MX2008008946A - Chimeric and humanised anti-human il-13 antibodies - Google Patents

Abstract

The present invention concerns immunoglobulins, particularly antibodies which specifically bind human lnterleukin 13 (hlL-13). Antibodies of the invention may be used in the treatment of a variety of diseases or disorders responsive to modulation of the interaction between hlL-13 and the human IL-13 receptor. Such diseases include severe asthma, atopic dermatitis, COPD and various fibrotic diseases. Pharmaceutical compositions comprising said antibodies and methods of manufacture are also disclosed.

Description

ANTI-ANTIBODIES ANTI-IL-13 (I NTERLEUCIN A 13) HUMAN CHEMICALS AND HUMANIZED FIELD OF THE INVENTION The present invention relates to immunoglobulins that specifically bind to interieucin 13 (IL-13) and, in particular, to human IL-13 (hIL-13). One embodiment of the invention relates to antibodies that specifically bind to hIL-13. The present invention also relates to methods of treating diseases or disorders with immunoglobulins, to pharmaceutical compositions comprising immunoglobulins and to manufacturing methods. Other aspects of the present invention will become apparent from the following description. BACKGROUND OF THE INVENTION Interleukin-13 (IL-13) IL-13 is a secreted cytosine of 12 kDa originally described as a cytosine derived from T cells that inhibits the production of inflammatory cytosine. Structural studies indicate that it has an arrangement in four helical beams maintained by two disulfide bonds. Although IL-13 has four potential glycosylation sites, analysis of native rat lung IL-13 has indicated that it occurs in the form of a non-glycosylated molecule. The expression of human IL-13 from NSO and COS-7 cells confirms this observation (Eisenmesser and col., J. Mol. Biol. 2001 310 (1): 2 31-241; Moy et al., J. Mol. Biol. 2001 310 (1): 219-230; Cannon-Carlson et al., Protein Expression and Purification 1998 12 (2): 239-248). IL-13 is a pleiotropic cytosine produced by a variety of cell types, including activated Th2 cells, mast cells, basophils, dendritic cells, keratinocytes and NKT cells. It can also be produced by virgin ThO, Th1, CD8 and CD45RA + T cells. IL-13 has immunoregulatory activities that partially overlap with those of IL4, this redundancy can be explained by the shared components in the IL4 and IL-13 receptors. IL-13 signals through the IL4 type II receptor, which is a heterodimer composed of the IL4Ra and IL-13Ra1 chains. IL-13Ra1 binds to IL-13 with low affinity (Kd = 2-10 nM), but when paired with IL4Ra, it binds with high affinity (Kd = 400 pM) and forms an IL-13 receptor chain functional (the human receptor is designated herein as "hlL-13R") which signals, resulting in activation of the JAK / STAT and IRS-1 / IRS-2 routes. An additional IL-13 receptor (IL-13Ra2) that binds to IL-13 with high affinity (Kd = 250 pM) has also been characterized. It is believed that IL-13Ra2 acts as a trap receptor that modulates IL-13 activity. IL-13 can also signal through the chain IL13Ra2 (Fichter-Feigl 2006 Nature Medicine 12: 99-106) to induce TGFbetal, and as such may contribute to fibrosis associated with asthmatic pathology.

