Patent Description:
ELR+ CXC chemokines (so-called because members of the chemokine family all possess an E-L-R amino acid motif immediately adjacent to their CXC motif) play an important role in a variety of pathogenic mechanisms, including the migration of neutrophils to sites of inflammation and angiogenesis. Neutrophils contribute to the pathogenesis of several acute and chronic inflammatory and autoimmune diseases.

Chemokines are grouped into four subfamilies: CXC, CC, (X)C, and CX3C. In the CXC chemokines, one amino acid separates the first two cysteines ("the CXC motif "). ELR+ CXC chemokines are ligands for CXCR l and/or CXCR2 chemokine receptors, which are G-protein coupled seven transmembrane domain-type receptors that specifically bind ELR+ CXC chemokines. The seven human ELR+ CXC chemokines are human growth-regulated oncogene ("Gro")-alpha (also known as CXCL1), human Gro-beta (also known as CXCL2), human Gro-gamma (also known as CXCL3), human ENA-<NUM> (also known as CXCL5 or human epithelial neutrophil activating peptide-<NUM>), human GCP-<NUM> (also known as CXCL6 or human granulocyte chemotactic protein-<NUM>), human NAP-<NUM> (also known as CXCL7 or human neutrophil activating protein-<NUM>), and human IL-<NUM> (also known as CXCL8 or human interleukin-<NUM>). All ELR+ CXC chemokines bind the CXCR2 receptor; moreover, some ELR+ CXC chemokines bind both CXCR l and CXCR2 receptors (i.e., CXCL6 and CXCL8), all of which contributes to redundancy in the activation pathways. Neutralizing all seven ELR+ CXC chemokines could impact the ability of CXCR1+ or CXCR2+ cells to migrate to sites of inflammation.

Antibodies that bind and neutralize all seven human ELR+ CXC chemokines have been previously described, e.g., in <CIT>, <CIT>, and <CIT>. Given their ability to bind and neutralize all seven human ELR+ CXC chemokines, those antibodies offer advantages over monotherapies targeting single human ELR+ CXC chemokines and combination therapies targeting multiple human ELR+ CXC chemokines. One of such antibodies that bind all seven human ELR+ CXC chemokines is Antibody <NUM> that comprises light chain complementarity determining regions ("LCDR") LCDR1, LCDR2, LCDR3, and heavy chain complementarity determining regions ("HCDR") HCDR1, HCDR2, HCDR3, wherein LCDR1 comprises SEQ ID NO: <NUM>, LCDR2 comprises SEQ ID NO: <NUM>, LCDR3 comprises SEQ ID NO: <NUM>, HCDR1 comprises SEQ ID NO: <NUM>, HCDR2 comprises SEQ ID NO: <NUM>, and HCDR3 comprises SEQ ID NO: <NUM>. Antibody <NUM> comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: <NUM> and a light chain variable region comprising the amino acid sequence of SEQ ID NO: <NUM>. Antibody <NUM> comprises a heavy chain having the amino acid sequence of SEQ ID NO: <NUM> and a light chain having the amino acid sequence of SEQ ID NO: <NUM>. It was shown that Antibody <NUM> binds an epitope that is common to all seven human ELR+ CXC chemokines and neutralize the activities of all seven human ELR+ CXC chemokines. By binding to all seven ELR+ CXC chemokines, both the CXCR1 and the CXCR2 pathways can be blocked, which may result in more effective inhibition of neutrophil trafficking.

Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory disease, which is associated with substantial co-morbidities and decreased quality of life. HS initially presents as tender subcutaneous nodules. These lesions may spontaneously rupture or coalesce to form deep dermal painful abscesses, and they often exude a purulent drainage. The inflammatory abscesses ultimately heal, producing fibrosis, dermal contractures, and induration of the skin. HS typically occurs after puberty, with average age of onset in the second or third decades of life; women are more likely to develop this disease.

It is now considered that HS lesions begin with follicular plugging which presumably results in occlusion and dilation of the pilosebaceous unit, with subsequent rupture (<NPL>). Extrusion of follicular contents (primarily consisting of corneocytes, bacteria, sebum products, and hair in the dermis) produces a chemotactic inflammatory response. The resulting influx of neutrophils, lymphocytes, and histiocytes lead to abscess formation.

