SEQ ID NO: 26)
>81B4VK32_140 L-CDR1
TASSSVSSSYFH (SEQ ID NO: 26)
>81B4VK32_141 L-CDR1
TASSSVSSSYFH (SEQ ID NO: 26)
>81B4VK32_147 L-CDR1
TASSSVSSSYFH (SEQ ID NO: 26)
>73C5VK39_2 L-CDR1
KASQDVGTNVL (SEQ ID NO: 27)
>73C5VK39_7 L—CDRl
KASQDVGTNVL (SEQ ID NO: 27)
>73C5VK39_15 L—CDRl
KASQDVGTNVL (SEQ ID NO: 27)
L-CDR2 Amino Acid ces
>81B4VK32_3 L-CDR2 (SEQ ID 102)
RTSTLAS
>81B4VK32_105 L-CDR2 (SEQ ID 103)
RTSILAS
>81B4VK32_116 L-CDR2 (SEQ ID 104)
RTSRLAS
>81B4VK32_127 L-CDR2 (SEQ ID 104)
RTSRLAS
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>81B4VK32_138 L—CDR2 (SEQ ID 104)
RTSRLAS
>81B4VK32_140 L—CDR2 (SEQ ID 105)
RTSQLAS
>81B4VK32_141 L—CDR2 (SEQ ID 106)
RTSKLAS
>81B4VK32_147 L-CDR2 (SEQ ID 140)
RTSHLAS
>73C5VK39_2 L—CDR2
SASYRHS (SEQ ID NO: 36)
>73C5VK39_7 L—CDR2
SASYRHS (SEQ ID NO: 36)
>73C5VK39_15 L-CDR2
SASYRHS (SEQ ID NO: 36)
L-CDR3 Amino Acid Seguences
>81B4VK32_3 L-CDR3
HQFHRSPLT (SEQ ID NO: 44)
>81B4VK32_105 L-CDR3
HQFHRSPLT (SEQ ID NO: 44)
K32_116 L-CDR3
HQFHRSPLT (SEQ ID NO: 44)
>81B4VK32_127 L—CDR3
HQFHRSPLT (SEQ ID NO: 44)
>81B4VK32_138 L-CDR3
HQFHRSPLT (SEQ ID NO: 44)
>81B4VK32_140 L-CDR3
HQFHRSPLT (SEQ ID NO: 44)
>81B4VK32_141 L-CDR3
HQFHRSPLT (SEQ ID NO: 44)
>81B4VK32_147 L—CDR3
HQFHRSPLT (SEQ ID NO: 44)
>73C5VK39_2 L-CDR3
QQYSRYPLT (SEQ ID NO: 45)
>73C5VK39_7 L-CDR3
QQYSRYPLT (SEQ ID NO: 45)
>73C5VK39_15 L—CDR3
QQYSRYPLT (SEQ ID NO: 45)
H-CDRI Amino Acid Seguences
>81B4VH33_49 H—CDRI
GYSFTSSWIH (SEQ ID NO: 53)
>81B4VH33_85T H—CDRI
GYSFTSSWIH (SEQ ID NO: 53)
>81B4VH33_90 H—CDRI
SWIH (SEQ ID NO: 53)
>81B4VH33_93 H—CDRI
GYSFTSSWIH (SEQ ID NO: 53)
>81B4VH50_22 H—CDRI
GYSFTSSWIH (SEQ ID NO: 53)
>81B4VH50_30 H—CDRI
SWIH (SEQ ID NO: 53)
H51_13 H—CDRI
GYSFTSSWIH (SEQ ID NO: 53)
>81B4VH51_15 H—CDRI
GYSFTSSWIH (SEQ ID NO: 53)
>81B4VH52_83 H—CDRI
GYSFTSSWIH (SEQ ID NO: 53)
>73C5VH46_4 H-CDR1
GFSLTDYAVH (SEQ ID NO: 107)
>73C5VH46_19 H-CDR1
GFSLTDYAVH (SEQ ID NO: 107)
>73C5VH46_40 H-CDR1
GFSLTDYAVH (SEQ ID NO: 107)
>73C5VH47_65 H-CDR1
GFSLTDYAVH (SEQ ID NO: 107)
H47_77 H—CDR1
GFSLTDYAVH (SEQ ID NO: 107)
>73C5VH58_91 H-CDR1
GFSLTDYAVH (SEQ ID NO: 107)
H-CDR2 Amino Acid Seguences
H33_49 H-CDR2
EINPGNVRTNYNENF (SEQ ID NO: 62)
>81B4VH33_85T H-CDR2
EINPGNVRTNYNENF (SEQ ID NO: 62)
>81B4VH33_90 H-CDR2
EINPGNVRTNYNENF (SEQ ID NO: 62)
>81B4VH33_93 H-CDR2
EINPGNVRTNYNENF (SEQ ID NO: 62)
>81B4VH50_22 H-CDR2
EILPGVVRTNYNENF (SEQ ID NO: 108)
>81B4VH50_30 H-CDR2
EINPGAVRTNYNENF (SEQ ID NO: 109)
>81B4VH51_13 H—CDR2
VRTNYNENF (SEQ ID NO: 110)
>81B4VH51_15 H-CDR2
EINPGAVRTNYNENF (SEQ ID NO: 109)
>81B4VH52_83 H—CDR2
EINPGSVRTNYNENF (SEQ ID NO: 111)
>73C5VH46_4 H-CDR2
STDYNAPFKS (SEQ ID NO: 64)
>73C5VH46_19 H-CDR2
VIWSDGSTDYNAPFKS (SEQ ID NO: 64)
>73C5VH46_40 H-CDR2
VIWSDGSTDYNAPFKS (SEQ ID NO: 64)
>73C5VH47_65 H-CDR2
VIWSDGSTDYNAPFKS (SEQ ID NO: 64)
>73C5VH47_77 H—CDR2
VIWSDGSTDFNAPFKS (SEQ ID NO: 63)
>73C5VH58_91 H-CDR2
VIWSDGSTDYNAPFKS (SEQ ID NO: 64)
H-CDR3 Amino Acid Seguences
H33_49 H—CDR3
VFYGEPYFPY (SEQ ID NO: 72)
>81B4VH33_85T H—CDR3
VFYGEPYFPY (SEQ ID NO: 72)
>81B4VH33_90 H—CDR3
VFYGEPYFPY (SEQ ID NO: 72)
>81B4VH33_93 H—CDR3
VFYGEPYFPY (SEQ ID NO: 72)
>81B4VH50_22 H—CDR3
VFYGEPYFPY (SEQ ID NO: 72)
>81B4VH50_30 H—CDR3
VFYGEPYFPY (SEQ ID NO: 72)
>81B4VH51_13 H—CDR3
VFYGEPYFPY (SEQ ID NO: 72)
>81B4VH51_15 H-CDR3
VFYGEPYFPY (SEQ ID NO: 72)
>81B4VH52_83 H—CDR3
VFYGEPYFPY (SEQ ID NO: 72)
>73C5VH46_4 H—CDR3
SWFAY (SEQ ID NO: 73)
>73C5VH46_19 H—CDR3
KGGYSGSWFAY (SEQ ID NO: 73)
>73C5VH46_40 H—CDR3
KGGYSGSWFAY (SEQ ID NO: 73)
>73C5VH47_65 H—CDR3
KGGYSGSWFAY (SEQ ID NO: 73)
>73C5VH47_77 H—CDR3
KGGYSGSWFAY (SEQ ID NO: 73)
>73C5VH58_91 H—CDR3
KGGYSGSWFAY (SEQ ID NO: 73)
In one aspect, a variable region of the present ion is linked to a constant region.
For example, a variable region of the present invention is linked to a constant region
shown below to form a heavy chain or a light chain of an antibody.
Heavy Chain Constant region linked downstream of a zed variable heavy region:
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGG
PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR
EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK
SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 112)
Light Chain Constant region linked downstream of a humanized variable light region:
SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ
DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:113)
Representative light chain and heavy chain sequences of the present invention are
shown below (humanized variable regions derived from antibodies 81 B4 and 7305
linked to constant regions).
Light Chain Amino Acid Seguences
>81B4VK32_3 Light Chain
EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSTLASGIPD
SGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSD
EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 114)
>81B4VK32_105 Light Chain
EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSILASGVPD
RFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSD
EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 115)
>81B4VK32_116 Light Chain
EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLASGVP
DRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 116)
>81B4VK32_127 Light Chain
EIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSRLASGVP
DRFSGSGSGTDFTLTISRLEPEDFAVYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 117)
>81B4VK32_13 8 Light Chain
QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLASGVP
DRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGAGTKLEIKRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 118)
>81B4VK32_140 Light Chain
SPGTLSLSPGERVTMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSQLASGIPD
RFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSD
EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 119)
>81B4VK32_141 Light Chain
QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSKLASGVP
DRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 120)
>81B4VK32_147 Light Chain
EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSHLASGIPG
RFSGSGSGTDFTLTISRLEPEDAAVYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSD
TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 121)
>73C5VK39_2 Light Chain
SPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIP
DRFSGSGSGTEFTLTISSLQSEDFAEYFCQQYSRYPLTFGQGTKLEIKRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 122)
>73C5VK39_7 Light Chain
EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIP
DRFSGSGSGTEFTLTISSLQSEDFAVYYCQQYSRYPLTFGQGTKLEIKRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 123)
>73C5vK39_15 Light Chain
EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIP
ARFSGSGSGTEFTLTISSLQSEDFAEYYCQQYSRYPLTFGQGTKLEIKRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 124)
Heavy Chain Amino Acid Sequences
>81B4vH33_49 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGNVRT
NYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVT
VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEA
AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL
PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT
VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 125)
>81B4vH33_85T Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGNVRT
NYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVT
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL
QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEA
AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL
PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT
VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 126)
>81B4vH33_90 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVKQAPGQGLEWMGEINPGNVR
TNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLV
TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV
LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPE
AAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP
REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY
TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK
LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 127)
>81B4vH33_93 Heavy Chain
WO 74569
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEINPGNVR
FRNRATLTRDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLV
TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV
LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPE
AAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP
REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY
TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK
LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 128)
>81B4vH50_22 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEILPGVVR
TNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLV
TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV
LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPE
AAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY
TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK
LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 129)
>81B4vH50_30 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGAVRT
NYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVT
VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEA
AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL
PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT
VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 130)
>81B4vH51_13 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGLVRT
NYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVT
VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL
QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEA
AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL
PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT
VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 131)
>81B4vH51_15 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGAVRT
NYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVT
VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL
QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEA
2012/064933
AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL
MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT
VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 132)
>81B4vH52_83 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGSVRT
NYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVT
VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL
QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEA
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL
PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT
VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 133)
>73C5VH46_4 Heavy Chain
SGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYN
APFKSRVTINKDTSKSQVSFKMSSVQAADTAVYYCARKGGYSGSWFAYWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAA
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE
QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP
SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 134)
>73C5VH46_19 Heavy Chain
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYN
APFKSRVTISKDTSKNQVSLKMNSLTTDDTAVYYCARKGGYSGSWFAYWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAA
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE
QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP
SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 135)
>73C5VH46_40 Heavy Chain
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYN
APFKSRVTISKDNSKSQVSLKMNSVTVADTAVYYCARKGGYSGSWFAYWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAA
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE
QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP
SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 136)
>73C5VH47_65 Heavy Chain
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWVRQPPGKGLEWIGVIWSDGSTDY
NAPFKSRVTISKDTSKNQVSFKLSSVTVDDTAVYYCARKGGYSGSWFAYWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAA
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE
QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP
SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 137)
>73C5VH47_77 Heavy Chain
QVQLQESGPGLVAPSETLSLTCTVSGFSLTDYAVHWIRQFPGKGLEWIGVIWSDGSTDF
NAPFKSRVTISKDTSKNQVSFKLSSVTTDDTAVYYCARKGGYSGSWFAYWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAA
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE
QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP
SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 138)
>73C5VH58_91 Heavy Chain
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYN
APFKSRVTISKDNSKSQVSFKMSSVTADDTAVYYCARKGGYSGSWFAYWGQGTLVTVS
SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAG
GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS
REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD
KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 139)
The CDRs listed above are defined using the Chothia ing system (Al-Lazikani et
al., (1997) JMB 273, 927-948).
In one aspect, an antibody of the present invention comprises 3 light chain CDRs and 3
heavy chain CDRs, for example as set forth above.
In one aspect, an antibody of the present ion comprises a light chain and a heavy
chain le region as set forth above. In one aspect, a light chain variable region of
the invention is fused to a light chain constant region, for e a kappa or lambda
nt region. In one aspect, a heavy chain variable region of the invention is fused to
a heavy chain constant region, for example lgA, lgD, lgE, lgG or lgM, in particular, lgG1,
lng, lgG3 or lgG4.
The t invention provides an L-36R antibody comprising a light chain
comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising
the amino acid sequence of SEQ ID NO: 125 (Antibody B1).
The present invention provides an anti-lL-36R antibody comprising a light chain
comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising
the amino acid sequence of SEQ ID NO: 126 (Antibody B2).
The present invention provides an anti-lL-36R antibody comprising a light chain
comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising
the amino acid sequence of SEQ ID NO: 127 (Antibody B3).
The present invention provides an anti-lL-36R antibody comprising a light chain
comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising
the amino acid sequence of SEQ ID NO: 125 ody B4).
The present invention provides an anti-lL-36R antibody comprising a light chain
comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising
the amino acid sequence of SEQ ID NO: 126 ody B5).
The present invention provides an anti-lL-36R antibody comprising a light chain
comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising
the amino acid ce of SEQ ID NO: 127 Antibody B6).
WO 74569
The present invention provides an anti-lL-36R antibody sing a light chain
comprising the amino acid sequence of SEQ ID NO: 123; and a heavy chain comprising
the amino acid sequence of SEQ ID NO: 138 (Antibody C3).
The present invention provides an anti-lL-36R antibody comprising a light chain
comprising the amino acid sequence of SEQ ID NO: 123; and a heavy chain comprising
the amino acid sequence of SEQ ID NO: 139 (Antibody C2).
The present invention provides an anti-lL-36R antibody comprising a light chain
comprising the amino acid sequence of SEQ ID NO: 124; and a heavy chain comprising
the amino acid sequence of SEQ ID NO: 138 (Antibody C1)
Representative antibodies of the t invention are shown below.
Table A.