The functional receptors of IL-13 are expressed in a wide range of cells, including airway epithelium, smooth muscle, mast cells, eosinophils, basophils, B cells, fibroblasts, monocytes and macrophages. T cells do not have functional receptors for IL-13 (Hilton et al., PNAS 1996 93 (1): 497-501; Caput et al., J. Biol. Chem. 1996 271 (28): 16921-16926; Hershey GK, J. Allerav Clin Immunol 2003 111 (4): 677-690). Both IL-13 and IL-4 act by modifying the immune and inflammatory responses promoting the inflammation associated with allergy and suppressing inflammation due to bacteria, viruses and intracellular pathogens. The main biological effects of IL-13 include: induction of B cell proliferation and regulation of isotype change to IgE; induction of MHC II expression and expression of CD23 in B cells and monocytes; positive regulation of VCAM-1 in endothelial cells; regulation of chemokine production; Activation of the function of mast cells, eosinophils and neutrophils, as well as inhibition of pro-inflammatory gene expression in populations of monocytes and macrophages. IL-13 has no proliferative effect on T cells. Therefore, unlike IL4, IL-13 does not appear to be important in the initial differentiation of CD4 T cells into Th2-type cells, but instead appears to be important in the effector phase of allergic inflammation (McKenzie et al., PNAS 1993 90 (8): 3735-3739; Wynn TA, Annu. Rev. Immunol. 200321: 425-456). IL-13 and Asthma Asthma is a chronic lung disease caused by inflammation of the lower respiratory tract, and is characterized by recurrent breathing problems. The patients' airways are sensitive and swollen or inflamed to some degree all the time, even when there are no symptoms. Inflammation results in narrowing of the airways and reduces air flow in and out of the lungs, making it difficult to breathe and leading to gasping, chest compression and coughing. Asthma is triggered by supersensitivity to allergens (eg, dust mites, pollens, molds), irritants (eg, smoke, fumes, strong odors), respiratory infections, exercise and dry weather. Triggers irritate the airways and the lining of the airways swells, becoming even more inflamed, then the mucus clogs the airways and the muscles around the airways are tensed until breathing becomes difficult and stressful and symptoms appear of asthma. There is strong evidence in animal models and patients that asthmatic inflammation and other pathologies are stimulated by deregulated Th2 responses to airborne allergens and other stimuli (Busse et al., Am. J. Resp. Crit. Care Med. 1995 152 (1) : 388-393). In particular, it is believed that IL-13 is the effector of the main cytosine type that stimulates a variety of cellular responses in the lung, including airway hyperreactivity, eosinophilia, goblet cell metaplasia, and mucus hypersecretion. Clinical evidence of the role of IL-13 in asthma The gene encoding IL-13 is located on chromosome 5q31. This region also contains genes encoding IL-3, IL-4, IL-5, IL-9 and GM-CSF, and has been linked to asthma. The genetic variants of IL-13 that are associated with asthma and atopy have been found in both the promoter and coding regions (Vercelli D, Curr Opin., Allerav Clin.Immunol., 2002 2 (5): 389-393). Functional study data are available for the coding variant IL-13 Q130 (hereinafter referred to as "IL-13 Q130"). The single nucleotide polymorphism (SNP) +2044 G to A found in the fourth exon results in a substitution of arginine for glutamine at position 130 (IL-13 Q130). Note also that in SEQ ID NO 9, this is equivalent to position 110, where the first amino acid residue "G" at the beginning of the amino acid sequence of mature human IL-13 is in position 1. It has been found that this variant is associated with asthma, increased levels of IgE and atopic dermatitis in Japanese and European populations. It is believed that IL-13 Q130 has enhanced stability compared to wild-type IL-13. It also has a slightly lower affinity for the trap receptor IL-13Ra2 and, Consistently with these observations, medium serum levels of IL-13 are higher in homozygous patients of the variant IL-13 Q130 compared with non-homozygous patients. These results indicate that IL-13 Q130 could influence the local and systemic concentrations of IL-13 (Kazuhiko et al., J. Allerqy Clin. Immunol.2002 109 (6): 980-987). High levels of IL-13 have been measured in both atopic and non-atopic asthmatics. In one study, mean serum levels of IL-13 of 50 pg / ml were measured in asthmatic patients, compared to 8 pg / ml in control patients (Lee et al., J ^ Asthma 2001 38 (8): 665-671) . Increased levels of IL-13 have also been measured in plasma, bronchoalveolar lavage fluid, lung and sputum biopsy specimens (Berry et al., J Allergy Clin.Immunol 2004 114 (5): 1106-1109; Kroegel et al. , Eur. Respir J. 1996 9 (5): 899-904; Huang et al., J. Immunol. 155 (5): 2688-2694; Humbert et al., J. Allerqy Clin. Immunol. 