There is no uniformly effective single therapy for HS resulting in numerous treatment modalities being employed. These include antibiotics, retinoids, hormones, immunosuppressive and anti-inflammatory agents, neurotoxins, radiotherapy, and surgery. The tumor necrosis factor inhibitor, adalimumab, was approved for the treatment of HS in <NUM>. However, many HS patients do not respond to adalimumab. There remains a substantial unmet medical need for effective therapies for treating HS.

Additionally, there is no prior description of any safe, tolerable and effective use of an antibody that binds and neutralizes all seven human ELR+ CXC chemokines in human patients.

Also mentioned are the following documents:.

The present invention provides an antibody that binds human growth-regulated oncogene ("Gro")-alpha, human Gro-beta, human Gro-gamma, human epithelial neutrophil activating peptide-<NUM>, human granulocyte chemotactic protein-<NUM>, human neutrophil activating protein-<NUM>, and human interleukin-<NUM>, wherein the antibody comprises light chain complementarity determining regions ("LCDR") LCDR1, LCDR2, LCDR3 and heavy chain complementarity determining regions ("HCDR") HCDR1, HCDR2, HCDR3, wherein LCDR1 comprises SEQ ID NO: <NUM>, LCDR2 comprises SEQ ID NO: <NUM>, LCDR3 comprises SEQ ID NO: <NUM>, HCDR1 comprises SEQ ID NO: <NUM>, HCDR2 comprises SEQ ID NO: <NUM>, and HCDR3 comprises SEQ ID NO: <NUM>, for use in the treatment of hidradenitis suppurativa.

Any reference to a method of treatment practiced on the human or animal body is to be interpreted as substances and compositions for use in such treatment.

The antibody may be for use in treating hidradenitis suppurativa in a human patient in need thereof by administering to the human patient a therapeutically effective amount of the antibody, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: <NUM> and a light chain variable region comprising the amino acid sequence of SEQ ID NO: <NUM>. In some embodiments, the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: <NUM> and a light chain having the amino acid sequence of SEQ ID NO: <NUM>.

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is intravenously. In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is subcutaneously.

As discussed below, the terminal half-life (t1/<NUM>) for Antibody <NUM> is estimated to be about <NUM> weeks. In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is once every two weeks. In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is weekly.

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is intravenously at a dose of about <NUM> to about <NUM> (e.g., about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>).

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is intravenously at a dose of about <NUM> to about <NUM> (e.g., about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>).

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> to about <NUM> (e.g., about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>) once every two weeks intravenously.

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> to about <NUM> (e.g., about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>) once every two weeks intravenously.

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> to about <NUM> (e.g., about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>) once every two weeks intravenously.

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> to about <NUM> (e.g., about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>) once every two weeks intravenously.

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> to about <NUM> once every two weeks intravenously.

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> once every two weeks intravenously.

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is with a loading dose prior to the specified intravenous dose. For example, the loading dose can be a high intravenous dose (e.g., about <NUM> to about <NUM>) with a shorter dosing interval (e.g., every week) for a few weeks (e.g., two, three, or four weeks). In some embodiments, the loading dose is <NUM> intravenously every week for a few weeks (e.g., two, three, or four weeks). In some embodiments, the loading dose is <NUM> intravenously every week for a few weeks (e.g., two, three, or four weeks). In some embodiments, the loading dose is <NUM> intravenously every week for a few weeks (e.g., two, three, or four weeks). In some embodiments, the loading dose is <NUM> intravenously every week for a few weeks (e.g., two, three, or four weeks). In some embodiments, the loading dose is <NUM> intravenously every week for a few weeks (e.g., two, three, or four weeks).

As shown below, the bioavailability for subcutaneous injection of Antibody <NUM> is estimated to be approximately <NUM>% of intravenous injection of Antibody <NUM>. In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is subcutaneously at a dose of about <NUM> to about <NUM> (e.g., about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>).

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is subcutaneously at a dose of about <NUM> to about <NUM> (e.g., about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>).

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> to about <NUM> (e.g., about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>) once every two weeks subcutaneously.

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> to about <NUM> (e.g., about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>) once every two weeks subcutaneously.

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> to about <NUM> (e.g., about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>) once every two weeks subcutaneously.

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> to about <NUM> (e.g., about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>) once every two weeks subcutaneously.

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> once every two weeks subcutaneously. In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> once every two weeks subcutaneously. In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> once every two weeks subcutaneously. In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> once every two weeks subcutaneously.