Anti
Light Chain Sequences Heavy Chain Sequences
body
B1 SPGTLSLSPGERATMSCTASSS QVQLVQSGAEVKKPGASVKVSCKASGYSFTS
VSSSYFHWYQQKPGQAPRLLIYRTSIL SWIHWVRQAPGQGLEWIGEINPGNVRTNYNE
ASGVPDRFSGSGSGTDFTLTISRLEPE NFRNKATMTVDTSISTAYMELSRLRSDDTAV
DFATYYCHQFHRSPLTFGQGTKLEIK YYCAVVFYGEPYFPYWGQGTLVTVSSASTK
RTVAAPSVFIFPPSDEQLKSGTASVV GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP
CLLNNFYPREAKVQWKVDNALQSGN SGALTSGVHTFPAVLQSSGLYSLSS
SQESVTEQDSKDSTYSLSSTLTLSKA VVTVPSSSLGTQTYICNVNHKPSNTKVDKRV
VYACEVTHQGLSSPVTKSF EPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKP
NRGEC (SEQ ID NO: 115) KDTLMISRTPEVTCVVVDVSHEDPEVKFNWY
VDGVEVHNAKTKPREEQYNSTYRVVSVLTV
LHQDWLNGKEYKCKVSNKALPAPIEKTISKA
KGQPREPQVYTLPPSREEMTKNQVSLTCLVK
GFYPSDIAVEWESNGQPENNYKTTPPVLDSD
GSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL
HNHYTQKSLSLSPGK (SEQ ID NO: 125)
EIVLTQSPGTLSLSPGERATMSCTASSS QVQLVQSGAEVKKPGASVKVSCKASGYSFTS
VSSSYFHWYQQKPGQAPRLLIYRTSIL SWIHWVRQRPGQGLEWIGEINPGNVRTNYNE
RFSGSGSGTDFTLTISRLEPE NFRNRVTMTVDTSISTAYMELSRLRSDDTAV
DFATYYCHQFHRSPLTFGQGTKLEIK YYCTVVFYGEPYFPYWGQGTLVTVSSASTKG
RTVAAPSVFIFPPSDEQLKSGTASVV PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV
CLLNNFYPREAKVQWKVDNALQSGN TVSWNSGALTSGVHTFPAVLQSSGLYSLSSV
SQESVTEQDSKDSTYSLSSTLTLSKA VTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP
DYEKHKVYACEVTHQGLSSPVTKSF HTCPPCPAPEAAGGPSVFLFPPKPKD
NRGEC (SEQ ID NO: 115) TLMISRTPEVTCVVVDVSHEDPEVKFNWYVD
GVEVHNAKTKPREEQYNSTYRVVSVLTVLH
QDWLNGKEYKCKVSNKALPAPIEKTISKAKG
VYTLPPSREEMTKNQVSLTCLVKGF
YPSDIAVEWESNGQPENNYKTTPPVLDSDGSF
FLYSKLTVDKSRWQQGNVFSCSVMHEALHN
HYTQKSLSLSPGK (SEQ ID NO: 126)
BS EIVLTQSPGTLSLSPGERATMSCTASSS QVQLVQSGAEVKKPGASVKVSCKASGYSFTS
VSSSYFHWYQQKPGQAPRLLIYRTSIL SWIHWVKQAPGQGLEWMGEINPGNVRTNYN
ASGVPDRFSGSGSGTDFTLTISRLEPE ENFRNKVTMTVDTSISTAYMELSRLRSDDTA
DFATYYCHQFHRSPLTFGQGTKLEIK VYYCTVVFYGEPYFPYWGQGTLVTVSSASTK
SVFIFPPSDEQLKSGTASVV GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP
CLLNNFYPREAKVQWKVDNALQSGN VTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
SQESVTEQDSKDSTYSLSSTLTLSKA VVTVPSSSLGTQTYICNVNHKPSNTKVDKRV
DYEKHKVYACEVTHQGLSSPVTKSF EPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKP
NRGEC (SEQ ID NO: 115) KDTLMISRTPEVTCVVVDVSHEDPEVKFNWY
VDGVEVHNAKTKPREEQYNSTYRVVSVLTV
LHQDWLNGKEYKCKVSNKALPAPIEKTISKA
KGQPREPQVYTLPPSREEMTKNQVSLTCLVK
GFYPSDIAVEWESNGQPENNYKTTPPVLDSD
SKLTVDKSRWQQGNVFSCSVMHEAL
KSLSLSPGK (SEQ ID NO: 127)
B4 QIVLTQSPGTLSLSPGERATMTCTASS QVQLVQSGAEVKKPGASVKVSCKASGYSFTS
SVSSSYFHWYQQKPGQAPRLWIYRTS SWIHWVRQAPGQGLEWIGEINPGNVRTNYNE
RLASGVPDRFSGSGSGTDFTLTISRLEP NFRNKATMTVDTSISTAYMELSRLRSDDTAV
EDAATYYCHQFHRSPLTFGAGTKLEI YYCAVVFYGEPYFPYWGQGTLVTVSSASTK
KRTVAAPSVF| FP PSDEQLKSGTASV GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP
VCLLNNFYPREAKVQWKVDNALQSG VTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
NSQESVTEQDSKDSTYSLSSTLTLSK VVTVPSSSLGTQTYICNVNHKPSNTKVDKRV
ADYEKHKVYACEVTHQGLSSPVTKS KTHTCPPCPAPEAAGGPSVFLFPPKP
FNRGEC (SEQ ID NO: 118) KDTLMISRTPEVTCVVVDVSHEDPEVKFNWY
VDGVEVHNAKTKPREEQYNSTYRVVSVLTV
LHQDWLNGKEYKCKVSNKALPAPIEKTISKA
KGQPREPQVYTLPPSREEMTKNQVSLTCLVK
GFYPSDIAVEWESNGQPENNYKTTPPVLDSD
GSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL
HNHYTQKSLSLSPGK (SEQ ID NO: 125)
B5 QIVLTQSPGTLSLSPGERATMTCTASS QVQLVQSGAEVKKPGASVKVSCKASGYSFTS
SVSSSYFHWYQQKPGQAPRLWIYRTS SWIHWVRQRPGQGLEWIGEINPGNVRTNYNE
RLASGVPDRFSGSGSGTDFTLTISRLEP NFRNRVTMTVDTSISTAYMELSRLRSDDTAV
EDAATYYCHQFHRSPLTFGAGTKLEI YYCTVVFYGEPYFPYWGQGTLVTVSSASTKG
KRTVAAPSVF| FP PSDEQLKSGTASV PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV
VCLLNNFYPREAKVQWKVDNALQSG GALTSGVHTFPAVLQSSGLYSLSSV
NSQESVTEQDSKDSTYSLSSTLTLSK VTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP
ADYEKHKVYACEVTHQGLSSPVTKS KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKD
FNRGEC (SEQ ID NO: 118) TLMISRTPEVTCVVVDVSHEDPEVKFNWYVD
GVEVHNAKTKPREEQYNSTYRVVSVLTVLH
QDWLNGKEYKCKVSNKALPAPIEKTISKAKG
QPREPQVYTLPPSREEMTKNQVSLTCLVKGF
YPSDIAVEWESNGQPENNYKTTPPVLDSDGSF
FLYSKLTVDKSRWQQGNVFSCSVMHEALHN
HYTQKSLSLSPGK (SEQ ID NO: 126)
SPGTLSLSPGERATMTCTASS QVQLVQSGAEVKKPGASVKVSCKASGYSFTS
SVSSSYFHWYQQKPGQAPRLWIYRTS SWIHWVKQAPGQGLEWMGEINPGNVRTNYN
RLASGVPDRFSGSGSGTDFTLTISRLEP ENFRNKVTMTVDTSISTAYMELSRLRSDDTA
EDAATYYCHQFHRSPLTFGAGTKLEI VYYCTVVFYGEPYFPYWGQGTLVTVSSASTK
KRTVAAPSVF| FP PSDEQLKSGTASV GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP
VCLLNNFYPREAKVQWKVDNALQSG VTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
NSQESVTEQDSKDSTYSLSSTLTLSK VVTVPSSSLGTQTYICNVNHKPSNTKVDKRV
KVYACEVTHQGLSSPVTKS EPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKP
FNRGEC (SEQ ID NO: 118) KDTLMISRTPEVTCVVVDVSHEDPEVKFNWY
VDGVEVHNAKTKPREEQYNSTYRVVSVLTV
NGKEYKCKVSNKALPAPIEKTISKA
KGQPREPQVYTLPPSREEMTKNQVSLTCLVK
GFYPSDIAVEWESNGQPENNYKTTPPVLDSD
GSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL
HNHYTQKSLSLSPGK (SEQ ID NO: 127)
Table B
Light Chain Seguences Heavy Chain Seguences
EIVMTQSPATLSVSPGVRATLSCKASQ QVQLQESGPGLVAPSETLSLTCTVSGFSLTDY
DVGTNVLWYQQKPGQAPRPLIYSASY AVHWIRQFPGKGLEWIGVIWSDGSTDFNAPF
RHSGIPARFSGSGSGTEFTLTISSLQSE KSRVTISKDTSKNQVSFKLSSVTTDDTAVYYC
CQQYSRYPLTFGQGTKLEIK ARKGGYSGSWFAYWGQGTLVTVSSASTKGP
RTVAAPSVFIFPPSDEQLKSGTASVVC SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT
LLNNFYPREAKVQWKVDNALQSGNS VSWNSGALTSGVHTFPAVLQSSGLYSLSSVV
QESVTEQDSKDSTYSLSSTLTLSKADY TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK
ACEVTHQGLSSPVTKSFNRG SCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDT
EC (SEQ ID NO: 124) LMISRTPEVTCVVVDVSHEDPEVKFNWYVDG
VEVHNAKTKPREEQYNSTYRVVSVLTVLHQ
DWLNGKEYKCKVSNKALPAPIEKTISKAKGQ
PREPQVYTLPPSREEMTKNQVSLTCLVKGFYP
SDIAVEWESNGQPENNYKTTPPVLDSDGSFFL
YSKLTVDKSRWQQGNVFSCSVMHEALHNHY
TQKSLSLSPGK (SEQ ID NO: 138)
EIVMTQSPATLSVSPGVRATLSCKASQ QVQLQESGPGLVKPSETLSITCTVSGFSLTDY
DVGTNVLWYQQKPGQAPRPLIYSASY AVHWIRQPPGKGLEWIGVIWSDGSTDYNAPF
RHSGIPDRFSGSGSGTEFTLTISSLQSE KSRVTISKDNSKSQVSFKMSSVTADDTAVYY
CQQYSRYPLTFGQGTKLEIK CARKGGYSGSWFAYWGQGTLVTVSSASTKG
RTVAAPSVFIFPPSDEQLKSGTASVVC PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV
LLNNFYPREAKVQWKVDNALQSGNS TVSWNSGALTSGVHTFPAVLQSSGLYSLSSV
QESVTEQDSKDSTYSLSSTLTLSKADY VTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP
EKHKVYACEVTHQGLSSPVTKSFNRG KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKD
EC (SEQ ID NO: 123) TPEVTCVVVDVSHEDPEVKFNWYVD
GVEVHNAKTKPREEQYNSTYRVVSVLTVLH
QDWLNGKEYKCKVSNKALPAPIEKTISKAKG
QPREPQVYTLPPSREEMTKNQVSLTCLVKGF
YPSDIAVEWESNGQPENNYKTTPPVLDSDGSF
TVDKSRWQQGNVFSCSVMHEALHN
HYTQKSLSLSPGK (SEQ ID NO: 139)
EIVMTQSPATLSVSPGVRATLSCKASQ QVQLQESGPGLVAPSETLSLTCTVSGFSLTDY
DVGTNVLWYQQKPGQAPRPLIYSASY AVHWIRQFPGKGLEWIGVIWSDGSTDFNAPF
RHSGIPDRFSGSGSGTEFTLTISSLQSE KSRVTISKDTSKNQVSFKLSSVTTDDTAVYYC
DFAVYYCQQYSRYPLTFGQGTKLEIK ARKGGYSGSWFAYWGQGTLVTVSSASTKGP
RTVAAPSVFIFPPSDEQLKSGTASVVC SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT
LLNNFYPREAKVQWKVDNALQSGNS VSWNSGALTSGVHTFPAVLQSSGLYSLSSVV
QESVTEQDSKDSTYSLSSTLTLSKADY TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK
EKHKVYACEVTHQGLSSPVTKSFNRG SCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDT
EC (SEQ ID NO: 123) LMISRTPEVTCVVVDVSHEDPEVKFNWYVDG
VEVHNAKTKPREEQYNSTYRVVSVLTVLHQ
DWLNGKEYKCKVSNKALPAPIEKTISKAKGQ
PREPQVYTLPPSREEMTKNQVSLTCLVKGFYP
SDIAVEWESNGQPENNYKTTPPVLDSDGSFFL
YSKLTVDKSRWQQGNVFSCSVMHEALHNHY
TQKSLSLSPGK (SEQ ID NO: 138)
The antibodies of the present invention are useful in methods for the treatment of
various es or disorders, for e immunological, inflammatory, autoimmune
diseases and respiratory diseases in . For example, the antibodies of the
present invention are useful in methods for the treatment of psoriasis, rheumatoid
arthritis, inflammatory bowel disease or psoriatic arthritis. For example, the dies of
the present invention are useful in methods for the treatment of chronic obstructive
pulmonary disorder (COPD) or asthma. For example, the antibodies of the present
invention are useful in s for the treatment of scleroderma, palmoplantar
pustulosis, generalized pustular psoriasis, diabetic nephropathy, lupus nephritis,
scleroderma, ankylosing spondylitis, deficiency in the lL-36 receptor antagonist
autoimmune disease (DITRA), deficiency in the lL-1 receptor nist autoimmune
disease (DIRA) or cryopyrin associated periodic syndromes (CAPS).
In some aspects, the humanized antibody ys blocking activity, whereby it
decreases the binding of lL-36 ligand to lL-36 receptor by at least 45%, by at least 50%,
by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, by
at least 80%, by at least 85%, by at least 90%, or by at least 95%. The ability of an
antibody to block binding of lL-36 ligand to the lL-36 receptor can be measured using
competitive binding assays known in the art. Alternatively, the blocking activity of an
antibody can be ed by ing the biological s of lL-36, such as the
production of lL-8, lL-6, and GM-CSF to determine if ing mediated by the lL-36
receptor is inhibited.
In a further aspect, the present invention provides a humanized anti-lL-36R antibody
having favorable biophysical properties. In one aspect, a humanized anti-lL-36R
dy of the present invention is present in at least 90% monomer form, or in at least
92% monomer form, or in at least 95% monomer form in a buffer. In a further aspect, a
humanized anti-lL-36R antibody of the present invention remains in at least 90%
r form, or in at least 92% r form, or in at least 95% r form in a
buffer for one month or for four months.
In one aspect, a humanized antibody of the t invention is Antibody B1, Antibody
B2, Antibody B3, Antibody B4, Antibody B5, Antibody B6, dy C1, Antibody C2, or
Antibody C3. Accordingly, in one embodiment, a humanized dy of the present
invention comprises the light chain ce of SEQ ID NO:115 and the heavy chain
sequence of SEQ ID NO:125 (Antibody B1). In another embodiment, a humanized
dy of the present invention comprises the light chain sequence of SEQ ID NO:115
and the heavy chain sequence of SEQ ID NO:126 (Antibody B2). In another
embodiment, a humanized antibody of the present invention comprises the light chain
sequence of SEQ ID NO:115 and the heavy chain sequence of SEQ ID NO:127
(Antibody B3). In another embodiment, a zed antibody of the present invention
comprises the light chain sequence of SEQ ID NO:118 and the heavy chain sequence
of SEQ ID NO:125 ody B4). In another embodiment, a humanized antibody of the
present invention comprises the light chain sequence of SEQ ID NO:118 and the heavy
chain sequence of SEQ ID NO:126 (Antibody B5). In another ment, a humanized
antibody of the present invention comprises the light chain sequence of SEQ ID NO:118
and the heavy chain sequence of SEQ ID NO:127 (Antibody B6). In another
embodiment, a humanized antibody of the present invention comprises the light chain
sequence of SEQ ID NO:124 and the heavy chain sequence of SEQ ID NO:138
(Antibody C1). In another embodiment, a humanized antibody of the present invention
comprises the light chain sequence of SEQ ID NO:123 and the heavy chain sequence
of SEQ ID NO:139 (Antibody C2). In another embodiment, a zed antibody of the
present invention comprises the light chain sequence of SEQ ID NO:123 and the heavy
chain sequence of SEQ ID NO:138 (Antibody C3).
In a further embodiment, a humanized antibody of the present invention consists of
the light chain sequence of SEQ ID NO:115 and the heavy chain sequence of SEQ ID
NO:125 (Antibody B1). In r embodiment, a humanized antibody of the present
invention consists of the light chain sequence of SEQ ID NO:115 and the heavy chain
sequence of SEQ ID NO:126 (Antibody B2). In r ment, a humanized
antibody of the present invention consists of the light chain sequence of SEQ ID
NO:115 and the heavy chain sequence of SEQ ID NO:127 (Antibody B3). In r
embodiment, a humanized antibody of the present invention consists of the light chain
sequence of SEQ ID NO:118 and the heavy chain sequence of SEQ ID NO:125
(Antibody B4). In r embodiment, a humanized antibody of the present ion
ts of the light chain sequence of SEQ ID NO:118 and the heavy chain sequence
of SEQ ID NO:126 (Antibody B5). In another embodiment, a humanized antibody of the
present invention consists of the light chain sequence of SEQ ID NO:118 and the heavy
chain sequence of SEQ ID NO:127 (Antibody B6). In another embodiment, a humanized
antibody of the t invention consists of the light chain sequence of SEQ ID
NO:124 and the heavy chain sequence of SEQ ID NO:138 ody C1). In another
embodiment, a humanized antibody of the present invention consists of the light chain
sequence of SEQ ID NO:123 and the heavy chain sequence of SEQ ID NO:139
(Antibody C2). In another embodiment, a humanized antibody of the present invention
consists of the light chain sequence of SEQ ID NO:123 and the heavy chain sequence
of SEQ ID NO:138 (Antibody 03).
In some embodiments, the humanized anti-IL-36B antibodies, including antigen-binding
fragments thereof, such as heavy and light chain variable s, comprise an amino
acid sequence of the residues derived from Antibody B1, Antibody B2, Antibody B3,
Antibody B4, Antibody B5, Antibody B6, Antibody C1, Antibody C2, or Antibody 03.
In a further embodiment, the present invention provides an anti-IL-36B antibody or
antigen-binding fragment thereof that competitively binds to human IL-36R with an
antibody of the present invention, for example Antibody B1, Antibody B2, Antibody B3,
Antibody B4, Antibody B5, Antibody B6, Antibody C1, dy C2 or Antibody 03
bed herein. The ability of an dy or antigen-binding fragment to itively
bind to IL-36B can be ed using competitive binding assays known in the art.
The humanized anti-IL-36B antibodies optionally include specific amino acid
substitutions in the consensus or germline framework regions. The specific substitution
of amino acid residues in these ork positions can improve various aspects of
antibody performance ing binding affinity and/or stability, over that demonstrated
in humanized antibodies formed by "direct swap" of CDRs or HVLs into the human
germline framework regions.
In some embodiments, the t invention describes other monoclonal antibodies
with alight chain variable region having the amino acid sequence set forth in any one of
SEQ ID NO:1-10. In some embodiments, the present invention describes other
monoclonal antibodies with a heavy chain variable region having the amino acid
ce set forth in any one of SEQ ID NO:11-20. Placing such CDRs into FRs of the
human consensus heavy and light chain variable domains will yield useful humanized
antibodies of the t invention.
In particular, the present invention provides monoclonal antibodies with the
combinations of light chain variable and heavy chain variable regions of SEQ ID
NO:1/11, 2/12, 3/13, 4/14, 5/15, 6/16, 7/17, 8/18, 9/19, 10/20. Such variable regions can
be combined with human constant regions.
In some embodiments, the present invention describes other humanized antibodies with
light chain variable region sequences having the amino acid ce set forth in any
one of SEQ ID NQ:76-86. In some embodiments, the present invention describes other
humanized antibodies with heavy chain le region sequences having the amino
acid ce set forth in any one of SEQ ID NQ:87-101. In particular, the present
invention provides monoclonal dies with the ations of light chain variable
and heavy chain variable regions of SEQ ID NO: 77/89, 80/88, 80/89, 77/87, 77/88,
80/87, 86/100, 85/101, 85/100. Such variable regions can be combined with human
constant regions.