1997 99 (5): 657-665). In vivo evidence of the involvement of IL-13 in asthma A series of studies have defined a critical effector role for IL-13 in the stimulation of pathology in mouse models of both acute and chronic allergic asthma. The high affinity IL-13 receptor (IL-13Ra2) or polyclonal anti-IL-13 antibodies have been used to neutralize IL-13 bioactivity in mice in these models. Blockade of IL-13 at the time of exposure to allergen completely inhibited airway hyperreactivity induced by OVA, eosinophilia and goblet cell metaplasia. In contrast, administration of antibody against IL-14 after sensitization and during the allergen challenge phase only partially reduced the asthmatic phenotype. Therefore, although exogenous IL-4 and IL-13 are both capable of inducing a phenotype similar to asthma, the effector activity of IL-13 appears to be superior to that of IL-4. These data suggest a primary role for IL-4 in immune induction (particularly for Th2 cell development and recruitment in the airways, and IgE production), while it is believed that IL-13 is primarily compromised in various effector results, including airway hyperreactivity, mucus overproduction and cell inflammation (Wills-Karp et al., Science 1998 282: 2258-2261; Grunig et al., Science 1998 282: 2261-2263; Taube et al., J. Immunol. 2002 169: 6482-6489; Blease et al., J. Immunol. 2001 166 (8): 5219-5224). In complementary experiments, pulmonary IL-13 levels have been elevated by overexpression in a transgenic mouse or by instilling IL-13 protein into the trachea of wild-type mice. In both circumstances, asthma-like characteristics were induced: non-specific airway hyperresponsiveness to cholinergic stimulation, pulmonary eosinophilia, epithelial cell hyperplasia, mucus cell metaplasia, subepithelial fibrosis, obstruction of airways and crystals similar to Charcot-Leyden. In addition, IL-13 was found to be a potent stimulator of matrix metalloproteinases and cathepsin proteases in the lung, resulting in emphysematous changes and mucus metaplasia. Therefore, IL-13 can be an important effector molecule in both asthma phenotypes and COPD disease (Zhu et al., J. Clin, Invest, 1999 103 (6): 779-788; Zheng et al., J. Clin. Invest. 2000 106 (9): 1081-1093). These data indicate that IL-13 activity is. both necessary and sufficient to produce several of the main clinical and pathological features of allergic asthma in well validated animal models. Chronic obstructive pulmonary disease (COPD) COPD is a generic term that covers various clinical syndromes, including emphysema and chronic bronchitis. The symptoms are similar to asthma, and COPD can be treated with the same drugs. COPD is characterized by a chronic, progressive and largely irreversible obstruction of the respiratory flow. The contribution of the individual to the course of the disease is unknown, but it is believed that smoking cigarettes causes 90% of cases. Symptoms include cough, chronic bronchitis, dyspnea and respiratory infections. Ultimately, the disease will lead to severe disability and death. Chronic bronchitis is diagnosed in patients with a history of cough or sputum production most days during minus 3 months of the year for more than 2 years in a row without any other explanation. Lung emphysema is characterized by an abnormal permanent enlargement of the breathing spaces and the destruction of the alveolar walls. IL-13 can play a role in the development of the COPD Human smokers who develop COPD have many types of inflammatory cells (neutrophils, macrophages, eosinophils) in the lung parenchyma. IL-13 is a proinflammatory Th2 cytosine, therefore, to model the progression of emphysema, Zheng et al. directed the overexpression of IL-13 to the airway epithelium in transgenic mice of IL-13. These animals developed emphysema and lung parenchymal inflammation and respiratory tract. They also developed mucus metaplasia reminiscent of chronic bronchitis (J. Clin.InvesJ 2000 106 (9): 1081-1093). It has also been reported that the promoter polymorphism of IL-13 (-1055 C to T) that is associated with allergic asthma has an increased frequency in patients with COPD compared with healthy controls. This implies a functional role for the polymorphism of the IL-13 promoter in the increased risk of developing COPD (Kraan et al., Genes and Immunity 2002 3: 436-439). In addition, an increased number of IL-13 and IL-4 positive cells was observed in smokers with chronic bronchitis, compared with asymptomatic smokers (Miotto et al., Eur. Resp. J. 2003 22: 602-608). However, a recent study To assess the level of expression of IL-13 in the lungs of patients with severe emphysema, no association was found between the levels of IL-13 and the disease (Boutten et al., Thorax 200459: 850-854). Allergic disease, including atopic dermatitis and allergic rhinitis IL-13 has also been implicated in atopic disorders such as atopic rhinitis and atopic dermatitis. Allergic rhinitis is the most common atopic disease in the United States, and it is estimated that it affects up to 25% of adults and more than 40% of children. There is a close relationship between allergic rhinitis and asthma. Both conditions share a common immunopathology and pathophysiology; they have similar immunological processes