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> to about <NUM> (e.g., about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>) weekly subcutaneously. In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> to about <NUM> weekly subcutaneously. In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> weekly subcutaneously. In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> weekly subcutaneously. In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> weekly subcutaneously. In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> weekly subcutaneously. In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is at a dose of about <NUM> weekly subcutaneously.

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is with a loading dose prior to the specified subcutaneous dose. For example, the loading dose can be a high subcutaneous dose (e.g., about <NUM> to about <NUM>) with a shorter dosing interval (e.g., every week or every three days) for a few weeks (e.g., two, three, or four weeks) to a few months (e.g., one, two, or three months). In some embodiments, the loading dose is <NUM> subcutaneously every week for a few weeks (e.g., two, three, or four weeks) to a few months (e.g., one, two, or three months). In some embodiments, the loading dose is <NUM> subcutaneously every week for a few weeks (e.g., two, three, or four weeks) to a few months (e.g., one, two, or three months). In some embodiments, the loading dose is <NUM> subcutaneously every week for a few weeks (e.g., two, three, or four weeks) to a few months (e.g., one, two, or three months). In some embodiments, the loading dose is <NUM> subcutaneously every week for a few weeks (e.g., two, three, or four weeks) to a few months (e.g., one, two, or three months). In some embodiments, the loading dose is <NUM> subcutaneously every week for a few weeks (e.g., two, three, or four weeks) to a few months (e.g., one, two, or three months). In some embodiments, the loading dose is <NUM> subcutaneously every week for a few weeks (e.g., two, three, or four weeks) to a few months (e.g., one, two, or three months). In some embodiments, the loading dose is <NUM> subcutaneously every week for a few weeks (e.g., two, three, or four weeks) to a few months (e.g., one, two, or three months).

In some embodiments, the loading dose is <NUM> subcutaneously every three days for a few weeks (e.g., two, three, or four weeks) to a few months (e.g., one, two, or three months). In some embodiments, the loading dose is <NUM> subcutaneously every three days for a few weeks (e.g., two, three, or four weeks) to a few months (e.g., one, two, or three months). In some embodiments, the loading dose is <NUM> subcutaneously every three days for a few weeks (e.g., two, three, or four weeks) to a few months (e.g., one, two, or three months). In some embodiments, the loading dose is <NUM> subcutaneously every three days for a few weeks (e.g., two, three, or four weeks) to a few months (e.g., one, two, or three months). In some embodiments, the loading dose is <NUM> subcutaneously every three days for a few weeks (e.g., two, three, or four weeks) to a few months (e.g., one, two, or three months). In some embodiments, the loading dose is <NUM> subcutaneously every three days for a few weeks (e.g., two, three, or four weeks) to a few months (e.g., one, two, or three months). In some embodiments, the loading dose is <NUM> subcutaneously every three days for a few weeks (e.g., two, three, or four weeks) to a few months (e.g., one, two, or three months). The subcutaneous loading dose can be achieved in a single injection or in a few separate injections (e.g., two, three or four injections).

In some embodiments, the antibody of the present invention that binds all seven human ELR+ CXC chemokines, e.g., Antibody <NUM>, or a pharmaceutical composition comprising such an antibody, is for use where administration is without a loading dose prior to the specified dose.

As used herein, the term "human ELR+ CXC chemokines" refers to the seven known CXC chemokines that have an E-L-R motif and that bind to CXCR l and/or CXCR2 receptor. The human ELR+ CXC chemokines are human Gro-alpha (also known as CXCL1) (SEQ ID NO: <NUM>), human Gro-beta (also known as CXCL2) (SEQ ID NO: <NUM>), human Gro-gamma (also known as CXCL3) (SEQ ID NO: <NUM>), human ENA-<NUM> (also known as CXCL5) (SEQ ID NO: <NUM>), human GCP-<NUM> (also known as CXCL6) (SEQ ID NO: <NUM>), human NAP-<NUM> (also known as CXCL7) (SEQ ID NO: <NUM>), and human IL-<NUM> (also known as CXCL8) (SEQ ID NO: <NUM>). Collectively, all seven human ELR+ CXC chemokines are called "human pan-ELR+ CXC chemokines" herein.