In a r embodiment, the present invention relates to an anti-IL-36R antibody or
antigen-binding fragment thereof comprising a humanized light chain variable domain
comprising the CDRs of SEQ ID NQ:77 and framework regions having an amino acid
sequence at least 90% identical, at least 93% cal or at least 95% identical to the
amino acid sequence of the framework regions of the variable domain light chain amino
acid sequence of SEQ ID NQ:77 and a humanized heavy chain le domain
comprising the CDRs of SEQ ID NQ:89 and framework regions having an amino acid
sequence at least 90% identical, at least 93% identical or at least 95% identical to the
amino acid sequence of the framework regions of the variable domain heavy chain
amino acid ce of SEQ ID NQ:89. In one embodiment, the anti-IL-36R antibody is
a humanized monoclonal antibody.
In a further embodiment, the present invention relates to an anti-IL-36R antibody or
antigen-binding fragment f comprising a humanized light chain variable domain
comprising the CDRs of SEQ ID NQ:8O and framework regions having an amino acid
sequence at least 90% identical, at least 93% cal or at least 95% identical to the
amino acid sequence of the framework regions of the variable domain light chain amino
acid sequence of SEQ ID NQ:8O and a humanized heavy chain variable domain
comprising the CDRs of SEQ ID NQ:88 and framework s having an amino acid
sequence at least 90% identical, at least 93% identical or at least 95% identical to the
amino acid sequence of the framework regions of the variable domain heavy chain
amino acid sequence of SEQ ID NQ:88. In one embodiment, the L-36R antibody is
a humanized monoclonal antibody.
In a further embodiment, the present invention relates to an anti-IL-36R antibody or
antigen-binding fragment thereof comprising a humanized light chain variable domain
comprising the CDRs of SEQ ID NQ:8O and ork regions having an amino acid
sequence at least 90% identical, at least 93% identical or at least 95% identical to the
amino acid sequence of the framework s of the variable domain light chain amino
acid sequence of SEQ ID NQ:8O and a humanized heavy chain le domain
comprising the CDRs of SEQ ID NQ:89 and framework regions having an amino acid
sequence at least 90% identical, at least 93% identical or at least 95% identical to the
amino acid sequence of the framework regions of the variable domain heavy chain
amino acid ce of SEQ ID NQ:89. In one embodiment, the anti-IL-36R dy is
a humanized monoclonal antibody.
In a further embodiment, the present invention relates to an anti-IL-36R dy or
antigen-binding fragment thereof comprising a humanized light chain variable domain
comprising the CDRs of SEQ ID NQ:77 and framework regions having an amino acid
sequence at least 90% identical, at least 93% identical or at least 95% identical to the
amino acid sequence of the framework s of the variable domain light chain amino
acid sequence of SEQ ID NO:77 and a humanized heavy chain variable domain
comprising the CDRs of SEQ ID NO:87 and framework regions having an amino acid
sequence at least 90% identical, at least 93% identical or at least 95% identical to the
amino acid sequence of the framework regions of the variable domain heavy chain
amino acid sequence of SEQ ID NO:87. In one embodiment, the anti-IL-36R antibody is
a humanized monoclonal antibody.
In a further embodiment, the t invention relates to an anti-IL-36R antibody or
antigen-binding fragment thereof comprising a humanized light chain variable domain
sing the CDRs of SEQ ID NO:77 and framework s having an amino acid
sequence at least 90% identical, at least 93% identical or at least 95% identical to the
amino acid sequence of the framework regions of the variable domain light chain amino
acid sequence of SEQ ID NO:77 and a humanized heavy chain variable domain
comprising the CDRs of SEQ ID NO:88 and framework regions having an amino acid
sequence at least 90% identical, at least 93% identical or at least 95% identical to the
amino acid sequence of the framework regions of the variable domain heavy chain
amino acid sequence of SEQ ID NO:88. In one embodiment, the anti-IL-36R antibody is
a humanized monoclonal antibody.
In a further embodiment, the present invention relates to an L-36R antibody or
n-binding fragment thereof comprising a humanized light chain variable domain
comprising the CDRs of SEQ ID NO:8O and framework regions having an amino acid
sequence at least 90% cal, at least 93% identical or at least 95% identical to the
amino acid sequence of the framework regions of the le domain light chain amino
acid sequence of SEQ ID NO:8O and a humanized heavy chain variable domain
comprising the CDRs of SEQ ID NO:87 and framework regions having an amino acid
sequence at least 90% identical, at least 93% identical or at least 95% cal to the
amino acid sequence of the framework regions of the variable domain heavy chain
amino acid sequence of SEQ ID NO:87. In one embodiment, the anti-IL-36R dy is
a humanized monoclonal antibody.
In a further embodiment, the t invention s to an anti-lL-36R antibody or
antigen-binding fragment thereof sing a humanized light chain variable domain
comprising the CDRs of SEQ ID NO:86 and framework regions having an amino acid
sequence at least 90% identical, at least 93% identical or at least 95% identical to the
amino acid sequence of the framework regions of the variable domain light chain amino
acid sequence of SEQ ID NO:86 and a humanized heavy chain variable domain
comprising the CDRs of SEQ ID NQ:1OO and ork regions having an amino acid
ce at least 90% identical, at least 93% identical or at least 95% identical to the
amino acid sequence of the framework regions of the variable domain heavy chain
amino acid sequence of SEQ ID NQ:100. In one embodiment, the anti-lL-36R dy
is a humanized monoclonal antibody.
In a r embodiment, the present invention relates to an anti-lL-36R antibody or
antigen-binding fragment thereof comprising a zed light chain variable domain
comprising the CDRs of SEQ ID NO:85 and framework regions having an amino acid
sequence at least 90% identical, at least 93% identical or at least 95% identical to the
amino acid sequence of the framework regions of the variable domain light chain amino
acid sequence of SEQ ID NO:85 and a humanized heavy chain variable domain
comprising the CDRs of SEQ ID NQ:101 and framework regions having an amino acid
ce at least 90% identical, at least 93% identical or at least 95% identical to the
amino acid sequence of the framework regions of the variable domain heavy chain
amino acid sequence of SEQ ID NQ:101. In one embodiment, the anti-lL-36R antibody
is a humanized monoclonal antibody.
In a further embodiment, the present invention relates to an L-36R antibody or
antigen-binding fragment thereof comprising a humanized light chain variable domain
comprising the CDRs of SEQ ID NO:85 and framework regions having an amino acid
ce at least 90% identical, at least 93% identical or at least 95% cal to the
amino acid ce of the framework regions of the variable domain light chain amino
acid sequence of SEQ ID NO:85 and a humanized heavy chain variable domain
comprising the CDRs of SEQ ID NQ:1OO and framework regions having an amino acid
sequence at least 90% identical, at least 93% identical or at least 95% identical to the
amino acid sequence of the framework regions of the variable domain heavy chain
2012/064933
amino acid sequence of SEQ ID NQ:100. In one embodiment, the anti-IL-36R dy
is a humanized monoclonal dy.
In some specific embodiments, the humanized anti-IL-36R antibodies disclosed herein
comprise at least a heavy or a light chain variable domain comprising the CDRs or
HVLs of the murine onal antibodies or zed antibodies as disclosed herein
and the PBS of the human ne heavy and light chain variable domains.
In one further aspect, the present invention provides an L-36R antibody or antigen-
binding fragment thereof comprising a light chain CDR1 (L-CDR1) sequence of any one
of SEQ ID NQ:21-29; a light chain CDR2 (L-CDR2) sequence of any one of SEQ ID
NQ:30-38; a light chain CDR3 (L-CDR3) sequence of any one of SEQ ID NQ:39-47; a
heavy chain CDR1 (H-CDR1) sequence of any one of SEQ ID NQ:48-56; a heavy chain
CDR2 (H-CDR2) sequence of any one of SEQ ID NQ:57-66; and a heavy chain CDR3
(H-CDR3) ce of any one of SEQ ID NQ:67-75. In one aspect, the anti-IL-36R
antibody or antigen-binding fragment thereof comprises a light chain variable region
comprising a L-CDR1 listed above, a L-CDR2 listed above and a L-CDR3 listed above,
and a heavy chain variable region comprising a H-CDR1 listed above, a H-CDR2 listed
above and a H-CDR3 listed above.
In a further aspect, the present invention provides an anti-IL-36R antibody or antigen-
binding nt thereof comprising:
a) a L-CDR1, a L-CDR2, a L-CDR3, a , a H-CDR2 and a H-CDR3
sequence of SEQ ID NQ:21, 30, 39, 48, 57 and 67, respectively; or
b) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3
sequence of SEQ ID NQ:22, 31, 40, 49, 58 and 68, respectively; or
c) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3
sequence of SEQ ID NQ:23, 32, 41, 50, 59 and 69, respectively; or
d) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3
sequence of SEQ ID NQ:24, 33, 42, 51, 60 and 70, respectively; or
e) a L-CDR1, a L-CDR2, a L-CDR3, a , a H-CDR2 and a H-CDR3
sequence of SEQ ID NQ:25, 34, 43, 52, 61 and 71, respectively; or
f) a L-CDR1, a L-CDR2, a , a H-CDR1, a H-CDR2 and a H-CDR3
sequence of SEQ ID NQ:26, 35, 44, 53, 62 and 72, respectively; or
g) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3
sequence of SEQ ID NQ:27, 36, 45, 54, 63 and 73, respectively; or
h) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3
sequence of SEQ ID NQ:27, 36, 45, 54, 64 and 74, respectively; or
i) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3
sequence of SEQ ID NQ:27, 36, 45, 54, 64 and 73, respectively; or
j) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3
sequence of SEQ ID NQ:28, 37, 46, 55, 65 and 74, respectively; or
k) a L-CDR1, a L-CDR2, a L-CDR3, a , a H-CDR2 and a H-CDR3
sequence of SEQ ID NQ:29, 38, 47, 56, 66 and 75, tively.
In a further aspect, the present invention es an anti-IL-36R dy or antigen-
binding fragment thereof comprising:
a) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3
sequence of SEQ ID NQ:26, 103, 44, 53, 62 and 72, respectively; or
b) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3
sequence of SEQ ID NQ:26, 104, 44, 53, 62 and 72, respectively; or
c) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3
sequence of SEQ ID NQ:27, 36, 45, 107, 63 and 73, tively; or
d) a L-CDR1, a , a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3
sequence of SEQ ID NQ:27, 36, 45, 107, 64 or 73, respectively.
In one aspect, the anti-IL-36R antibody or antigen-binding fragment f comprises a
light chain variable region comprising a L-CDR1, L-CDR2 and L-CDR3 combination
listed above, and a heavy chain variable region comprising a H-CDR1, H-CDR2 and H-
CDR3 combination listed above.
In specific embodiments, it is plated that chimeric antibodies with switched CDR
regions (i.e., for example switching one or two CDRs of one of the mouse antibodies or
humanized antibody derived therefrom with the analogous CDR from another mouse
antibody or humanized dy derived therefrom) between these exemplary
immunoglobulins may yield useful antibodies.
In certain embodiments, the humanized anti-lL-36R antibody is an antibody fragment.
Various antibody nts have been generally discussed above and there are
techniques that have been developed for the production of antibody fragments.
nts can be d via proteolytic digestion of intact antibodies (see, e.g.,
Morimoto et al., 1992, Journal of Biochemical and sical Methods 24:107-117; and
Brennan et al., 1985, Science 229:81). Alternatively, the fragments can be produced
directly in recombinant host cells. For example, Fab'-SH fragments can be directly
recovered from E. coli and chemically d to form F(ab')2 fragments (see, e.g.,
Carter et al., 1992, Bio/Technology 10:163-167). By another approach, F(ab')2
fragments can be ed directly from recombinant host cell e. Other techniques
for the production of antibody fragments will be apparent to the skilled practitioner.
Accordingly, in one aspect, the present ion provides dy fragments
comprising the CDRs described , in particular one of the combinations of L-
CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 described herein. In a further
aspect, the present invention provides antibody fragments comprising the variable
regions described herein, for example one of the combinations of light chain variable
regions and heavy chain variable regions described herein.
Certain embodiments include an F(ab')2 fragment of a humanized anti-lL-36R antibody
comprise a light chain sequence of any of SEQ ID NO: 115 or 118 in combination with a
heavy chain sequence of SEQ ID NO: 125, 126 or 127. Such embodiments can include
an intact antibody comprising such an F(ab')2.
Certain embodiments include an F(ab')2 fragment of a humanized anti-lL-36R antibody
comprise a light chain ce of any of SEQ ID NO: 123 or 124 in combination with a
heavy chain sequence of SEQ ID NO: 138 or 139. Such embodiments can include an
intact antibody sing such an F(ab')2.
In some embodiments, the antibody or antibody fragment includes a constant region
that mediates effector function. The constant region can provide antibody-dependent
cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and/or
complement-dependent cytotoxicity (CDC) responses against an lL-36R sing
target cell. The or domain(s) can be, for example, an Fc region of an lg molecule.
The effector domain of an antibody can be from any suitable vertebrate animal species
and isotypes. The isotypes from different animal species differ in the abilities to mediate
effector functions. For e, the ability of human globulin to mediate CDC
and ADCC/ADCP is generally in the order of lglegG1zlgG3>lgG2>lgG4 and
lgG1zlgG3>lgG2/lgM/lgG4, respectively. Murine immunoglobulins mediate CDC and
ADCC/ADCP generally in the order of murine lglegG3>>lgG2b>lgG2a>>lgG1 and
lgG2a>lgG1>>lgG3, respectively. In r example, murine lnga mediates
ADCC while both murine lnga and lgM mediate CDC.
Antibody Modifications
The humanized L-36R antibodies and agents can include modifications of the
humanized anti-lL-36R dy or antigen-binding fragment thereof. For example, it
may be desirable to modify the dy with respect to effector function, so as to
enhance the effectiveness of the antibody in treating cancer. One such modification is
the introduction of cysteine residue(s) into the Fc region, thereby allowing interchain
disulfide bond formation in this region. The homodimeric antibody thus generated can
have improved internalization capability and/or increased complement-mediated cell
g and/or dy-dependent cellular cytotoxicity (ADCC). See, for example, Caron
et al., 1992, J. Exp Med. 176:1191-1195; and Shopes, 1992, J. Immunol. 148:2918-
2922. meric antibodies having enhanced umor activity can also be
prepared using heterobifunctional cross-linkers as described in Wolff et al., 1993,
Cancer Research 53: 2560-2565. Alternatively, an antibody can be engineered to
contain dual Fc regions, enhancing complement lysis and ADCC capabilities of the
antibody. See Stevenson et al., 1989, Anti-Cancer Drug Design 3: 219-230.
Antibodies with improved ability to support ADCC have been generated by modifying
the glycosylation pattern of their Fc region. This is possible since antibody glycosylation
at the asparagine residue, N297, in the CH2 domain is involved in the interaction
between lgG and Fcy receptors prerequisite to ADCC. Host cell lines have been
engineered to express antibodies with d glycosylation, such as increased bisecting
N-acetylglucosamine or reduced fucose. Fucose reduction provides r
enhancement to ADCC activity than does increasing the presence of bisecting N-
acetylglucosamine. Moreover, enhancement of ADCC by low fucose dies is
independent of the Fclella V/F rphism.
Modifying the amino acid sequence of the Fc region of antibodies is an alternative to
glycosylation engineering to enhance ADCC. The binding site on human lgG1 for Fcy
receptors has been ined by extensive mutational analysis. This led to the
generation of humanized lgG1 antibodies with PC mutations that increase the binding
affinity for Fclella and enhance ADCC in vitro. Additionally, Fc variants have been
obtained with many different permutations of binding properties, e.g., improved binding
to specific chR receptors with unchanged or diminished binding to other FcyR
receptors.
Another aspect includes conjugates sing the humanized antibody or
fragments thereof conjugated to a cytotoxic agent such as a chemotherapeutic agent, a
toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or
fragments thereof), or a radioactive e (Le, a radioconjugate).
Chemotherapeutic agents useful in the generation of such immunoconjugates have
been described above. tically active toxins and fragments thereof that can be
used to form useful immunoconjugates include diphtheria A chain, nonbinding active
fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A
chain, abrin A chain, in A chain, alpha-sarcin, Aleurites fordii proteins, dianthin
proteins, Phytolaca americana proteins (PAPI, PAP”, and PAP-S), Momordica
tia inhibitor, curcin, crotin, Sapaonaria officinalis inhibitor, gelonin, mitogellin,
restrictocin, phenomycin, enomycin, the tricothecenes, and the like. A variety of
radionuclides are available for the tion of radioconjugated humanized anti-lL-36R
antibodies. Examples include 212Bi, 131I, 131In, 90Y, and 186Re.
Conjugates of the zed anti-lL-36R antibody and cytotoxic or chemotherapeutic
agent can be made by known s, using a variety of bifunctional protein coupling
agents such as N-succinimidyl(2—pyridyldithiol) propionate (SPDP), iminothiolane (IT),
bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters
(such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), ido
compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives
(such as bis-(p-diazoniumbenzoyl)-ethylenediamine), yanates (such as toluene
2,6—diisocyanate), and tive fluorine compounds (such as 1,5-difluoro-2,4-
dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in
Vitetta et al., 1987, Science 238:1098. Carbonlabeled 1-isothiocyanatobenzyl
methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent
for conjugation of radionucleotide to the antibody. Conjugates also can be formed with a
cleavable linker.