in which eosinophils and Th2 lymphocytes in nasal and bronchial tissue play a role. It is believed that excessive production of Th2 cytokines, particularly IL-4 and IL-5, is critical in the pathogenesis of allergic disease. IL-13 shares several effector characteristics and functions with IL-4 and this, combined with the functional overlap in the use of the receptor, intracellular signaling components and genetic organization of IL-4 and IL-13, provides convincing (albeit indirect) evidence ) of a role of IL-13 in the promotion or maintenance of immediate human hypersensitivity in vivo. This has been corroborated by Li et al. (Li et al J. Immunol 1998, 161: 7007), which showed that atopic subjects with rhinitis Seasonal allergy exhibited significantly stronger IL-13 responses in response to Ag-dependent but not polyclonal activation. Atopic dermatitis is a common chronic pruritic relapsing inflammatory disease. Injured skin of patients with atopic dermatitis is histologically characterized by an infiltrate of inflammatory T cells, which during the acute phase is associated with the predominance of expression of IL-4, IL-5 and IL-13 (Simón et al., J Allergy Clin. Immunol., 2004; 114: 887; Hamid et al., J Allergy Clin. Immunol. nineteen ninety six; 98: 225). In addition, Tazawa et al. have shown that IL-13 mRNA (but not IL-4) is significantly upregulated in subacute and chronic dermal lesions of patients with atopic dermatitis (Tazawa et al., Arch. Derm. Res. 2004; 296: 459) . The frequency of circulating CD4 + and CD8 + T cells expressing IL-13 also increases significantly in these patients (Aleksza et al., British J. Dermatol, 2002: 147; 1135). This increased IL-13 activity is believed to result from elevated levels of serum IgE, thus contributing to the pathogenesis of atopic dermatitis.

In addition, increased production of IL-13 by neonatal CD4 + T cells is a useful marker for identifying newborns at high risk of later development of allergic diseases, especially atopic dermatitis (Ohshima et al., Pediatr. Res. 2002; 51: 195 ). Additional evidence was provided Importance of IL-13 in the etiology of atopic dermatitis by Simon et al. (Simón et al., J. Allergy Clin. Immunol., 2004; 114: 887); topical treatment with tacrolimus ointment (an immunosuppressive drug that inhibits intracellular signaling pathways for cytosine production) resulted in significant clinical and histological improvement of atopic skin lesions, accompanied by significant reductions in local expression of Th2 cytokines , including IL-13. In addition, it has been shown that IL-13 Ra1 (a cell surface protein that together with IL-4Ra forms a functional receptor for IL-13) is overexpressed in suprabasal keratinocytes in the skin of patients with atopic dermatitis, and that the IL- 13 was able to positively regulate the IL-13 Ra1 mRNA in vitro (Wongpiyabovorn et al., J. Dermatol, Science 2003; 33:31). These data collectively indicate that interventions targeting IL-13, including an IL-13 monoclonal antibody, can provide an effective approach for the treatment of human allergic disease. Esophageal eosinophilia The accumulation of eosinophils in the esophagus is a common medical problem in patients with various diseases, including gastroesophageal reflux disease, eosinophilic esophagitis, eosinophilic gastroenteritis and parasitic infections. Esophageal eosinophilia is associated with allergic responses, and repeated exposure of mice to airborne allergens established a link between allergic inflammation of the respiratory tract and esophageal eosinophils. It is believed that Th2 cells induce inflammation associated with eosinophilia by secreting a series of cytosines, including IL-4 and IL-13, which activate the inflammatory and effector pathways both directly and indirectly. IL-13 appears to be particularly important, because it is produced in large quantities by Th2 cells and regulates multiple traits of allergic disease (eg, IgE production, mucus overproduction, eosinophilic recruitment and survival, and hyperresponsiveness of Respiratory tract Eosinophils can generate functionally active IL-13 after exposure to GM-CSF and / or IL-5 under in vitro conditions, ex vivo, and in vivo in eosinophilic inflammatory responses (Schmid-Grendelmeier J. Immunology, 2002 , 169: 1021-1027) IL-13 delivered to the lung of wild type mice, deficient in STAT-6, eotaxin-1 or IL-5, by intratracheal administration, established that the lung inflammation triggered by IL-13 is associated with the development of esophageal eosinophilia (Mishra et al., Gastroenterol, 2003; 125: 1419) Taken together, these data provide evidence of a role for IL-13 in esophageal eosinophilia. Oncology training Another important area of interest is targeting IL-13 or IL-13 receptors to inhibit the growth of certain types of tumors It is believed that host defenses mediated by type 1 T cells mediate optimal tumor rejection in vivo, and deviation to a Th2 type response may contribute to block tumor rejection and / or the promotion of tumor recurrence (Kobayashi M. et al., J. Immunol, 1998; 160: 5869).