The term "antibody," as used herein, refers to monoclonal immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (HCVR) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2, and CH3. Each light chain is comprised of a light chain variable region (LCVR) and a light chain constant region, CL. The HCVR and LCVR regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each HCVR and LCVR is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The CDR regions in HCVR are termed HCDRl, HCDR2, and HCDR3. The CDR regions in LCVR are termed LCDRl, LCDR2, and LCDR3. The CDRs contain most of the residues which form specific interactions with the antigen. There are currently three systems of CDR assignments for antibodies that are used for sequence delineation. The Kabat CDR definition (<NPL>)) is based upon antibody sequence variability. The Chothia CDR definition (<NPL>);<NPL>)) is based on three-dimensional structures of antibodies and topologies of the CDR loops. The Chothia CDR definitions are identical to the Kabat CDR definitions with the exception of HCDR1 and HCDR2. For the purposes of the present invention, a hybrid of the Kabat and Chothia definitions are used to define CDRs. The assignment of amino acids in the HCVR and LCVR regions is in accordance with the Kabat numbering convention. It is further understood that the term "antibody" encompasses any cellular post-translational modifications to the antibody including, but not limited to, acylation and glycosylation.

As used herein, the term "septa-specific antibody" refers to an antibody that binds all seven human ELR+ CXC chemokines with high affinity (e.g., with binding affinity (KD) in the range of from about <NUM> × <NUM>-<NUM> M to about <NUM> × <NUM>-<NUM> M).

As used herein, a "patient" refers to a human with a disease, disorder, or condition that would benefit from a decreased level of human ELR+ CXC chemokines or decreased bioactivity induced by human ELR+ CXC chemokines.

As used herein, "treatment" or "treating" refers to all processes wherein there may be a slowing, controlling, or stopping of the progression of the disorders disclosed herein, but does not necessarily indicate a total elimination of all disorder symptoms. Treatment includes administration of an antibody of the present invention for treatment of a disease or condition in a patient, particularly in a human.

The primary objective of this study is to explore the safety and tolerability of a single dose of Antibody <NUM> in healthy subjects, including Japanese subjects, in order to define an appropriate dose range for further clinical research. The endpoints for this objective are incidence of SAEs (serious adverse events) and TEAEs (treatment-emergent adverse events). The secondary objective of this study is to characterize the pharmacokinetics (PK) of Antibody <NUM>, including estimation of the bioavailability following subcutaneous (SC) administration of a single dose of Antibody <NUM>, in healthy subjects, including Japanese subjects. The endpoints include Cmax (maximum observed drug concentration), tmax (time to reach Cmax), AUCs (area under the concentration-time curve during dosing interval at steady) and the presence of antidrug antibodies.

In this study, Antibody <NUM> has been administered to <NUM> healthy subjects in a single-ascending dose study in which doses of <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> of Antibody <NUM> were administered as a slow intravenous (IV) infusion; or the dose of <NUM> of Antibody <NUM> was administered by SC injection to assess the bioavailability. In addition, skin blisters were induced in subjects who received IV doses of <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> of Antibody <NUM> to assess neutrophil chemotaxis and accumulation.

There were no deaths or serious adverse events (SAEs) reported. Adverse events (AEs) reported were graded using the Common Terminology Criteria for Adverse Events (CTCAE). All AEs reported were Grade <NUM>, except for <NUM> subject who reported a Grade <NUM> event, which the investigator considered to be unrelated to study drug.

There were no clinically significant changes in hematology (including peripheral blood neutrophil counts) or urinalysis.

There were no clinically significant changes in vital signs or electrocardiograms (ECG).

Antibody <NUM> exhibited linear PK in the dose range tested, with an estimated terminal half-life (t1/<NUM>) of approximately <NUM> weeks. The estimated bioavailability for SC injection of Antibody <NUM> is approximately <NUM>% of IV injection.

The preliminary pharmacodynamic (PD) assessment was focused on the percentage of neutrophils present in the blister fluid. The neutrophil data were highly variable, but a trend of dose-dependent decreases of neutrophils in the blister fluid was observed.

The primary objective is to assess the safety and tolerability of multiple intravenous doses of Antibody <NUM> in patients with skin disease, e.g., hidradenitis suppurativa. The endpoints for this objective are incidence of SAEs (serious adverse events) and TEAEs (treatment-emergent adverse events).

The secondary objectives are to estimate the PK parameters of Antibody <NUM> following IV administration in patients with skin disease, e.g., HS; and to assess the potential development of antidrug antibodies and their impact on safety and PK of Antibody <NUM>. The endpoints include Cmax (maximum observed drug concentration), tmax (time to reach Cmax), AUCs (area under the concentration-time curve during dosing interval at steady) and the presence of antidrug antibodies.