The humanized L-36R antibodies disclosed herein can also be ated as
immunoliposomes. Liposomes ning the antibody are prepared by s known
in the art, such as described in Epstein et al., 1985, Proc. Natl. Acad. Sci. USA 82:3688;
Hwang et al., 1980, Proc. Natl. Acad. Sci. USA 77:4030; and US. Pat. Nos. 4,485,045
and 4,544,545. Liposomes having ed circulation time are disclosed, for example,
in US. Pat. No. 556.
Particularly useful liposomes can be generated by the reverse phase evaporation
method with a lipid composition comprising atidylcholine, cholesterol and PEG-
derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through
filters of defined pore size to yield liposomes with the desired diameter. Fab' fragments
of an antibody disclosed herein can be conjugated to the liposomes as described in
Martin et al., 1982, J. Biol. Chem. 257:286—288 via a disulfide interchange reaction. A
chemotherapeutic agent (such as doxorubicin) is optionally contained within the
liposome. See, e.g., Gabizon et al., 1989, J. National Cancer Inst. 81(19):1484.
The antibodies described and disclosed herein can also be used in ADEPT (Antibody-
Directed Enzyme Prodrug Therapy) procedures by conjugating the antibody to a
prodrug-activating enzyme that converts a prodrug (e.g., a peptidyl chemotherapeutic
agent), to an active anti-cancer drug. See, for e, WO 81/01145, WO 88/07378,
and US. Pat. No. 4,975,278. The enzyme component of the immunoconjugate useful
for ADEPT is an enzyme e of acting on a prodrug in such a way so as to covert it
2012/064933
into its more active, cytotoxic form. Specific enzymes that are useful in ADEPT e,
but are not limited to, alkaline phosphatase for converting phosphate-containing
prodrugs into free drugs; lfatase for converting sulfate-containing prodrugs into
free drugs; cytosine deaminase for converting non-toxic 5-fluorocytosine into the anti-
cancer drug, 5-fluorouracil; ses, such as serratia protease, thermolysin, subtilisin,
carboxypeptidases, and cathepsins (such as cathepsins B and L), for converting
peptide-containing prodrugs into free drugs; D-alanylcarboxypeptidases, for converting
prodrugs containing D-amino acid substituents; carbohydrate-cleaving enzymes such as
B-galactosidase and neuraminidase for converting glycosylated prodrugs into free
drugs; B-lactamase for converting drugs tized with B-lactams into free drugs; and
penicillin es, such as penicillin V amidase or penicillin G amidase, for converting
drugs derivatized at their amine nitrogens with phenoxyacetyl or phenylacetyl groups,
respectively, into free drugs. Alternatively, antibodies having enzymatic activity
("abzymes") can be used to convert the prodrugs into free active drugs (see, for
example, Massey, 1987, Nature 328: 457-458). Antibody-abzyme conjugates can be
prepared by known methods for delivery of the abzyme to a tumor cell tion, for
example, by covalently binding the enzyme to the humanized anti-lL-36R
antibody/heterobifunctional crosslinking ts discussed above. Alternatively, fusion
ns comprising at least the antigen binding region of an dy sed herein
linked to at least a functionally active portion of an enzyme as described above can be
ucted using recombinant DNA techniques (see, e.g., Neuberger et al., 1984,
Nature 312:604-608).
In certain embodiments, it may be desirable to use a humanized anti-lL-36R antibody
nt, rather than an intact antibody, to increase tissue penetration, for example. It
may be desirable to modify the antibody fragment in order to increase its serum half life.
This can be achieved, for example, by incorporation of a salvage receptor binding
epitope into the antibody fragment. In one method, the appropriate region of the
antibody fragment can be altered (e.g., mutated), or the epitope can be incorporated
into a peptide tag that is then fused to the antibody fragment at either end or in the
middle, for e, by DNA or peptide synthesis. See, e.g., WO 96/32478.
In other ments, covalent modifications of the humanized anti-lL-36R antibody
are also included. Covalent modifications include modification of nyl residues,
histidyl residues, lysinyl and amino-terminal residues, arginyl residues, tyrosyl residues,
carboxyl side groups (aspartyl or glutamyl), glutaminyl and asparaginyl es, or
seryl, or threonyl residues. Another type of covalent modification involves chemically or
enzymatically coupling glycosides to the antibody. Such modifications may be made by
chemical synthesis or by enzymatic or chemical cleavage of the antibody, if applicable.
Other types of covalent modifications of the antibody can be introduced into the
le by reacting targeted amino acid residues of the antibody with an organic
derivatizing agent that is capable of reacting with selected side chains or the amino- or
carboxy-terminal residues.
l of any carbohydrate moieties present on the antibody can be accomplished
chemically or enzymatically. al deglycosylation is described by Hakimuddin et
al., 1987, Arch. Biochem. Biophys. 259:52 and by Edge et al., 1981, Anal. Biochem.,
118:131. Enzymatic cleavage of carbohydrate moieties on antibodies can be achieved
by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al.,
1987, Meth. Enzymol 138:350.
Another type of useful covalent modification comprises g the dy to one of a
variety of nonproteinaceous polymers, e.g., hylene glycol, polypropylene glycol, or
polyoxyalkylenes, in the manner set forth in one or more of US. Pat. No. 835,
US Pat. No. 4,496,689, US. Pat. No. 4,301,144, US. Pat. No. 4,670,417, US. Pat.
No. 4,791,192 and US. Pat. No. 337.
Humanization and Amino Acid Sequence Variants
Amino acid sequence variants of the anti-lL-36R antibody can be prepared by
introducing appropriate nucleotide changes into the anti-lL-36R dy DNA, or by
e synthesis. Such variants include, for example, deletions from, and/or insertions
into and/or substitutions of, es within the amino acid sequences of the anti-lL-36R
antibodies of the examples herein. Any combination of deletions, insertions, and
substitutions is made to arrive at the final construct, provided that the final construct
possesses the desired characteristics. The amino acid changes also may alter post-
translational processes of the humanized or variant anti-lL-36R dy, such as
changing the number or position of ylation sites.
A useful method for fication of certain residues or regions of the anti-lL-36R
antibody that are preferred locations for mutagenesis is called "alanine scanning
mutagenesis," as described by Cunningham and Wells (Science, 244:1081-1085
(1989)). Here, a residue or group of target es are identified (e.g., charged
residues such as arg, asp, his, lys, and glu) and replaced by a neutral or negatively
d amino acid (typically alanine) to affect the interaction of the amino acids with
lL-36R antigen. Those amino acid locations demonstrating functional sensitivity to the
substitutions then are d by ucing further or other variants at, or for, the sites
of substitution. Thus, while the site for introducing an amino acid sequence variation is
predetermined, the nature of the mutation per se need not be ermined. For
e, to analyze the performance of a mutation at a given site, alanine scanning or
random nesis is conducted at the target codon or region and the expressed anti-
lL-36R antibody variants are screened for the desired activity.
Amino acid ce insertions include amino- and/or carboxyl-terminal fusions ranging
in length from one e to polypeptides containing a hundred or more residues, as
well as intrasequence insertions of single or multiple amino acid residues. Examples of
terminal insertions include an anti-lL-36R antibody fused to an epitope tag. Other
insertional variants of the anti-lL-36R antibody molecule include a fusion to the N- or C-
terminus of the anti-lL-36R antibody of an enzyme or a polypeptide which ses the
serum half-life of the antibody.
Another type of variant is an amino acid substitution variant. These variants have at
least one amino acid residue in the anti-lL-36R antibody molecule removed and a
different residue inserted in its place. The sites of greatest interest for substitutional
nesis include the hypervariable regions, but FR alterations are also
contemplated. Conservative substitutions are shown in Table 5 under the heading of
"preferred substitutions". If such substitutions result in a change in biological activity,
then more substantial changes, denominated "exemplary substitutions", or as further
described below in reference to amino acid classes, may be introduced and the
products screened.
TABLE C:
Original Residue Exemplary Substitutions Preferred Substitutions
Ala (A) val; leu; ile val
Arg (R) lys; gln; asn lys
Asn (N) gln; his; asp, lys; arg gin
Asp (D) glu; asn glu
Cys (C) ser; ala ser
Gin (Q) asn; glu asn
Glu (E) asp; gln asp
Gly (G) ala ala
His (H) arg; asn; gln; lys; arg
lie (I) leu; val; met; ala; phe; norleucine leu
Leu (L) ile; norleucine; val; met; ala; phe ile
Lys (K) arg; gln; asn arg
Met (M) leu; phe; ile leu
Phe (F) tyr; leu; val; ile; ala; tyr
Pro (P) ala ala
Ser (8) thr thr
Thr (T) ser ser
Trp (W) tyr; phe tyr
Tyr (Y) p; thr; ser phe
Val (V) leu; ile; met; phe ala; norleucine; leu
In protein chemistry, it is generally accepted that the ical properties of the
antibody can be accomplished by selecting substitutions that differ significantly in their
effect on maintaining (a) the structure of the polypeptide backbone in the area of the
substitution, for example, as a sheet or helical conformation, (b) the charge or
hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain.
Naturally occurring residues are d into groups based on common side-chain
properties:
(1) hydrophobic: norleucine, met, ala, val, leu, lie;
(2) neutral hydrophilic: cys, ser, thr;
(3) acidic: asp, glu;
(4) basic: asn, gin, his, lys, arg;
(5) residues that nce chain orientation: gly, pro; and
(6) aromatic: trp, tyr, phe.
Non-conservative substitutions will entail exchanging a member of one of these s
for another class.
Any cysteine residue not involved in maintaining the proper conformation of the
humanized or variant anti-lL-36R antibody also may be substituted, generally with
serine, to e the ive stability of the molecule, prevent aberrant crosslinking,
or provide for established points of conjugation to a cytotoxic or cytostatic compound.
Conversely, cysteine bond(s) may be added to the antibody to improve its stability
(particularly where the antibody is an antibody fragment such as an Fv fragment).
A type of substitutional variant involves substituting one or more hypervariable region
residues of a parent antibody (e.g., a humanized or human antibody). Generally, the
resulting variant(s) selected for further development will have improved biological
properties ve to the parent antibody from which they are generated. A ient
way for ting such substitutional variants is ty maturation using phage
display. Briefly, several hypervariable region sites (e.g., 6-7 sites) are mutated to
generate all possible amino substitutions at each site. The antibody variants thus
generated are displayed in a lent fashion from filamentous phage particles as
fusions to the gene lll product of M13 packaged within each particle. The phage-
displayed variants are then ed for their biological activity (e.g., binding affinity). In
order to identify candidate hypervariable region sites for modification, alanine ng
mutagenesis can be performed to fy hypervariable region residues contributing
significantly to antigen g. Alternatively, or in addition, it may be beneficial to
analyze a crystal structure of the n-antibody complex to identify contact points
between the dy and human lL-36R. Such contact residues and neighboring
residues are candidates for substitution according to the techniques elaborated herein.
Once such variants are generated, the panel of variants is subjected to screening as
described herein and antibodies with superior properties in one or more nt assays
may be selected for r development.
Another type of amino acid t of the antibody alters the original glycosylation
n of the antibody. By "altering" is meant deleting one or more carbohydrate
moieties found in the antibody, and/or adding one or more glycosylation sites that are
not present in the antibody.
In some embodiments, it may be desirable to modify the antibodies of the ion to
add glycosylations sites. Glycosylation of antibodies is typically either N-linked or O-
linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of
an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-
X-threonine, where X is any amino acid except proline, are the recognition sequences
for enzymatic attachment of the carbohydrate moiety to the asparagine side chain.
Thus, the presence of either of these tripeptide ces in a polypeptide creates a
potential glycosylation site. O-linked ylation refers to the attachment of one of the
sugars N-aceylgalactosamine, galactose, or xylose to a hydroxyamino acid, most
commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also
be used. Thus, in order to glycosylate a given protein, e.g., an antibody, the amino acid
sequence of the protein is engineered to contain one or more of the above-described
tripeptide sequences (for N-linked glycosylation sites). The alteration may also be made
by the addition of, or substitution by, one or more serine or threonine residues to the
sequence of the original antibody (for O-linked glycosylation sites).
Nucleic acid les ng amino acid sequence variants of the anti-IL-36R
antibody are prepared by a variety of methods known in the art. These methods include,
but are not limited to, isolation from a natural source (in the case of naturally occurring
amino acid sequence variants) or preparation by oligonucleotide-mediated (or site-
ed) mutagenesis, PCR mutagenesis, and cassette mutagenesis of an earlier
prepared variant or a non-variant n of the anti-IL-36R antibody.
Polynucleotides, Vectors, Host Cells, and Recombinant Methods
Other embodiments encompass isolated polynucleotides that comprise a sequence
encoding a humanized anti-IL-36R antibody, vectors, and host cells comprising the
polynucleotides, and recombinant techniques for production of the humanized antibody.
The isolated polynucleotides can encode any desired form of the anti-IL-36R antibody
including, for example, full length monoclonal antibodies, Fab, Fab', F(ab')2, and Fv
fragments, diabodies, linear antibodies, single-chain antibody molecules, and
multispecific antibodies formed from dy fragments.
Some embodiments include isolated polynucleotides comprising sequences that encode
the light chain variable region of an antibody or antibody fragment having the amino
acid sequence of any of SEQ ID NO: SEQ ID 0. Some embodiments include
isolated polynucleotides comprising sequences that encode the heavy chain variable
region of an antibody or dy fragment having the amino acid sequence of SEQ ID
Some embodiments include ed polynucleotides comprising ces that encode
the light chain variable region of an antibody or antibody fragment having the amino
acid sequence of any of SEQ ID NQ:76-86. Some embodiments include isolated
polynucleotides comprising ces that encode the heavy chain variable region of
an antibody or antibody fragment having the amino acid ce of SEQ ID NO: 87-
101.
Some embodiments include isolated polynucleotides comprising sequences that encode
the light chain of an dy having the amino acid sequence of any of SEQ ID
NO:114-124. Some embodiments include isolated cleotides comprising
sequences that encode the heavy chain of an antibody having the amino acid sequence
of SEQ ID NO:125-139.
In one aspect, the isolated polynucleotide sequence(s) encodes an antibody or antibody
fragment having a light chain and a heavy chain variable region sing the amino
acid sequences of SEQ ID NO:115 and SEQ ID NO:127, respectively; SEQ ID NO:118
and SEQ ID NO:126, respectively; SEQ ID NO:118 and SEQ ID NO:127, respectively;
SEQ ID NO:115 and SEQ ID NO:125, respectively; SEQ ID NO:115 and SEQ ID
NO:126, respectively; SEQ ID NO:118 and SEQ ID NO:125, respectively; SEQ ID
NO:124 and SEQ ID , tively; SEQ ID NO:123 and SEQ ID NO:139,
tively; SEQ ID NO:123 and SEQ ID NO:138, respectively.
The polynucleotide(s) that comprise a sequence encoding a humanized anti-lL-36R
antibody or a fragment or chain thereof can be fused to one or more regulatory or
control sequence, as known in the art, and can be contained in suitable expression
vectors or host cell as known in the art. Each of the polynucleotide molecules encoding
the heavy or light chain variable domains can be ndently fused to a
polynucleotide sequence ng a constant domain, such as a human constant
domain, enabling the production of intact antibodies. Alternatively, polynucleotides, or
ns thereof, can be fused together, providing a template for production of a single
chain antibody.
For recombinant tion, a polynucleotide encoding the antibody is inserted into a
replicable vector for cloning (amplification of the DNA) or for sion. Many suitable
vectors for expressing the recombinant antibody are available. The vector components
generally include, but are not limited to, one or more of the following: a signal sequence,
an origin of replication, one or more marker genes, an enhancer element, a promoter,
and a transcription termination sequence.
The humanized anti-lL-36R antibodies can also be produced as fusion ptides, in
which the antibody is fused with a heterologous polypeptide, such as a signal sequence
or other polypeptide having a specific cleavage site at the amino terminus of the mature
protein or polypeptide. The heterologous signal sequence selected is typically one that
is recognized and processed (i.e., cleaved by a signal ase) by the host cell. For
prokaryotic host cells that do not recognize and process the humanized anti-lL-36R
antibody signal sequence, the signal sequence can be substituted by a prokaryotic
signal sequence. The signal sequence can be, for example, alkaline phosphatase,
penicillinase, otein, heat-stable enterotoxin ll leaders, and the like. For yeast
ion, the native signal sequence can be substituted, for example, with a leader
sequence obtained from yeast invertase alpha-factor (including romyces and
Kluyveromyces or leaders), acid phosphatase, C. albicans glucoamylase, or the
signal described in 3646. In mammalian cells, mammalian signal sequences as
well as viral secretory leaders, for example, the herpes simplex gD signal, can be used.
The DNA for such precursor region is ligated in reading frame to DNA encoding the
humanized anti-lL-36R antibody.
Expression and cloning vectors contain a nucleic acid sequence that enables the vector
to replicate in one or more selected host cells. Generally, in cloning vectors this
sequence is one that enables the vector to replicate independently of the host
somal DNA, and includes origins of replication or autonomously replicating
sequences. Such sequences are well known for a variety of bacteria, yeast, and
viruses. The origin of ation from the plasmid pBR322 is suitable for most Gram-
negative bacteria, the 2—1). plasmid origin is le for yeast, and various viral origins
(SV40, polyoma, adenovirus, VSV, and BPV) are useful for cloning vectors in
mammalian cells. Generally, the origin of replication component is not needed for
mammalian expression vectors (the SV4O origin may typically be used only because it
contains the early promoter).