Several animal studies using transplantable tumor cell lines support this notion, demonstrating that Statß, IL-4, and IL-13 (produced, in part, by NKT cells) were capable of inhibiting tumor rejection (Terabe et al., Nat. Immunol., 2000; 1: 515; Kac et al., J. Immunol., 2000; 165: 6024-28; Ostrand-Rosenberg et al., J. Immunol., 2000; 165: 6015). The potent antitumor activity in the absence of Stat-6 was believed to be due to the enhancement of tumor-specific IFNg production and CTL activity. In addition, it has been shown that a loss of NKT cells reduces the production of IL-13, with a concomitant rise in tumor recurrence, indicating that IL-13, produced in part by NKT cells, is important for immunosurveillance (Terabe and col. Nat. Immunol., 2000; 1: 515). As such, these findings suggest that inhibitors of IL-13 or new IL-13 antagonists, including IL-13 mAb, may be effective as cancer immunotherapy by interfering with the negative regulatory role that IL-13 plays in the negative regulation of immune responses to tumor cells. In addition to reinforcing the antitumor defenses associated with Th of type 1, inhibitors of IL-13 may also be able to block the growth of tumor cells more directly. For example, in chronic B-cell lymphocytic leukemia (B-CLL) and Hodgkin's disease, IL-13 blocks apoptosis or promotes the proliferation of tumor cells (Chaouchi et al Blood 1996; 87: 1022; Kapp et al. J. EXP. Med. 1999; 189: 1939). B-CLL is a clinically heterogeneous disease originating from B lymphocytes that involves an apoptotic defect in leukemic cells. It is believed that IL-13 does not act as a direct growth factor, but protects tumor cells from spontaneous apoptosis in vitro (Chaouchi et al Blood 1996; 87: 1022; Lai et al., J. Immunol., 1999: 162 : 78) and can contribute to B-CLL by preventing the death of neoplastic cells. Hodgkin's disease is a type of lymphoma that primarily affects young adults and accounts for approximately 7,500 cases a year in the United States. Cancer is characterized by the presence of large multinucleated Hodgkin / Reed-Sternberg (H / RS) cells. In a large majority of cases, the population of malignant cells arises from B cells. Several cell lines derived from Hodgkin's disease, as well as lymph node tissue taken from patients with Hodgkin's lymphoma, overexpress IL-13 and / or IL-13. (Kapp et al J. Exp. Med. 1999; 189: 1939, Billard et al., Eur. Cvtokine Netw. 1997; 8:19; Skinnider et al. cabbage. Blood 2001; 97: 250; Oshima et al., Cell Immunol. 2001; 211: 37). It has been shown that anti-IL-13 neutralizing mAbs or IL-13 antagonists inhibit the proliferation of H / RS cells in a dose-dependent manner (Kapp ef al, J. Exp. Med. 1999; 189: 1939; Oshima et al., Cell Immunol., 2001; 211: 37). Similarly, the delivery of soluble IL-13Ra2 trap receptor to NOD / SCID mice with a cell line derived from implanted Hodgkin's disease delayed tumor onset and growth, and potentiated survival, demonstrating that neutralization of IL-13 can suppress the growth of Hodgkin's lymphoma in vitro and in vivo (Trieu et al Cancer Research 2004; 64: 3271). Collectively, these studies indicate that IL-13 stimulates proliferation of H / RS cells in an autocrine manner (Kapp et al J. Exp. Med. 1999; 189: 1939; Ohshima et al., Histopatholoav 2001; 38: 368). The neutralization of IL-13 may therefore represent an attractive and effective treatment for Hodgkin's disease and other B cell-associated cancers by inhibiting the growth of tumor cells while at the same time enhancing the antitumor defenses. Intestinal inflammatory diseases There is a possible role for IL-13 in the pathogenesis of inflammatory bowel disease (Eli). Inflammatory bowel disease comprises a series of diseases classified clinically as ulcerative colitis, Crohn and indeterminate colitis. Its main manifestation is chronic intestinal inflammation due to an exaggerated immune response with an imbalance in the activation of Th1 and Th2 lymphocytes in the intestinal mucosa. This has been demonstrated in animal models of Crohn's disease (Bamias et al., Gastroenterol. 