The exploratory objectives are to explore the dose- and exposure-response relationship for appropriate clinical endpoints for the dermatological condition and other PD measures (e.g., clinical rating scores). The endpoints include HiSCR, abscess and inflammatory nodule counts, modified Sartorius score, HS-PGA score, and Patient's Global Assessment of Skin Pain (via Numeric Rating Scale).

This is a multicenter, randomized, placebo-controlled, and multiple ascending dose study in patients with skin disease, e.g., HS. The patient and investigator are blinded to study treatment. Screening occurs up to <NUM> days prior to the first dose of Antibody <NUM>.

Patients participating in the study receive a slow IV infusion over a minimum period of <NUM> minutes, or longer after completion of the infusion, at the investigator's discretion. Antibody <NUM> or placebo is administered every <NUM> weeks (Q2W) for a total of <NUM> doses. The Q2W dosing frequency is selected because the t1/<NUM> of Antibody <NUM> is approximately <NUM> weeks. The dose levels for patients with HS are <NUM> and <NUM> of Antibody <NUM>, which are selected based on the NCT02148627 study.

Samples for PK analysis are taken prior to each infusion, at the end of the first infusion, and for <NUM> weeks after the final dose. Clinical laboratory safety tests, vital signs, and ECGs are assessed throughout the dosing period, and for <NUM> weeks after the final dose. Immunogenicity (antidrug antibodies) are assessed at multiple time points, with the final sample being taken <NUM> weeks after the last infusion of study medication.

Eligibility of patients for study enrollment is based on the results of screening medical history, physical examination (including weight, height, and temperature), vital signs, clinical laboratory tests, and ECGs.

The nature of any conditions present at the time of the physical examination and any preexisting conditions or relevant medical history are documented.

Screening may occur up to <NUM> days prior to enrollment. Patients who are not enrolled within <NUM> days of screening may be subjected to an additional medical assessment and/or clinical measurements to confirm their eligibility. Some tests may be repeated, at the discretion of the investigator, and do not constitute "rescreening".

Patients are eligible for inclusion in the study only if they meet all of the following criteria at screening and/or enrollment:.

Four HS patients have been intravenously dosed with <NUM> of Antibody <NUM> every <NUM> weeks (Q2W) for a total of <NUM> doses; and one HS patient received placebo with the same dose and dosing regimen. After <NUM> weeks of treatment (<NUM> weeks after the last dose), three of the four HS patients dosed with <NUM> of Antibody <NUM> observed a >= <NUM>% reduction in their counts of abscesses and inflammatory nodules, with one of the four HS patients meeting all of the criteria for the Hidradenitis Suppurativa Clinical Response (HiSCR) endpoint.

Three HS patients have been intravenously dosed with <NUM> of Antibody <NUM> every <NUM> weeks (Q2W) for a total of <NUM> doses. After <NUM> weeks of treatment (<NUM> weeks after the last dose), all three HS patients dosed with <NUM> of Antibody <NUM> observed a >= <NUM>% reduction in their counts of abscesses and inflammatory nodules, and all three patients met all of the criteria for the HiSCR endpoint.

There have been no deaths, SAEs, or discontinuations due to AEs observed in this study.

Therefore, Antibody <NUM> can be used to safely and effectively treat hidradenitis suppurativa in human patients.

Claim 1:
An antibody that binds human growth-regulated oncogene ("Gro")-alpha, human Gro-beta, human Gro-gamma, human epithelial neutrophil activating peptide-<NUM>, human granulocyte chemotactic protein-<NUM>, human neutrophil activating protein-<NUM>, and human interleukin-<NUM>, wherein the antibody comprises light chain complementarity determining regions ("LCDR") LCDR1, LCDR2, LCDR3 and heavy chain complementarity determining regions ("HCDR") HCDR1, HCDR2, HCDR3, wherein LCDR1 comprises SEQ ID NO: <NUM>, LCDR2 comprises SEQ ID NO: <NUM>, LCDR3 comprises SEQ ID NO: <NUM>, HCDR1 comprises SEQ ID NO: <NUM>, HCDR2 comprises SEQ ID NO: <NUM>, and HCDR3 comprises SEQ ID NO: <NUM>, for use in the treatment of hidradenitis suppurativa.