Expression and cloning vectors may contain a gene that encodes a selectable marker to
facilitate fication of expression. Typical selectable marker genes encode proteins
that confer resistance to antibiotics or other toxins, e.g., ampicillin, in,
methotrexate, or tetracycline, or alternatively, are ment auxotrophic deficiencies,
or in other atives supply specific nutrients that are not present in complex media,
e.g., the gene ng D-alanine racemase for Bacilli.
One example of a selection scheme es a drug to arrest growth of a host cell. Those
cells that are successfully transformed with a heterologous gene produce a n
conferring drug ance and thus survive the selection regimen. Examples of such
dominant selection use the drugs neomycin, mycophenolic acid, and hygromycin.
Common selectable markers for mammalian cells are those that enable the
fication of cells competent to take up a nucleic acid encoding a humanized anti-IL-
36R antibody, such as DHFR (dihydrofolate reductase), thymidine kinase,
metallothionein-l and -II (such as primate metallothionein genes), adenosine
deaminase, ornithine decarboxylase, and the like. Cells transformed with the DHFR
selection gene are first identified by culturing all of the transformants in a culture
medium that contains methotrexate (Mtx), a competitive antagonist of DHFR. An
appropriate host cell when wild-type DHFR is employed is the Chinese hamster ovary
(CHO) cell line deficient in DHFR activity (e.g., DG44).
Alternatively, host cells (particularly wild-type hosts that contain endogenous DHFR)
ormed or co-transformed with DNA sequences encoding anti-lL-36R antibody,
wild-type DHFR protein, and another selectable marker such as aminoglycoside 3'-
phosphotransferase (APH), can be selected by cell growth in medium containing a
ion agent for the selectable marker such as an aminoglycosidic otic, e.g.,
kanamycin, neomycin, or G418. See, e.g., U.S. Pat. No. 4,965,199.
Where the inant production is performed in a yeast cell as a host cell, the TRP1
gene present in the yeast plasmid YRp7 (Stinchcomb et al., 1979, Nature 282: 39) can
be used as a selectable marker. The TRP1 gene provides a ion marker for a
mutant strain of yeast lacking the ability to grow in tryptophan, for example, ATCC No.
44076 or PEP4-1 (Jones, 1977, Genetics 85:12). The presence of the trp1 lesion in the
yeast host cell genome then provides an effective environment for detecting
transformation by growth in the absence of phan. Similarly, Leu2p-deficient yeast
strains such as ATCC 20,622 and 38,626 are complemented by known plasmids
bearing the LEU2 gene.
In addition, vectors derived from the 1.6 pm ar plasmid pKD1 can be used for
transformation of Kluyveromyces . Alternatively, an expression system for large-
scale production of recombinant calf chymosin was ed for K. lactis (Van den Berg,
1990, Bio/Technology 8:135). Stable multi-copy expression vectors for secretion of
mature recombinant human serum albumin by industrial strains of Kluyveromyces have
also been disclosed (Fleer et al., 1991, Bio/Technology 9:968—975).
Expression and cloning vectors usually contain a promoter that is recognized by the
host organism and is operably linked to the nucleic acid molecule ng an anti-IL-
36R antibody or polypeptide chain thereof. Promoters suitable for use with prokaryotic
hosts include phoA promoter, B-lactamase and lactose promoter systems, alkaline
phosphatase, tryptophan (trp) promoter system, and hybrid promoters such as the tac
promoter. Other known bacterial promoters are also suitable. Promoters for use in
bacterial systems also will contain a Shine-Dalgarno (S.D.) sequence operably linked to
the DNA encoding the humanized L-36R antibody.
Many eukaryotic promoter sequences are known. Virtually all eukaryotic genes have an
AT-rich region d imately 25 to 30 bases upstream from the site where
ription is initiated. Another sequence found 70 to 80 bases upstream from the
start of transcription of many genes is a CNCAAT region where N may be any
nucleotide. At the 3' end of most eukaryotic genes is an AATAAA sequence that may be
the signal for addition of the poly A tail to the 3' end of the coding sequence. All of these
sequences are suitably inserted into eukaryotic expression vectors.
Examples of suitable promoting sequences for use with yeast hosts include the
promoters for 3-phosphoglycerate kinase or other glycolytic s, such as enolase,
glyceraldehydephosphate dehydrogenase, hexokinase, te decarboxylase,
ofructokinase, glucosephosphate isomerase, 3-phosphoglycerate mutase,
pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase, and
inase.
lnducible ers have the additional advantage of transcription controlled by growth
conditions. These include yeast promoter s for alcohol dehydrogenase 2,
isocytochrome C, acid phosphatase, derivative enzymes ated with nitrogen
lism, metallothionein, glyceraldehydephosphate dehydrogenase, and
enzymes responsible for maltose and galactose utilization. Suitable vectors and
promoters for use in yeast expression are further described in EP . Yeast
enhancers also are advantageously used with yeast promoters.
Humanized anti-lL-36R antibody transcription from vectors in mammalian host cells is
controlled, for example, by promoters obtained from the genomes of viruses such as
polyoma virus, fowlpox virus, adenovirus (such as Adenovirus 2), bovine papilloma
virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian
Virus 40 (SV40), from heterologous mammalian promoters, e.g., the actin promoter or
an immunoglobulin promoter, or from heat-shock promoters, provided such ers
are compatible with the host cell systems.
The early and late promoters of the SV40 virus are conveniently obtained as an SV4O
restriction fragment that also contains the SV40 viral origin of replication. The ate
early promoter of the human cytomegalovirus is conveniently obtained as a Hindlll E
restriction fragment. A system for expressing DNA in mammalian hosts using the bovine
papilloma virus as a vector is disclosed in U.S. Pat. No. 4,419,446. A modification of this
system is described in U.S. Pat. No. 4,601,978. See also Reyes et al., 1982, Nature
297:598—601, disclosing expression of human p-interferon cDNA in mouse cells under
the control of a thymidine kinase promoter from herpes simplex virus. Alternatively, the
Rous a virus long terminal repeat can be used as the promoter.
Another useful element that can be used in a recombinant expression vector is an
enhancer sequence, which is used to se the transcription of a DNA encoding a
humanized anti-lL-36R antibody by higher eukaryotes. Many enhancer sequences are
now known from ian genes (e.g., globin, elastase, albumin, d-fetoprotein, and
insulin). Typically, however, an enhancer from a otic cell virus is used. es
include the SV40 enhancer on the late side of the replication origin (bp 0), the
cytomegalovirus early er enhancer, the polyoma enhancer on the late side of the
replication origin, and adenovirus enhancers. See also Yaniv, 1982, Nature -18
for a description of ing elements for activation of eukaryotic ers. The
enhancer may be spliced into the vector at a position 5' or 3' to the humanized anti-IL-
36R antibody-encoding sequence, but is preferably located at a site 5' from the
promoter.
2012/064933
Expression vectors used in eukaryotic host cells (yeast, fungi, insect, plant, animal,
human, or nucleated cells from other multicellular organisms) can also contain
sequences necessary for the termination of transcription and for stabilizing the mRNA.
Such sequences are commonly available from the 5' and, occasionally 3', untranslated
s of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide
segments ribed as polyadenylated nts in the untranslated portion of the
mRNA encoding anti-lL-36R antibody. One useful transcription termination component
is the bovine growth hormone polyadenylation region. See WO94/11026 and the
expression vector disclosed therein. In some embodiments, humanized anti-lL-36R
antibodies can be expressed using the CHEF system. (See, e.g., US. Pat. No.
,888,809; the disclosure of which is incorporated by reference herein.)
Suitable host cells for cloning or expressing the DNA in the vectors herein are the
prokaryote, yeast, or higher ote cells described above. le prokaryotes for
this purpose include eubacteria, such as Gram-negative or Gram-positive sms,
for example, Enterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter,
EnNinia, Klebsiella, Proteus, Salmonella, e.g., ella typhimurium, Serratia, e.g.,
Serratia marcescans, and Shigella, as well as Bacilli such as B. subtilis and B.
licheniformis (e.g., B. licheniformis 41 P disclosed in DD 266,710 published Apr. 12,
1989), Pseudomonas such as P. aeruginosa, and omyces. One preferred E. coli
cloning host is E. coli 294 (ATCC 31,446), although other strains such as E. coli B, E.
coli X1776 (ATCC 31,537), and E. coli W3110 (ATCC 27,325) are suitable. These
examples are illustrative rather than limiting.
In on to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are
le g or expression hosts for humanized anti-lL-36Rantibody-encoding
vectors. Saccharomyces cerevisiae, or common baker's yeast, is the most commonly
used among lower eukaryotic host microorganisms. However, a number of other
genera, species, and strains are commonly available and useful herein, such as
Schizosaccharomyces pombe; Kluyveromyces hosts such as, e.g., K. lactis, K. fragilis
(ATCC 12,424), K. bulgaricus (ATCC 16,045), K. wickeramii (ATCC 24,178), K. waltii
(ATCC 56,500), K. drosophilarum (ATCC 36,906), K. thermotolerans, and K. marxianus;
yarrowia (EP 402,226); Pichia pastors (EP 183,070); a; Trichoderma reesia (EP
244,234); Neurospora crassa; Schwanniomyces such as Schwanniomyces occidentalis;
and filamentous fungi such as, e.g., Neurospora, Penicillium, Tolypocladium, and
Aspergillus hosts such as A. nidulans and A. niger.
Suitable host cells for the expression of glycosylated humanized anti-lL-36R antibody
are derived from multicellular organisms. Examples of invertebrate cells include plant
and insect cells, including, e.g., numerous baculoviral strains and variants and
corresponding permissive insect host cells from hosts such as Spodoptera frugiperda
(caterpillar), Aedes aegypti (mosquito), Aedes albopictus (mosquito), Drosophila
melanogaster (fruitfly), and Bombyx mori (silk worm). A variety of viral s for
transfection are ly available, e.g., the L-1 variant of Autographa californica NPV
and the Bm-5 strain of Bombyx mori NPV, and such viruses may be used, particularly
for transfection of Spodoptera frugiperda cells.
Plant cell es of cotton, corn, potato, soybean, petunia, tomato, and tobacco can
also be utilized as hosts.
In another aspect, expression of humanized anti-lL-36R is carried out in vertebrate
cells. The propagation of vertebrate cells in culture (tissue e) has become routine
procedure and techniques are widely ble. es of useful mammalian host cell
lines are monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651),
human embryonic kidney line (293 or 293 cells subcloned for growth in suspension
e, (Graham et al., 1977, J. Gen Virol. 36: 59), baby r kidney cells (BHK,
ATCC CCL 10), Chinese hamster ovary cells/-DHFR1 (CHO, Urlaub et al., 1980, Proc.
Natl. Acad. Sci. USA 77: 4216; e.g., DG44), mouse sertoli cells (TM4, Mather, 1980,
Biol. Reprod. 23:243-251), monkey kidney cells (CV1 ATCC CCL 70), African green
monkey kidney cells (VERO-76, ATCC CRL-1587), human al oma cells
(HELA, ATCC CCL 2), canine kidney cells (MDCK, ATCC CCL 34), buffalo rat liver cells
(BRL 3A, ATCC CRL 1442), human lung cells (W138, ATCC CCL 75), human liver cells
(Hep G2, HB 8065), mouse mammary tumor (MMT 060562, ATCC CCL51), TR1 cells
(Mather et al., 1982, Annals NY. Acad. Sci. 383: 44-68), MRC 5 cells, FS4 cells, and
human hepatoma line (Hep G2).
Host cells are transformed with the above-described expression or cloning vectors for
humanized anti-lL-36R antibody production and ed in conventional nutrient media
modified as appropriate for inducing promoters, selecting transformants, or amplifying
the genes encoding the desired sequences.
The host cells used to produce a humanized L-36R antibody described herein may
be cultured in a variety of media. Commercially available media such as Ham's F10
(Sigma-Aldrich Co., St. Louis, Mo.), Minimal Essential Medium , (Sigma-Aldrich
Co.), RPMl-1640 (Sigma-Aldrich Co.), and Dulbecco's Modified Eagle's Medium
((DMEM), Sigma-Aldrich Co.) are suitable for culturing the host cells. In addition, any of
the media described in one or more of Ham et al., 1979, Meth. Enz. 58: 44, Barnes et
al., 1980, Anal. Biochem. 102: 255, U.S. Pat. No. 4,767,704, U.S. Pat. No. 4,657,866,
U.S. Pat. No. 4,927,762, U.S. Pat. No. 4,560,655, U.S. Pat. No. 5,122,469, WO
90/103430, and WO 87/00195 may be used as culture media for the host cells. Any of
these media may be supplemented as ary with hormones and/or other growth
factors (such as insulin, errin, or epidermal growth factor), salts (such as sodium
chloride, calcium, magnesium, and phosphate), buffers (such as HEPES), nucleotides
(such as adenosine and thymidine), antibiotics (such as gentamicin), trace elements
(defined as inorganic compounds usually present at final concentrations in the
micromolar range), and glucose or an equivalent energy source. Other supplements
may also be included at appropriate concentrations that would be known to those skilled
in the art. The e conditions, such as temperature, pH, and the like, are those
usly used with the host cell selected for expression, and will be apparent to the
ordinarily skilled n.
When using recombinant techniques, the antibody can be produced intracellularly, in
the periplasmic space, or directly secreted into the medium. If the dy is ed
intracellularly, the cells may be ted to release protein as a first step. Particulate
debris, either host cells or lysed fragments, can be removed, for e, by
centrifugation or ultrafiltration. Carter et al., 1992, Bio/Technology 10:163-167 describes
a procedure for isolating antibodies that are secreted to the asmic space of E. coli.
Briefly, cell paste is thawed in the presence of sodium acetate (pH 3.5), EDTA, and
phenylmethylsulfonylfluoride (PMSF) over about 30 minutes. Cell debris can be
WO 74569
removed by centrifugation. Where the antibody is secreted into the medium,
supernatants from such expression systems are generally first concentrated using a
commercially available protein concentration filter, for example, an Amicon or Millipore
Pellicon iltration unit. A protease inhibitor such as PMSF may be ed in any of
the foregoing steps to inhibit proteolysis and antibiotics may be included to prevent the
growth of adventitious contaminants. A variety of methods can be used to e the
antibody from the host cell.
The antibody composition ed from the cells can be purified using, for example,
hydroxylapatite chromatography, gel electrophoresis, dialysis, and affinity
chromatography, with affinity chromatography being a typical purification technique. The
suitability of protein A as an affinity ligand depends on the s and isotype of any
immunoglobulin Fc domain that is t in the antibody. Protein A can be used to
purify antibodies that are based on human gamma1, gamma2, or gamma4 heavy
chains (see, e.g., Lindmark et al., 1983 J. lmmunol. Meth. 62:1-13). Protein G is
recommended for all mouse es and for human gamma3 (see, e.g., Guss et al.,
1986 EMBO J. 5:1567-1575). A matrix to which an affinity ligand is attached is most
often agarose, but other matrices are available. Mechanically stable matrices such as
controlled pore glass or poly(styrenedivinyl)benzene allow for faster flow rates and
shorter processing times than can be achieved with agarose. Where the antibody
ses a CH3 domain, the Bakerbond ABXTM resin (J. T. Baker, Phillipsburg, NJ.) is
useful for purification. Other techniques for protein purification such as fractionation on
an ion-exchange column, ethanol precipitation, reverse phase HPLC, tography
on silica, tography on heparin SEPHAROSETM chromatography on an anion or
cation exchange resin (such as a polyaspartic acid column), chromatofocusing, SDS—
PAGE, and ammonium sulfate precipitation are also available depending on the
antibody to be recovered.
Following any preliminary cation step(s), the mixture comprising the dy of
interest and contaminants may be subjected to low pH hydrophobic interaction
chromatography using an elution buffer at a pH between about 2.5-4.5, typically
performed at low salt concentrations (e.g., from about 0-0.25M salt).
Also included are nucleic acids that hybridize under low, moderate, and high stringency
conditions, as d herein, to all or a portion (e.g., the portion encoding the variable
) of the nucleotide sequence represented by isolated polynucleotide ce(s)
that encode an antibody or antibody fragment of the present invention.The hybridizing
portion of the hybridizing nucleic acid is typically at least 15 (e.g., 20, 25, 30 or 50)
nucleotides in length. The hybridizing portion of the izing nucleic acid is at least
80%, e.g., at least 90%, at least 95%, or at least 98%, identical to the sequence of a
portion or all of a nucleic acid ng an anti-lL-36R polypeptide (e.g., a heavy chain
or light chain variable region), or its complement. Hybridizing nucleic acids of the type
described herein can be used, for e, as a cloning probe, a primer, e.g., a PCR
, or a diagnostic probe.
Non-Therapeutic Uses
The antibodies described herein are useful as affinity purification agents. In this
process, the antibodies are immobilized on a solid phase such a Protein A resin, using
methods well known in the art. The immobilized antibody is contacted with a sample
containing the lL-36R protein (or fragment thereof) to be ed, and thereafter the
support is washed with a suitable solvent that will remove substantially all the material in
the sample except the lL-36R n, which is bound to the immobilized antibody.
y, the t is washed with another suitable solvent that will release the lL-36R
protein from the antibody.