2005; 128: 657) and ulcerative colitis (Heller et al., Immunitv 2002; 17: 629). Neutralization of IL-13 by administration of IL-13Ra2-Fc prevented colitis in a murine Th2 model of human ulcerative colitis (Heller et al., Immunitv 2002; 17: 629). In addition, the production of IL-13 rapidly replaces that of IL-4 in this model, and the production of IL-13 can be induced by stimulation of NKT cells, suggesting that tissue damage may be the result of toxic activity of IL-13 on epithelial cells. There is some human evidence to support these findings: the frequency of rectal biopsy samples positive for IL-13 from patients with ulcerative colitis was significantly higher than in inflammatory and non-inflammatory control subjects, and a higher rate of IL-4 expression was observed and IL-13 in acute ulcerative colitis than in non-acute colitis (Inoue et al., Am. J. Gastroenterol, 1999; 94: 2441). In addition, Akido et al. characterized immune activity in the outer muscles of intestinal segments of patients with Crohn's disease and found that IL-4 and IL-13 mediated the hyper-contractibility of intestinal smooth muscle cells via a STAT-6 route. The authors concluded that this route may contribute to the hyper-contractibility of the intestinal muscles in Crohn's disease (Akiho et al., Am. J. Phvsiol. Gastrointest., Liver Phvsiol., 2005: 288: 619). Thus, an IL-13 mAb, possibly in combination with molecules directed to other cytosines, may provide an approach for stopping or slowing the progression of Eli. Psoriasis and psoriatic arthritis Psoriasis is a chronic dermal disease characterized by hyperproliferation of keratinocytes and an immunological cellular infiltrate, including activated T cells, which produces various cytosines that may influence the phenotype of epidermal keratinocytes. CDw60 is a carbohydrate carrier molecule that is positively regulated on the surface of psoriatic basal and suprabasal keratinocytes of psoriatic skin. IL-4 and IL-13 secreted from T cells derived from psoriatic lesions have been shown to positively regulate the expression of CDw60 in keratinocytes (Skov et al., Am J Pathol. 1997; 15: 675), while interferon gamma blocked the induction of CDwdO mediated by IL-4 / IL-13 in cultured keratinocytes (Huang et al., J. Invest, Dermatol, 2001; 116: 305). Therefore, it is believed that the expression of CDw60 on psoriatic epidermal keratinocytes is induced at least in part by IL-13 secreted by activated T cells within the lesion. In addition, IL-13 Ra1 and IL-4Ra, cell surface proteins that together form a receptor complex for IL- 13, are expressed differently in skin biopsies from patients with and without psoriasis (Cancino-Diaz et al., J. Invest, Dermatol, 2002; 119: 1114; Wongpiyabovorn et al., J. Dermatol, Science 2003; 33: 31 ), and in vitro experiments demonstrated that IL-13 (but not IL-4) could positively regulate the expression of IL-13Ra1 (Wongpiyabovorn et al., J. Dermatol, Science 2003; 33: 31). Since IL-13 has an effect on a variety of cell types, these studies suggest that the IL-13 receptor may play a role in the early inflammatory process of psoriasis.

Psoriatic arthritis is characterized by synovitis that is mediated by both pro-inflammatory and anti-inflammatory cytokines. The role of IL-13 in various forms of arthritis has been receiving increasing interest. Spadaro et al. have observed significantly higher levels of IL-13 in synovial fluid from patients with psoriatic arthritis and rheumatoid arthritis than in patients with osteoarthritis. In addition, levels of IL-13 in synovial fluid were significantly higher than in serum of patients with psoriatic arthritis, and the ratio of IL-13 in synovial fluid / serum was markedly higher in the psoriatic arthritis group than in the arthritis group. rheumatoid, suggesting a possible role of locally produced IL-13 in synovial tissues of patients with psoriatic arthritis (Spadaro et al .. Ann.Rum.Dis.2002; 61: 174).