Anti-lL-36R antibodies, for example humanized anti-lL-36R antibodies, are also useful
in diagnostic assays to detect and/or quantify lL-36R protein, for example, detecting lL-
36R expression in specific cells, tissues, or serum. The anti-lL-36R dies can be
used diagnostically to, for example, monitor the development or progression of a
disease as part of a clinical testing procedure to, e.g., determine the cy of a given
treatment and/or prevention regimen. Detection can be tated by coupling the anti-
lL-36R antibody. Examples of detectable substances include various enzymes,
prosthetic groups, fluorescent materials, luminescent materials, bioluminescent
materials, radioactive materials, positron emitting metals using various positron
emission tomographies, and nonradioactive paramagnetic metal ions. See, for
example, U.S. Patent No. 4,741,900 for metal ions which can be conjugated to
antibodies for use as diagnostics according to the present ion.
The anti-lL-36R antibodies can be used in methods for diagnosing an lL-36R-
associated disorder (e.g., a disorder characterized by abnormal expression of lL-36R)
or to determine if a subject has an increased risk of ping an lL-36R-associated
disorder. Such methods include ting a biological sample from a subject with an
lL-36R antibody and detecting binding of the antibody to lL-36R. By "biological sample"
is intended any biological sample obtained from an individual, cell line, tissue culture, or
other source of cells potentially sing lL-36R. Methods for obtaining tissue
biopsies and body fluids from mammals are well known in the art.
In some embodiments, the method can further comprise comparing the level of lL-36R
in a patient sample to a control sample (e.g., a t that does not have an -
associated er) to determine if the patient has an lL-36R-associated er or is
at risk of developing an lL-36R-associated disorder.
It will be advantageous in some ments, for example, for diagnostic purposes to
label the antibody with a detectable moiety. Numerous detectable labels are available,
including radioisotopes, scent labels, enzyme substrate labels and the like. The
label may be indirectly conjugated with the dy using various known techniques.
For example, the antibody can be conjugated with biotin and any of the three broad
categories of labels mentioned above can be conjugated with avidin, or vice versa.
Biotin binds selectively to avidin and thus, the label can be conjugated with the antibody
in this indirect manner. Alternatively, to achieve indirect conjugation of the label with the
antibody, the antibody can be conjugated with a small hapten (such as digoxin) and one
of the different types of labels mentioned above is conjugated with an anti-hapten
antibody (e.g., anti-digoxin antibody). Thus, indirect conjugation of the label with the
antibody can be achieved.
Exemplary sotopes labels include 358, 14C, 125l, 3H, and 131l. The dy can be
labeled with the radioisotope, using the ques described in, for example, Current
Protocols in Immunology, Volumes 1 and 2, 1991, Coligen et al., Ed. Wiley-lnterscience,
New York, N.Y., Pubs. Radioactivity can be measured, for example, by scintillation
couang.
Exemplary fluorescent labels include labels d from rare earth chelates (europium
es) or fluorescein and its derivatives, rhodamine and its derivatives, dansyl,
Lissamine, phycoerythrin, and Texas Red are available. The fluorescent labels can be
conjugated to the antibody via known techniques, such as those disclosed in Current
Protocols in Immunology, for example. Fluorescence can be quantified using a
fluorimeter.
There are various well-characterized enzyme-substrate labels known in the art (see,
e.g., U.S. Pat. No. 4,275,149 for a review). The enzyme generally catalyzes a al
alteration of the chromogenic substrate that can be measured using various techniques.
For example, alteration may be a color change in a ate that can be ed
spectrophotometrically. Alternatively, the enzyme may alter the fluorescence or
chemiluminescence of the substrate. Techniques for fying a change in
fluorescence are described above. The chemiluminescent substrate becomes
electronically excited by a chemical reaction and may then emit light that can be
measured, using a chemiluminometer, for example, or donates energy to a fluorescent
acceptor.
Examples of enzymatic labels include luciferases such as firefly luciferase and bacterial
luciferase (U.S. Pat. No. 4,737,456), luciferin, 2,3-dihydrophthalazinediones, malate
dehydrogenase, urease, peroxidase such as horseradish dase (HRPO), alkaline
phosphatase, B-galactosidase, glucoamylase, lysozyme, saccharide es (such as
glucose e, galactose oxidase, and glucosephosphate dehydrogenase),
heterocydic oxidases (such as uricase and xanthine oxidase), lactoperoxidase,
eroxidase, and the like. Techniques for conjugating enzymes to dies are
described, for example, in O'Sullivan et al., 1981, Methods for the Preparation of
Enzyme-Antibody Conjugates for use in Enzyme Immunoassay, in Methods in Enzym.
(J. Langone & H. Van s, eds.), Academic press, N.Y., 73: 147-166.
Examples of enzyme-substrate combinations include, for example: Horseradish
dase (HRPO) with hydrogen peroxidase as a substrate, wherein the hydrogen
peroxidase oxidizes a dye precursor such as orthophenylene diamine (OPD) or
3,3',5,5'-tetramethyl benzidine hydrochloride (TMB); alkaline phosphatase (AP) with
para-Nitrophenyl phosphate as chromogenic substrate; and B-D-galactosidase (B-D-
Gal) with a chromogenic ate such as p-nitrophenyl-B-D-galactosidase or
fluorogenic substrate 4-methylumbelliferyl-B-D-galactosidase.
Numerous other enzyme-substrate combinations are available to those skilled in the art.
For a general review of these, see U.S. Pat. No. 4,275,149 and U.S. Pat. No.
4,318,980.
In another embodiment, the humanized anti-lL-36R antibody is used unlabeled and
ed with a labeled antibody that binds the humanized anti-lL-36R dy.
The antibodies described herein may be employed in any known assay method, such
as itive binding assays, direct and indirect sandwich assays, and
immunoprecipitation assays. See, e.g., Zola, Monoclonal Antibodies: A Manual of
Techniques, pp. 147-158 (CRC Press, Inc. 1987).
The anti-lL-36R antibody or antigen g fragment thereof can be used to inhibit the
binding of ligand to the lL-36 receptor. Such s comprise stering an anti-
lL-36R antibody or antigen binding fragment thereof to a cell (e.g., a mammalian cell) or
cellular environment, whereby signaling mediated by the lL-36 receptor is inhibited.
These s can be performed in vitro or in vivo. By lar environment” is
intended the tissue, medium, or extracellular matrix surrounding a cell. The L-36R
antibody or antigen binding fragment thereof is administered to the cellular nment
of a cell in such a manner that the antibody or fragment is capable of binding to lL-36R
molecules outside of and surrounding the cell, therefore, preventing the binding of lL-36
ligand to its or.
Diagnostic Kits
An anti-lL-36R antibody can be used in a diagnostic kit, Le, a packaged combination of
reagents in predetermined amounts with instructions for ming the diagnostic
assay. Where the antibody is labeled with an enzyme, the kit may include substrates
WO 74569
and cofactors required by the enzyme such as a ate precursor that provides the
detectable chromophore or fluorophore. In addition, other additives may be included
such as stabilizers, buffers (for example a block buffer or lysis buffer), and the like. The
relative amounts of the various reagents may be varied widely to provide for
concentrations in solution of the reagents that substantially optimize the sensitivity of
the assay. The reagents may be provided as dry powders, usually lyophilized, including
excipients that on dissolution will provide a reagent solution having the appropriate
concentration.
Therapeutic Uses
In another embodiment, a humanized anti-lL-36R antibody disclosed herein is useful in
the treatment of various ers associated with the expression of lL-36R as
described herein. Methods for treating an lL-36R associated disorder comprise
administering a therapeutically effective amount of a humanized anti-lL-36R antibody to
a t in need f.
The humanized anti-lL-36R antibody or agent is administered by any suitable means,
including parenteral, subcutaneous, intraperitoneal, intrapulmonary, and asal, and,
if desired for local immunosuppressive treatment, intralesional stration ding
perfusing or otherwise contacting the graft with the antibody before transplantation). The
humanized anti-lL-36R antibody or agent can be administered, for e, as an
infusion or as a bolus. Parenteral infusions e uscular, intravenous,
intraarterial, eritoneal, or subcutaneous administration. In addition, the humanized
anti-lL-36R antibody is suitably administered by pulse infusion, particularly with
declining doses of the antibody. In one , the dosing is given by injections, most
preferably intravenous or subcutaneous injections, depending in part on whether the
administration is brief or chronic.
For the prevention or treatment of disease, the appropriate dosage of antibody will
depend on a variety of factors such as the type of disease to be treated, as defined
above, the severity and course of the disease, whether the antibody is administered for
preventive or therapeutic purposes, previous therapy, the patients clinical history and
response to the antibody, and the discretion of the attending physician. The dy is
suitably administered to the patient at one time or over a series of treatments.
Depending on the type and severity of the disease, about 1 ug/kg to 20 mg/kg (e.g., 0.1-
mg/kg) of antibody is an initial candidate dosage for stration to the patient,
whether, for example, by one or more separate administrations, or by continuous
infusion. A typical daily dosage might range from about 1 ug/kg to 100 mg/kg or more,
depending on the factors mentioned above. For repeated administrations over several
days or longer, depending on the condition, the treatment is ned until a desired
ssion of disease symptoms occurs. However, other dosage regimens may be
. The progress of this therapy is easily monitored by conventional techniques and
assays. An ary dosing regimen is that disclosed in WO 94/04188.
The term “suppression” is used herein in the same context as “amelioration” and
“alleviation” to mean a lessening of one or more characteristics of the disease.
The antibody composition will be formulated, dosed, and administered in a fashion
consistent with good medical practice. Factors for consideration in this context include
the particular disorder being treated, the ular mammal being treated, the clinical
condition of the individual patient, the cause of the disorder, the site of delivery of the
agent, the method of administration, the scheduling of administration, and other factors
known to medical practitioners. The "therapeutically effective amount" of the antibody to
be administered will be governed by such considerations, and is the minimum amount
necessary to prevent, ameliorate, or treat the disorder associated with lL-36R
expression.
The antibody need not be, but is ally, formulated with one or more agents
currently used to prevent or treat the er in on. The effective amount of such
other agents depends on the amount of humanized anti-lL-36R23p19 antibody present
in the formulation, the type of disorder or treatment, and other factors discussed above.
These are generally used in the same dosages and with stration routes as used
hereinbefore or about from 1 to 99% of the heretofore employed dosages.
ceutical Compositions and Administration Thereof
A composition comprising an IL-36R binding agent (e.g., an anti-IL-36R antibody) can
be administered to a subject having or at risk of having an immunological disorder,
respiratory disorder or a cancer. The invention further provides for the use of a IL-36R
binding agent (e.g., an anti-IL-36R antibody) in the cture of a medicament for
tion or treatment of a cancer , atory disorder or immunological disorder.
The term ct" as used herein means any mammalian patient to which an IL-
36Rbinding agent can be administered, including, e.g., humans and non-human
mammals, such as primates, rodents, and dogs. Subjects specifically intended for
treatment using the methods described herein include humans. The antibodies or
agents can be administered either alone or in combination with other compositions in
the prevention or treatment of the immunological disorder, respiratory disorder or
cancer. Such compositions which can be administered in ation with the
antibodies or agents include methotrexate (MTX) and immunomodulators, e.g.
antibodies or small molecules.
Examples of antibodies for use in such ceutical compositions are those that
comprise a antibody or antibody fragment having the light chain variable region amino
acid sequence of any of SEQ ID NO: 1-10. Examples of antibodies for use in such
pharmaceutical compositions are also those that comprise a zed antibody or
antibody fragment having the heavy chain variable region amino acid sequence of any
of SEQ ID NO:11-20.
r es of antibodies for use in such pharmaceutical compositions are also
those that comprise a humanized antibody or antibody fragment having the light chain
variable region amino acid sequence of any of SEQ ID NQ:76-86. Preferred antibodies
for use in such pharmaceutical compositions are also those that comprise a humanized
antibody or antibody fragment having the heavy chain variable region amino acid
sequence of any of SEQ ID NO:87-101.
Further es of antibodies for use in such pharmaceutical compositions are also
those that comprise a humanized antibody or antibody fragment having the light chain
le region and heavy chain variable region of any of SEQ ID NO: 77 and 89, SEQ
ID NO: 80 and 88, SEQ ID NO: 80 and 89, SEQ ID NO: 77 and 87, SEQ ID NO: 77 and
88, SEQ ID NO: 80 and 87, SEQ ID NO: 86 and 100, SEQ ID NO: 85 and 101, or SEQ
ID NO: 85 and 10.
Further examples of antibodies for use in such pharmaceutical compositions are also
those that comprise a humanized antibody having the light chain region amino acid
sequence of any of SEQ ID NO:115, 118, 123 or 124. Preferred dies for use in
such pharmaceutical compositions are also those that comprise humanized dy
having the heavy chain variable region amino acid sequence of any of SEQ ID NO:125,
126,127,138 or 139.
Further examples of antibodies for use in such pharmaceutical compositions are also
those that comprise Antibody B1, Antibody B2, Antibody B3, Antibody B4, Antibody B5,
Antibody B6, Antibody C1, dy C2 or dy C3.
Various delivery systems are known and can be used to administer the lL-36R g
agent. Methods of introduction include but are not limited to intradermal, intramuscular,
intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The IL-
36R binding agent can be stered, for example by infusion, bolus or injection, and
can be administered together with other biologically active agents such as
herapeutic . Administration can be systemic or local. In preferred
embodiments, the administration is by subcutaneous injection. Formulations for such
injections may be prepared in for example prefilled syringes that may be administered
once every other week.
In specific embodiments, the lL-36R binding agent composition is administered by
injection, by means of a catheter, by means of a suppository, or by means of an implant,
the implant being of a porous, non-porous, or gelatinous material, including a
membrane, such as a sialastic ne, or a fiber. Typically, when administering the
composition, materials to which the anti-lL-36R antibody or agent does not absorb are
used.
In other embodiments, the anti-lL-36R antibody or agent is red in a controlled
release system. In one embodiment, a pump may be used (see, e.g., Langer, 1990,
Science 249:1527-1533; Sefton, 1989, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald
et al., 1980, Surgery 88:507; Saudek et al., 1989, N. Engl. J. Med. 321 :574). In another
embodiment, polymeric als can be used. (See, e.g., Medical Applications of
Controlled Release (Langer and Wise eds., CRC Press, Boca Raton, Fla., 1974);
lled Drug Bioavailability, Drug Product Design and Performance (Smolen and
Ball eds., Wiley, New York, 1984); Ranger and Peppas, 1983, Macromol. Sci. Rev.
Macromol. Chem. 23:61. See also Levy et al., 1985, Science 228:190; During et al.,
1989, Ann. Neurol. 25:351; Howard et al., 1989, J. urg. 71:105.) Other controlled
release systems are discussed, for example, in Langer, supra.
An lL-36R binding agent (e.g., an L-36R antibody) can be administered as
ceutical compositions comprising a therapeutically effective amount of the
binding agent and one or more pharmaceutically ible ingredients.
In typical embodiments, the pharmaceutical composition is formulated in accordance
with routine procedures as a pharmaceutical composition adapted for intravenous or
subcutaneous administration to human beings. Typically, compositions for
administration by injection are solutions in sterile ic s . Where
necessary, the pharmaceutical can also include a solubilizing agent and a local
anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the
ingredients are supplied either separately or mixed together in unit dosage form, for
example, as a dry lyophilized powder or water free concentrate in a hermetically sealed
container such as an ampoule or sachette indicating the quantity of active agent. Where
the ceutical is to be administered by infusion, it can be dispensed with an
infusion bottle containing sterile pharmaceutical grade water or saline. Where the
pharmaceutical is administered by injection, an ampoule of sterile water for injection or
saline can be provided so that the ingredients can be mixed prior to administration.
Further, the pharmaceutical composition can be ed as a pharmaceutical kit
comprising (a) a container containing a lL-36R binding agent (e.g., an anti-lL-36R
antibody) in lyophilized form and (b) a second container containing a ceutically
acceptable diluent (e.g., sterile water) for injection. The pharmaceutically acceptable
diluent can be used for reconstitution or dilution of the lyophilized L-36R antibody
or agent. Optionally associated with such container(s) can be a notice in the form
ibed by a governmental agency regulating the manufacture, use or sale of
pharmaceuticals or biological products, which notice reflects al by the agency of
manufacture, use or sale for human administration.
The amount of the lL-36R binding agent (e.g., anti-lL-36R antibody) that is ive in
the treatment or prevention of an immunological disorder or cancer can be ined
by standard clinical techniques. In addition, in vitro assays may optionally be employed
to help identify optimal dosage ranges. The precise dose to be employed in the
formulation will also depend on the route of administration, and the stage of
immunological disorder or cancer, and should be decided according to the judgment of
the practitioner and each patient's circumstances. Effective doses may be extrapolated
from dose-response curves derived from in vitro or animal model test systems.
Generally, the dosage of an anti-lL-36R dy or lL-36R g agent administered
to a patient with an immunological disorder or lL-36R-expressing cancer is typically
about 0.1 mg/kg to about 100 mg/kg of the subject's body weight. The dosage
administered to a subject is about 0.1 mg/kg to about 50 mg/kg, about 1 mg/kg to about
mg/kg, about 1 mg/kg to about 20 mg/kg, about 1 mg/kg to about 15 mg/kg, or about
1 mg/kg to about 10 mg/kg of the t's body weight.
Exemplary doses include, but are not limited to, from 1 ng/kg to 100 mg/kg. In some
embodiments, a dose is about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg,
about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9
mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14
mg/kg, about 15 mg/kg or about 16 mg/kg. The dose can be administered, for example,
daily, once per week (weekly), twice per week, thrice per week, four times per week,
five times per week, six times per week, biweekly or monthly, every two months, or
every three months. In specific embodiments, the dose is about 0.5 mg/kg/week, about
1 mg/kg/week, about 2 mg/kg/week, about 3 mg/kg/week, about 4 mg/kg/week, about 5
mg/kg/week, about 6 week, about 7 mg/kg/week, about 8 mg/kg/week, about 9
mg/kg/week, about 10 mg/kg/week, about 11 mg/kg/week, about 12 mg/kg/week, about
13 mg/kg/week, about 14 mg/kg/week, about 15 week or about 16 mg/kg/week.
In some embodiments, the dose ranges from about 1 mg/kg/week to about 15
mg/kg/week.
In some embodiments, the pharmaceutical compositions comprising the lL-36R binding
agent can further se a therapeutic agent, either conjugated or unconjugated to
the binding agent. The anti-lL-36R antibody or lL-36R g agent can be co-
administered in combination with one or more eutic agents for the treatment or
prevention of immunological disorders or cancers.
Such combination therapy administration can have an additive or synergistic effect on
disease ters (e.g., severity of a symptom, the number of symptoms, or
frequency of relapse).
With respect to therapeutic regimens for combinatorial administration, in a specific
embodiment, an anti-lL-36R antibody or lL-36R g agent is administered
concurrently with a therapeutic agent. In another specific embodiment, the therapeutic
agent is administered prior or subsequent to administration of the L-36R antibody
or lL-36R binding agent, by at least an hour and up to several months, for example at
least an hour, five hours, 12 hours, a day, a week, a month, or three months, prior or
subsequent to administration of the anti-lL-36R antibody or lL-36R binding agent.
Articles of Manufacture
In another aspect, an article of manufacture containing materials useful for the
treatment of the disorders described above is ed. The article of manufacture
ses a container and a label. Suitable containers include, for example, bottles,
vials, syringes, and test tubes. The containers may be formed from a variety of
als such as glass or plastic. The container holds a composition that is effective for
ng the condition and may have a sterile access port. For example, the container
may be an enous on bag or a vial having a stopper pierceable by a
hypodermic injection needle. The active agent in the composition is the humanized anti-
lL-36R antibody. The label on or associated with the container indicates that the
composition is used for treating the condition of choice. The article of manufacture may
WO 74569
further comprise a second container comprising a pharmaceutically-acceptable buffer,
such as phosphate-buffered saline, Ringer's solution, and dextrose solution. It may
further e other materials desirable from a commercial and user standpoint,
including other s, diluents, filters, needles, syringes, and package inserts with
instructions for use.
The invention is further described in the following examples, which are not intended to
limit the scope of the ion.
The antibodies of the present invention are further described in the Examples below.
Examples
e 1: Identification of Anti-human |L-36R Antibodies
Multiple mouse strains were immunized with recombinantly produced human lL-36R
(ECD — extracellular domain: amino acids 20-332 of Genbank Accession #NP_OO3845)
protein and those which generated a strong titer response taken into traditional
hybridoma generation. Fusion products eliciting a strong g to human lL-36R
(ECD) yet no binding to human lL-1R1 (the most d lL-1R family member) were
ned and re-screened. Multiple hybridomas were identified to yield monoclonal
antibodies which bound and lized signaling from lL-36R (see examples 2, 3, and
4). Variable domains were cloned from the hybridomas using standard PCR primer
sets. The variable domains and specific CDRs of representative monoclonal antibodies
are described above. All of the mouse antibodies were converted to chimeric
antibodies consisting of the mouse variable domains on human constant domains (hu
lthKO / kappa). The hu lngKO (Knock gut) has two replacement ons
(Leu234Ala and Leu235Ala) that eliminate ADCC and CDC activity by reducing effector
functions such as FcyR and complement binding. The variable domains of the mouse
and chimeric antibodies are identical. Chimeric antibodies are ted to confirm the
WO 74569
function of the antibody and to ensure the correct variable domain sequence has been
obtained.
Example 2: Molecular g Affinities of Identified Mouse Anti-human |L-36R
dies
A) Kinetics and binding affinities of anti-lL-36R antibodies binding to recombinant
human lL-36R were measured using the Proteon (Bio-Rad, Hercules, CA) using
material generated from hybridoma following single column purification. The binding
ties of all the mouse leads to human lL-36R run at a single lL-36R surface coat
concentration was estimated to be . The binding affinities of the mouse
antibodies to human lL-36R run at 7 different surface densities (globally fit) is shown in
Table 1. Binding of the chimeric anti-lL36R lgGs is equivalent to the respective mouse
leads.
Table 1: Binding affinity of mouse anti-human lL-36R antibodies.
Lead Binding KD (pM)
Mouse 7305 57
Mouse 73F6 25
Mouse 7808 63
Mouse 81A1 16
Mouse 81 B4 24
Mouse 33D10 9
B) Molecular selectivity over mouse lL-36R and human lL-1R1
The mouse and chimeric L-36R antibodies were also injected over either a mouse
lL-36R or a human lL-1R1 surface at a tration of 100 nM. The binding signal to
mouse lL-36R and to human lL-1R1 for these antibodies measured using the Fortebio
Octet (Fortebio, Menlo Park, CA) is zero, which indicates these antibodies selectively
bind to human lL-36R. The binding of the anti-lL-36R antibodies to human lL-36R was
2012/064933
also analyzed in the ce of 50% human serum and no significant effect of serum
on binding on-rate was observed demonstrating high specificity.
Example 3: y of mouse and chimeric anti-human |L-36R antibodies in
functional human and cynomolgus assays
Protocols: Human NCI/ADR-RES cells QNFKB/Cytokine release assa vs
Reagents:
R&D Systems: truncated rh IL36B
R&D Systems: truncated rh lL36y
R&D Systems: truncated rh lL36d:
MA6000 Phospho- NFKB (Ser536) Whole Cell Lysate Kit
Meso Scale Diagnostics, LLC
MSD ELISA custom human 96-well 4-spot assay
Meso Scale Diagnostics, LLC
NCI/ADR-RES cells were plated at 45000 cells/well, in RPMI media with 0.25% serum
in a 96well plate. One platewas utilized for the analysis of pNFKB and another for
cytokine release. The plates were then incubated overnight at 37°C, 5% C02 Ligands
(lL360c, B, or y) and antibodies were diluted at 4x desired concentration in serum starved
(SS) media. Antagonists odies) were added to cells prior to . For pNFKB:
NCI cells +/- ligand and nist were incubated for 1 hour, 37°C, 5% C02 Media
was then aspirated and cells were lysed in 100 ul/well Complete lysis Buffer on ice
30min. Lysate was then centrifuged at 2500RPM, 20min, 4°C, and transferred to an
MSD ELISA plate and assayed for pNFKB as per the manufacturer’s protocol. For
Cytokine release: 18-24 hours after stimulation, supernatants were transferred to an
MSD ELISA plate and assayed for cytokine as per manufacturer’s protocol.
Protocol: QNFKB (S5362 MSD ELISA for BaF/3 Cynomolgus lL-36R Cells
BaF/3 cynomolgus lL-36R cells were plated at 90,000 cells/well in 88 media in a 96well
plate 100 ul media was added to control wells. Antagonists (antibodies) were diluted
at 4x d concentration and 50 ul was added to each well. Ligands (lL36d, B, or 7)
were diluted at 4x desired tration in 88 media and Soul were added to each well
(for final volume of 200 pl). Plates were incubated for 15 min, 37°C, 5% COZ Plates
were fuged briefly, media was aspirated and cells were lysed in 100 ul/well
Complete Lysis Buffer (see MSD pNFKB protocol) and incubated on ice 30min. Lysates
were then centrifuged at 2500RPM, 20min, 4°C and transferred to an MSD ELISA plate.
Lysates were then evaluated for pNFKB activity using the MSD kit as described above.
s: ngo results for mouse anti-human lL-36R antibodies in human functional
assays (pNFKB and ne e) and a cynomolgus functional assay (pNFkB) with
human lL-36 ligands are shown in Table 2. IC90 results for chimeric anti-human lL-
36R dies in human functional assays (pNFKB and cytokine release) and a
cynomolgus functional assay (pNFKB) with human lL-36 ligands are shown in Table 3.
Table 2: Potency of mouse antibodies in functional cell assays
(isotype controls demonstrated no inhibition of activity at highest concentration
tested for samples)
IIIIIIIIIII7376E RES 33D10 73C5 8 8 8D1 1D1 E11 B8 B12 8
“III-”Emutrun-lL-36a
----ImmllnflflIC90(nM) 1.3 3.4 3 4.2 1.4
----III----fltrun-lL-36g
”"flfllflflflfltrun-lL-36a
---EIMII-flflfltrun-lL-36b
----I“mflflfltrun-lL-36g
”Illa-mun"trun-lL-36a
1 1 1
trun-IL-36b ND ND ND
|c90 (nM) o .5 3.8 5.1 ND 5.8 5.3 0.3
III-mun“trun-IL-36g
”In-Inn“trun-IL-36a
III-IIHMHHHtrun-IL-36b
III-“MIHHHtrun-IL-36g
IIIIII
36a -----E----pNFKB |C90 (nM) >4000 0.2 0.5 00 1 2.4 >4000 >4000 >4000
-trun-IL-geb -----m----|C90 (nM) >333 1.6 0.7 3 2.1 3.5 >333 >333 >333
-trun-IL-geg --H-------|C90 (nM) >333 1.5 3 1.5 1 5.1 >333 >333 >333
Table 3: Potency of chimeric antibodies in functional cell assays
(isotype controls demonstrated no inhibition of activity at highest concentration
tested for samples)
NCI/ADR-RES— C33D10 C73C5 C3134
IIItrun-IL-36a |C90 13
III“trun-IL-36b |C90
-—--ntrun-IL-36g |C90
IIII“trun-IL-36a |C90
IIII“trun-IL-36b |C90
IIII“trun-IL-36g |C90
IIII“trun-IL-36a |C90
IIII“trun-IL-36b |C90
III“trun-IL-36g |C90
run-IL-36a |C90
IIItrun-IL-36b |C90 0,1
1 12
trun- |L-36g |C90
(nM)
FOL (nM)
-_n-“(nM) 7.9
-—n-n(nM) 1.3
_—___
-_“-pNFKB (nM) 1.2
-_“-n(nM) 4.1
M) 4.3
Example 4: Binding of mouse anti-human lL-36R antibodies to human lL-36R
expressing cells
Protocol for bind/n of antibodies b flow 0 fomez‘r
HEK293 cells transfected with full-length human |L-36R or NCI/ADR-RES cells were
passaged for 24 hours prior to staining. Cells were removed from flasks by g with
ml of 5 mM EDTA in PBS, and then incubated at 37°C for 10 min with an additional
ml of 5 mM EDTA and 2.5 ml of Accumax to declump/disperse cells. Antibodies
were then diluted to ied concentrations in PBS + 2% BSA, and cells incubated for
min at room temperature. Excess antibody was then washed by adding 200 pl of
PBS and then centrifuged. Secondary reagent was then added at 50 pl per well and
cells are incubated for 15 min at room temperature and then washed as above. Cells
were resuspended in 200 pl PBS and analyzed by flow cytometry. The binding EC5o’s
for the mouse anti-human |L-36R dies binding to human |L-36R HEK
transfectants are shown in Table 4.
Table 4
Clone EC5O(M) binding to HEK-|L-36R
cells
33D10 4.748e-O1O
67E7 5.321 e-O1 O
73F6 7.456e- 010
76E10 4.257e-010
7808 52896-010
81A1 2.7956-010
81B4 3.0166-010
89A12 6.0896-010
Example 5: Production of Humanized |L-36R Antibodies
In order to reduce potential immunogenicity following administration in man the mouse
anti-human lL-36R monoclonal antibodies 81 B4 and 7305 were ‘humanized’ through a
design and screening process. Human framework sequences were ed for the
mouse leads based on the framework homology, CDR structure, conserved canonical
residues, conserved interface packing residues and other parameters. The specific
substitution of amino acid residues in these framework ons can improve various
aspects of antibody performance including binding ty and/or stability, over that
demonstrated in humanized antibodies formed by "direct swap" of CDRs or HVLs into
the human germline framework regions. Fabs that showed better or equal binding and
improved expression as compared to the chimeric parent Fab were selected for further
characterization. Representative humanized variable regions for antibody 81 B4 and
7305 are shown in are shown the specification n. In this manner, Antibody B1 to
dy B6 were zed antibodies derived from mouse dy 81 B4 (cloned
into a human lng KO (KO=knock-out)/kappa backbone. Antibodies B1 to B6 are
shown in Table A. Antibody Ct to Antibody 03 were humanized dies derived
from mouse antibody 7305 (cloned into a human lng -KO (KO=knock-out)/kappa
backbone. Antibodies Ct to 03 are shown in Table C.
Example 6: Binding of humanized |L-36R antibodies
Kinetics and binding affinities of humanized anti-lL-36R antibodies binding to
recombinant human lL-36R were measured using the Proteon (Bio-Rad, Hercules, CA).
Human lL-36R was immobilized at 5 different surface densities and s analyzed
using global fit (see Table 5 showing results of three experiments). Binding of the
zed antibodies to NCl/ADR-RES cells via flow cytometry was ed using
protocol described in Example 4 (See Table 5 for E090 values).
Table 5 — Molecular and Cellular Binding affinities of humanized uman |L-
36R antibodies.
Antibody (LC + HC) KB 1 Standard Deviation (pM) 1M)
B1 - 32_138 + 33_49 27 12.5
32 - 32_138 + 33_85 32 15.4
B3 - 32_138 + 33_90 20:2.2
- 24:7
BG-32105+33 49 4114.9
Example 7: Potency of humanized anti-human |L-36R antibodies in functional
human assays
onal blockade of signaling with the humanized lL-36R variants from human
NCl/ADR-RES cells were tested as described in Example 3. ngo results for the
humanized anti-human lL-36R antibodies in human onal assays (pNFKB and
cytokine release) with human lL-36 ligands are shown in Table 6.
Table 6: Potency [ngo (nM)] of humanized antibodies in human functional
R-RES cell assays
ts equal averages of at least 2 experiments. lsotype controls demonstrated
no inhibition of activity at highest tration tested for samples)
-------m
I-I-I-I-IflflpNFKtrun-IL-
III-“nuntrun-ILI-I-I-I-I-I36g
I-I-I-I-I-n
tr”“'”'
3.2 2.9 2.7 2.9 2.5 2.3 NA NA NA
I-I-I-I-I-I
Example 8: Potency of anti-lL-36R antibodies in functional human primary
keratinocyte assays
Protocols: Human rimar e idermal noc te NFkB/C tokine release assa s
Cells were plated at 30,000 cells/well in culture media in 96 well plates and incubated
overnight at 37°C, 5% COZ Assays were then performed as described in Example 3.
Results: ngo results for mouse, chimeric, and humanized anti-lL-36R antibodies in
human primary keratinocyte assays (pNFkB and lL-8 release) stimulated with human IL-
36 ligands are shown in Table 7, Table 8, and Table 9, respectively.
Table 7 (isotype controls demonstrated no inhibition of activity at t
concentration tested for samples)
33D10 73C5 73F6 78C8 81A1 8184
trun-IL-
36a |C90 1.3
(nM)
trun-IL-
36b |C90 1.1
trun-IL-
36g |C90 . . 1.3 10.6 ND 0.5
(nM)
-trun-IL- 36a |C90 . . 17.8 19.3 ND 0.7
(nM)
trun-IL-
36b |C90 1.2
(nM)
trun-IL-
36g |C90 0.8 2.4 2.1 3.6 ND 0.5
Table 8: Potency of chimeric anti-lL-36R antibodies in primary human
keratinocyte assays
(isotype controls demonstrated no inhibition of ty at highest concentration
tested for s)
C73C5 C81A1 C81B4
NHK -
$232-$338 ND
-Egg-m ND
-raga-52b 87
Table 9: Potency of humanized anti-lL-36R antibodies in y human
keratinocyte assays
(isotype controls demonstrated no tion of activity at highest concentration
tested for samples)
11111111 - -
-11111111 - -
111111111
1.1111111
-.11111111
Example 9 Potency of anti-lL-36R dies in onal human primary
intestinal epithelial cell assays
Protocols: Human rimar intestinal e ithelial cell NFkB/C tokine release assa s
Cells were plated at 30,000 cells/well in culture media in 96we|| plate and incubated
overnight at 37°C, 5% COz_Assays were then performed as described in Example 3.
Results: ICgo results for mouse anti-IL-36R antibodies in human primary intestinal
epithelial cell assays (pNFkB and IL-8 release) stimulated with human IL-36 ligands are
shown in Table 10.
Table 10: Potency of mouse anti-lL-36R dies in primary human intestinal
epithelial cell assays
(isotype ls demonstrated no tion of ty at highest concentration
tested for samples)
73C5 8184
trun-IL-36a |C9O
21 1.3
(nM)
trun-IL-36b |C9O
7.4
( )
’(crunilL-36g |C9O 32 9.5
trun-IL-36a |C9O
123 5.8
(nM)
’(crunilL-36b |C9O 154 9.8
’(crunilL-36g |C9O ND 16
Example 10: Potency of anti-lL-36R antibodies in functional human primary
intestinal myofibroblast assays
Protocols: Human primary intestinal myofibroblast QNFKB/Cytokine release assays
Cells were plated at 30,000 cells/well in culture media in 96wel| plate and incubated at
37°C, 5% COz_Assays were then performed as described in Example 3.