Potential role of IL-13 in other conditions Acute graft-versus-host disease is a severe case of morbidity and mortality after stem cell transplantation, and is directly related to the degree of incompatibility of human leukocyte antigen (HLA) between donor and receiver. Jordán et al. identified for the first time IL-13 as a typical Th2 cytosine that occurs abundantly during non-coincident, unrelated MLRs (mixed lymphocytic reaction, an in vitro assay to fine-tune donor selection after initial HLA typing) (Jordan and col J. Immunol, Methods: 2002; 260: 1). The same group subsequently showed that the production of IL-13 by donor T cells is predictive of acute graft-versus-host disease (ElCHa) after transplantation of unrelated donor stem cells (Jordán et al Blood 2004; 103: 717). All patients with severe Grade III ElCHa after stem cell transplantation had donors that produced very high pre-transplant IL-13 responses, demonstrating a significant link between the levels of IL-13 and ElCHa, and raising the possibility that IL-13 may be directly responsible for some of the pathologies associated with ElCHa. Accordingly, a therapy based on specific blockade of IL-13 may be useful for the treatment of ElCHa post-stem cell transplantation. Diabetic nephropathy is one of the main causes of end-stage renal disease in the western world. Although the incidence of nephropathy due to type 1 diabetes is decreasing, type 2 diabetes mellitus is now the single most common cause of kidney failure in the US, Japan, and Europe. In addition, this group of patients has a very poor prognosis of maintenance dialysis due to the extremely high mortality caused by cardiovascular events. It is increasingly clear that hemodynamic, metabolic and structural changes are interwoven, and various enzymes, transcription factors and growth factors have been identified that play a role in the pathogenesis of this disease. Particularly, TGF-β is important in the development of renal hypertrophy and the accumulation of extracellular matrix components, and is considered the key cytosine in mediating the formation of collagen in the kidney (Cooper, Diabetoloaia 2001; 44: 1957; Wolf. Eur. J. Clin. Invest. 2004; 34 (12): 785). In experimental and human diabetic nephropathy, the bioactivity of TGF-1 increases, and the administration of TGF-β1a antibodies to diabetic mice led to the improvement of renal function and to a reduced accumulation of extracellular matrix. It has recently been shown in a transgenic mouse model of pulmonary fibrosis that IL-13 mediates its effects at least in part by regulating the production and activation of TGF-β and collagen deposition (Lee et al., J. Exp. Med. 2001).; 194: 809; Zhu et al., J. Clin. Invest. 1999; 103: 779), thus establishing a direct functional link between IL-13 and TGF-β. Accordingly, a similar role for IL-13 in the regulation of TGF-β1 activity in the diabetic kidney can be envisaged, and interventions targeting IL-13 could potentially play a role in the management of diabetic nephropathy. Fibrotic conditions Pulmonary fibrosis is an inappropriate and damaging scarring condition of the lungs that leads to disability and often death. The term covers a variety of different conditions with different etiologies, pathologies and responses to treatment. In some cases, the cause of fibrosis is identified. Causes include: (1) inhaled profibrotic material such as asbestos or silicon, or hard metal powder, (2) inhaled organic material to which the patient has an idiosyncratic immune response that leads to fibrosis (eg, farmer's lung), (3) drugs such as nitrofurantoin, amiodarone and methotrexate (4) in association with a systemic inflammatory disease such as systemic sclerosis or rheumatoid arthritis. However, in many cases, the underlying cause or condition is not identified. Many of the patients are diagnosed with idiopathic pulmonary fibrosis (IPF). This is a relatively rare condition (20 / 100,000 prevalence). The diagnosis is based on the absence of an identified cause combined with certain radiological and pathological features, particularly honeycombing on CT or lung biopsy. The disease is usually seen in older patients (> 50) and often follows an inexorable course of progressive pulmonary deficiency leading to death, with a median survival of 2-5 years. In addition, patients have the most unpleasant experience of dyspnea progression for months or years. This initially limits physical activity, but in the terminal phase, which may last several months, the patient is dyspneic even at rest and is also oxygen dependent. Currently there is no satisfactory treatment for this disease. The current treatment usually takes the form of corticosteroids and immunosuppressants such as azathioprine. However, corticosteroids can be ineffective in many patients and their side effects can make the situation worse. There are many potential treatments under investigation, including interferon gamma, which has shown a tendency to improve survival in a large recent study, and perfenidone. There is evidence that IL-13 and cytokines associated with the Th2 phenotype are involved in the process of fibrosis in tissue repair (Wynn TA, Nat. Rev. Immunol. 