Results: ICgo results for anti-lL-36R antibodies in human primary intestinal
myofibroblast assays (pNFkB and lL-8 release) stimulated with human lL-36 ligands are
shown in Table 11 and Table 12,.
Table 11 : Potency of mouse and chimeric anti-lL-36R dies in primary
human inal roblast assays
(isotype controls demonstrated no inhibition of activity at highest concentration
tested for samples)
trun-IVI|-L36a |C9O
pNFKB
trun-IVI|-L36b |C9O
n(M)
t run- |L-36g |C9O
n(M)
trun- |L-36a |C9O
lL-8 n(M)
trun- |L-36b |C9O
trun-IL-36g |C9O
(nM)
Table 12: Potency of humanized L-36R antibodies in primary human
intestinal myofibroblast assays
(isotype controls demonstrated no inhibition of activity at highest concentration
tested for samples)
'33 BS BG
pNFkB Emilia 9'8 5-4 3-2
T233153? 3-7 1.7 2.8
T233??? 2-6 1.7 3.7
Tabitha? 4'4 3-8 2-1
lL-8
T233153? 2-8 2.6 2.0
T531536)“; 5-8 6-7 5.2
Example 11 : Potency of anti-lL-36R antibodies in functional human primary
dermal fibroblast assays
ols: Human primary dermal last QNFKB/Cztokine release assays
Cells were plated at 30,000 cells/well in culture media in 96well plate and incubated
overnight at 37°C, 5% COz_Assays were then performed as described in Example 3.
Results: ngo results for anti-lL-36R antibodies in human primary dermal fibroblast
assays (pNFkB and lL-8 release) stimulated with human lL-36 ligands are shown in
Table 13 and Table 14,.
Table 13: y of mouse and chimeric anti-lL-36R antibodies in primary
human dermal fibroblast assays
(isotype controls demonstrated no inhibition of activity at highest concentration
tested for samples)
81B4 C81B4
trun-lL-36a |C9O
1.9 1.8
pNFKB (nM)
t -lL-36 IC9O
L-36a |C9O
t -lL-36blC9O
t(2:2)-lL-36g IC9O
0.4 0.3
Table 14: Potency of humanized anti-lL-36R antibodies in y human dermal
fibroblast assays
(isotype ls demonstrated no inhibition of ty at highest concentration
tested for samples)
trun-lL-36a |C9O
PNFKB ---n
trun-IL-36b |C9O
_trun-IL-36g IC90"‘1-
WO 74569
(nM) ——
-----
----
Example 12: Potency of mouse anti-lL-36R antibodies in functional human
primary proximal tubular cell assays
Protocol: human rimar roximal tubular cells NFkB/C tokine release assa s.
Cells were plated at 5,000 cells/well in culture media in 96well plate and incubated
overnight at 37°C, 5% COz_Assays were med as described in Example 3.
Results: ICgo results for mouse, chimeric, and humanized anti-lL-36R dies in
human primary proximal tubular cell assays (IL-8 release) stimulated with human lL-36
ligands are shown in Table 15.
Table 15: Potency of mouse and human L-36R antibodies in primary human
proximal tubular cell assays
(isotype controls demonstrated no inhibition of ty at highest concentration
tested for samples)
BS 86
-trun-lL-36a 5 ND
lL-8 |C9O (nM)
trun-lL-36b 5 ND
|C9O (nM)
trun-lL-36g 3 ND
|C9O (nM)
2012/064933
Example 13: Inhibition of lL-8 production from lL-367 stimulated reconstructed
human mis
Protocol reconstructed epidermis
Anti-lL-36R antibodies (1.5 ug/ml) were pre-incubated with reconstructed human
epidermis and stimulated with human recombinant lL-36y (20 ng/ml). Recombinant
human lL-1B (20 ng/ml; R & D Systems) was used as a positive control. After 24 hours
in culture, cell supernatants were collected and assayed for lL-8 s for lL-8 are
described in Example 3). s were tested in triplicate and the average pg/ml 1
standard error is shown in the table below (Table 16).
Table 16
Average lL-8 (pg/ml)
dy Cytokine Stimulation +/- Standard Error
Noantibody 57.31153
Example 14: Inhibition of lL-36 ligand induced S100A7 and S100A12 gene
expression in reconstructed human epidermis
Stimulation of reconstructed human epidermis with agonsitic lL-36 s induces
S100A7 and S100A12 gene expression. S100A7 and S100A12 are genes located
within the epidermal differentiation complex.
Protocol: Reconstructed human epidermis were incubated with anti-lL-36R dies
(1.5 ug/ml) and stimulated with human recombinant lL-36y (20 ng/ml). Recombinant
human lL-1B (20 ng/mL; R & D Systems) was used as a positive control. After 24 hours
in culture at 5% 002 and 37°C, RNA was isolated from the reconstructed human
epidermis and assayed for gene expression by real-time reverse trancriptasepolymerase
chain on. Relative expression was calculated using the 2AACt method.
Samples were tested in triplicate and the e expression 1 standard error is shown
in the table below (Table 17).
Table 17
Mean S100A7 Mean S100A12
Antibody Cytokine Expression +/- sion +/-
Stimulation Standard Error Standard Error
No antibody None 1.00 :r 0.79 1.00 :r 0.47
33D10 None 3.92 :r 0.36 1.93 :r 0.02
No antibody 20 ng/mL IL-1B 76.03 1 24.66 47.84 i 9.24
33D1O 20 ng/mL IL-1B 95.83 i 11.83 76.41 i 6.92
No antibody 20 ng/mL lL-36y 19.57 i 3.26 20.53 i 5.21
33D1O 20 ng/mL |L-36v 3.47 i 1.37 2.01 i 0.35
Example 15: Efficacy of anti-lL-36R antibody in Xenotransplant Model of Psoriasis
ol: Blood and sional skin biopsies were obtained from 24 psoriasis patients
that were clinically diagnosed by a dermatologist. Skin biopsies were transplanted onto
immune-deficient NIH-Ill mice and allowed to t for a period of four to five weeks.
Peripheral blood mononuclear cells (PBMC) were isolated from blood collected from
each donor at the time of biopsy for intradermal injection into the engrafted skin. Prior
to injection, PBMC were stimulated with with 1 ug/ml Staphylococcal Enterotoxin B
(Toxin Technologies, Florida, USA) and 80 U/ml human inant lL-2 (Peprotech
lnc., Oosterhout, The Netherlands). Autologous PBMC were intradermally injected with
7.5 x 10"5 cells in PBS to synchronize the induction of skin inflammation and the
psoriasis phenotype. Three weeks after the injection of cells, the biopsies were retrieved
from the mice and analyzed by histology.
Histological staining was performed on cryo-preserved skin tissue of all groups.
Diagonal cross sections (8 pm), covering all ayers, were prepared as described in
Figure 4. For assessment of epidermal ess, two rial sections were
randomly chosen from the center of the biopsy and stained with haematoxylin-
eosin.Subsequently, sections were evaluated at a 100-fold magnification. Over the
entire
length of the biopsy, ridge lengths were measured in both sections using an
Olympus DP71 camera and CellAD imaging software (V2.7, Munster, Germany).
Ridge length is defined as: the distance between the upper edge of the stratum
granulosum to the bottom of the ridge. es were scored at random and in a
blinded fashion.
Results for the average epidermal ess and maximum epidermal thickness for
each treatment group are shown in Table 18. s for the net change in mal
thickness in each treatment group are shown in Table 19.
Table 18
33D10
Table 19
_Average Epidermal Thickness Maximum Epidermal Thickness
2012/064933
—mmnmmmnmUntreated 36. 2 31. 9 52. 6 40.0
Vehicle 43.5 30.9 18 63.4 52.0
Example 16: The sub-chronic pulmonary inflammation after 3 weeks of cigarette
smoke exposure in wild type and interleukin-1 receptor-like 2 homozygous
knockout mice
Protocol: Wild type or interleukin-1 receptor-like 2 mice were exposed to cigarette
smoke for 3 weeks to induce ary distress. Weeks 1 and 2 consisted of 5
consecutive exposure days, while mice were exposed for 4 utive days during
week 3. Mice were exposed to 5 cigarettes each day with 24 minute intervals of
cigarette exposure (16 minutes) and fresh air (8 minutes). Eighteen hours following the
final re, mice were lavaged with 2 x 0.8 ml of Hank’s Salt Solution (0.6mM
EDTA). The supernatant and cell pellet were collected from the bronchial alveolar
lavage following centrifugation for 10 s. Total macrophage and neutrophil cell
counts in the bronchial alveolar lavage for each exposure group are shown in Table 20.
Table 20
Total Cells Cell Counts x 10A5
Mouse mean SD N SEM
WT 2.21 1.47 9 0.49
|L1RL2 KO 2.45 0.87 6 0.36
WT + OS 9.07 2.83 10 0.90
IL-1RL2 KO + OS 5.32 1.03 10 0.32
Macrophages Cell Counts x 10A5
Mouse mean SD N SEM
WT 2.08 1.62 9 0.54
WO 74569
|L1RL2 KO 2.40 0.86 0.35
WT + C8 3.36 1.46 10 0.46
IL-1RL2 KO + C8 3.22 0.86 10 0.27
Neutrophils Cell Countsx1 0‘5
Mouse mean SD SEM
WT 0.002 0.004 0.001
|L1RL2 KO 0.013 0.016 0.007
WT + C8 5.698 2.751 10 0.870
IL-1RL2 KO + C8 2.083 0.749 10 0.237
WE
Claims (47)
1. An anti-interleukin-36R (anti-IL-36R) antibody or antigen-binding fragment f, wherein the antibody or antigen-binding nt thereof comprises: a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105, 106 or 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain le region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (HCDR2 ); the amino acid ce of SEQ ID NO: 72 (H-CDR3).
2. An anti-IL-36R dy or antigen-binding fragment thereof ing to claim 1, wherein the antibody or antigen-binding fragment thereof comprises: a) a light chain le region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 102 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (HCDR2 ); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).
3. An anti-IL-36R antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises: a) a light chain le region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 103 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid ce of SEQ ID NO: 62, 108, 109, 110 or 111 (HCDR2 ); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).
4. An anti-IL-36R antibody or antigen-binding fragment f according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises: a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 104 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and AH26(10651560_1):RTK b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (HCDR2 ); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).
5. An anti-IL-36R antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof ses: a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 105 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (HCDR2 ); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).
6. An anti-IL-36R antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises: a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid ce of SEQ ID NO: 106 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 3); and b) a heavy chain variable region comprising the amino acid ce of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (HCDR2 ); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).
7. An anti-IL-36R antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises: a) a light chain variable region sing the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 140 2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (HCDR2 ); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).
8. An L-36R antibody or antigen-binding nt thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the amino acid sequence of any one of SEQ ID NO: 76, 77, 78, 79, 80, 81, 82 or 83; AH26(10651560_1):RTK and a heavy chain variable region comprising the amino acid ce of any one of SEQ ID NO: 87, 88, 89, 90, 91, 92, 93, 94 or 95.
9. An anti-IL-36R antibody or antigen-binding fragment thereof according to claim 8, n the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region sing the amino acid ce of SEQ ID NO: 87;or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or a light chain le region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89.
10. An anti-IL-36R antibody or antigen-binding fragment thereof ing to claim 8, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87;or a light chain variable region comprising the amino acid ce of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89.
11. An anti-IL-36R antibody according to claim 1, wherein the dy comprises a light chain comprising the amino acid sequence of any one of SEQ ID NO: 114, 115, 116, 117, 118, 119, 120 or 121; and a heavy chain comprising the amino acid sequence of any one of SEQ ID NO: 125, 126, 127, 128, 129, 130, 131, 132 or 133.
12. An anti-IL-36R antibody, wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125.
13. An anti-IL-36R antibody, wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain sing the amino acid sequence of SEQ ID NO: 126. AH26(10651560_1):RTK
14. An anti-IL-36R antibody, wherein the antibody comprises a light chain comprising the amino acid ce of SEQ ID NO: 115; and a heavy chain sing the amino acid sequence of SEQ ID NO: 127.
15. An anti-IL-36R antibody, wherein the antibody ses a light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125.
16. An L-36R antibody, wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126.
17. An anti-IL-36R antibody, wherein the antibody thereof comprises a light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127.
18. An anti-IL-36R antibody or antigen-binding fragment thereof, n the antibody or antigen-binding fragment thereof comprises: a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 103 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).
19. An anti-IL-36R antibody or antigen-binding fragment f, wherein the antibody or antigen-binding fragment thereof comprises: a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid ce of SEQ ID NO: 104(L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid ce of SEQ ID NO: 62 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3). AH26(10651560_1):RTK
20. An anti-IL-36R antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87.
21. An anti-IL-36R dy or antigen-binding fragment f, wherein the antibody or n-binding nt f comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region sing the amino acid sequence of SEQ ID NO: 88.
22. An anti-IL-36R antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid ce of SEQ ID NO: 89.
23. A pharmaceutical composition comprising an antibody or antigen-binding fragment according to claim 11 and a pharmaceutically acceptable carrier.
24. A pharmaceutical ition sing an antibody or antigen-binding fragment according to claim 12 and a pharmaceutically acceptable carrier.
25. A pharmaceutical composition comprising an antibody or antigen-binding fragment according to claim 13 and a pharmaceutically acceptable carrier.
26. A ceutical composition comprising an antibody or antigen-binding fragment according to claim 14 and a pharmaceutically acceptable carrier.
27. A ceutical composition comprising an antibody or antigen-binding fragment according to claim 15 and a pharmaceutically acceptable carrier.
28. A pharmaceutical composition comprising an antibody or antigen-binding fragment according to claim 16 and a pharmaceutically acceptable carrier.
29. A pharmaceutical composition comprising an antibody or antigen-binding fragment according to claim 17 and a pharmaceutically acceptable carrier. AH26(10651560_1):RTK
30. A pharmaceutical composition comprising an antibody or antigen-binding fragment according to claim 8 and a pharmaceutically acceptable carrier.
31. A pharmaceutical composition comprising an antibody or antigen-binding fragment according to claim 20 and a pharmaceutically acceptable carrier.
32. A pharmaceutical composition comprising an antibody or antigen-binding fragment according to claim 21 and a pharmaceutically acceptable r.
33. A pharmaceutical composition comprising an antibody or antigen-binding fragment according to claim 22 and a pharmaceutically acceptable carrier.
34. A ceutical composition comprising an antibody or antigen-binding fragment according to claim 18 and a pharmaceutically able carrier.
35. A pharmaceutical composition comprising an antibody or antigen-binding fragment according to claim 19 and a pharmaceutically acceptable carrier.
36. A pharmaceutical composition comprising an antibody or antigen-binding fragment ing to claim 1 and a pharmaceutically able r.
37. An antibody or n-binding fragment or pharmaceutical composition according to any one of claims 1 to 36, for use in a method for the treatment of ulcerative colitis.
38. Use of an antibody or antigen-binding nt according to any one of claims 1 to 22 or a pharmaceutical composition according to any one of claims 23 to 36, for the manufacture of a medicament for the treatment of a disease, wherein the disease is ed from an inflammatory disease, an autoimmune disease, a respiratory disease, a metabolic disorder, an epithelial mediated inflammatory disorder, fibrosis and cancer.
39. The use according to claim 38, wherein the disease is selected from psoriasis, inflammatory bowel e, psoriatic arthritis, le sclerosis, rheumatoid arthritis, COPD, c asthma and ankylosing spondylitis.
40. The use according to claim 38 and/or 39, wherein the disease is Crohn’s disease. AH26(10651560_1):RTK
41. The use according to claim 38 and/or 39, wherein the disease is ulcerative colitis.
42. An isolated polynucleotide comprising a sequence encoding an anti-IL-36R antibody or n-binding fragment according to any one of claims 1 to 22, preferably a DNA or RNA sequence.
43. An isolated polynucleotide according to claim 42, encoding a sequence as defined by one or more of SEQ ID NOs. 1 to 140.
44. A vector comprising a polynucleotide ing to claim 42 and/or 43, preferably an expression vector, more preferred a vector comprising the polynucleotide according to the invention in functional association with an expression control sequence.
45. A host cell comprising a polynucleotide according to claim 42 and/or 43, and/or a vector according to claim 44, wherein the host cell is not within a human.
46. A method for the production of an anti-IL-36R antibody or antigen-binding fragment ing to any one of claims 1 to 22, preferably a recombinant production method comprising the use of a polynucleotide according to claim 42 and/or 43, and/or of a vector according to claim 44 and/or of a host cell according to claim 45.
47. The method according to claim 46, comprising the steps (a) ating the host cell under conditions ng the expression of the anti-IL-36R antibody or antigen-binding fragment and (b) recovering the anti-IL-36R antibody or antigen-binding nt. Boehringer Ingelheim ational GmbH By the Attorneys for the Applicant SPRUSON & FERGUSON Per: AH26(10651560_1):RTK
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
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US201161560554P | 2011-11-16 | 2011-11-16 | |
US61/560,554 | 2011-11-16 | ||
US201261644111P | 2012-05-08 | 2012-05-08 | |
US61/644,111 | 2012-05-08 | ||
US201261713713P | 2012-10-15 | 2012-10-15 | |
US61/713,713 | 2012-10-15 | ||
PCT/US2012/064933 WO2013074569A1 (en) | 2011-11-16 | 2012-11-14 | Anti il-36r antibodies |
Publications (2)
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NZ623425A NZ623425A (en) | 2015-12-24 |
NZ623425B2 true NZ623425B2 (en) | 2016-03-30 |
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