2004 4: 583-594; Jakubzick et al., Am. J. Pathol, 2004 164 (6): 1989-2001, Jakubzick et al., Immunol Res. 2004 30 (3): 339-349; Jakubzick et al., J. Clin. Pathol. 2004 57: 477 -486). IL-13 and IL-4 have been implicated in a variety of fibrotic conditions. Fibrosis Hepatica induced by Schistosoma appears to be dependent on IL-13, and there is limited evidence that IL-13 is involved in the pathogenesis of scleroderma (Hasegawa et al., J. Rheumatol., 1997 24: 328-332; Riccieri et al. , Clin.Ruumatol., 2003 22: 102-106) In terms of pulmonary fibrosis, in vitro studies have shown that IL-13 promotes a fibrogenic phenotype. Animal studies have shown high levels of IL-13 expression in artificially induced models of fibrosis, and that fibrosis can be reduced by eliminating IL-13. IL-13 promotes a profibrotic phenotype. At the cellular level, there are several mechanisms by which IL-13 can promote fibrosis. Signaling routes and the importance of these various mechanisms are not well defined. There is evidence that IL-13 acts on the fibroblast both to promote the production of collagen and to inhibit its degradation, thus favoring a fibrotic phenotype. Dermal fibroblasts possess IL-13 receptors (= IL-4 type II receptor), and exposure of cultured dermal fibroblasts to IL-13 leads to positive regulation of collagen generation (Oriente et al., J. Pharmacol. Exp. Ther. 2000 292: 988-994). IL-4 has a similar effect, but more transient. A human pulmonary fibroblast cell line (ICIG7) expresses the type II IL-4 receptor (Jinnin et al., X. Biol. Chem. 2004 279: 41783-41791). The exposure of these Cells to IL-13 promotes the secretion of a variety of inflammatory and profibrotic mediators: GM-CSF, G-CSF, VCAM betal integrin (Doucet et al., Int. Immunol. 1998 10 (10): 1421-1433). The production of IL-13 proteins inhibited the matrix metalloproteinases 1 and 3 induced by IL-1a and by dermal fibroblasts, which would tend to reduce the degradation of the EC matrix (Oriente et al., J. Pharmacol. Exp. Ther. 2000 292: 988-994). IL-13 acts synergistically with TGF-β. on human fibroblasts obtained by asthmatic airway biopsy promoting the expression of tissue inhibitor of metalloproteinase 1 (TIMP-1). Degradation of the extracellular matrix is effected by matrix metalloproteinases, which are inhibited by TIMP-1. This action of IL-13 would thus tend to reduce matrix degradation (Zhou et al., Am.

J. Phvsiol. Cell Phvsiol. 2005288: C435-C442) Overexpression of IL-13 in transgenic mice leads to subepithelial fibrosis, epithelial cell hypertrophy, goblet cell hyperplasia, crystal deposition (mammalian acid chitinase), airway hyperreactivity, interstitial fibrosis, hypertrophy of type 2 cells and accumulation of surfactant (Zhu et al., J. Clin.Research 1999 103 (6): 779-788). Different strains of mice have different sensitivities to bleomycin-induced pulmonary fibrosis. The rats C57B1 / 6J, which are sensitive, exhibit rapid up-regulation of IL-13, IL-13Ra and IL-4 (as well as TGFβ, TNFRα and IL1Rs) in response to bleomycin. BALB / c mice, which are not sensitive, do not show positive regulation of IL-13. Belperio et al. (Am. J. Resoir, Cell Mol. Biol. 2002 27: 419-42) studied the expression and role of IL-13, IL-4 and CC C10 chemokine in a model of bleomycin fibrosis in mouse. Lung tissue levels of both IL-13 and IL-4 increased in response to bleomycin. Previous neutralization of IL-13 using polyclonal anti-IL-13 antibodies significantly reduced pulmonary fibrosis in response to bleomycin, as assessed by the pulmonary levels of hydroxyproline. Despite the increased expression of IL-4 in the same model, the neutralization of IL-4 had no effect on pulmonary fibrosis. In another model of acute pulmonary fibrosis induced by FITC in BALB / c mice, the absence of IL-13 (in gene cancellations), but not of IL-4, protected against pulmonary fibrosis. There is no added protection in gene knockdown of IL-4 in IL-13 gene knockouts (Kolodsick et al., J. Immunol. 172: 4068-4076). The protective effect of the absence of IL-13 is not due to the difference in cellular recruitment in the lung: in all gene knockouts and BALB / c, the total cell numbers recruited are similar, so that the initial inflammatory component seems not be affected The recruitment eosinophilic is lower in gene knockdowns of IL-4 and IL-13 compared to BALB / c, but since IL-4 - / - were not protected against fibrosis, this can not explain the difference in fibrosis. Perhaps surprisingly, there was no difference in cytosine levels between IL-13 + / + and - / -, including IL10, MCP-1, interferon gamma, TGF-γ. In addition, the same number of lung fibroblasts from different animals was isolated after FITC, but in IL-13 - / - mice, the production of collagen I is reduced. This indicates that the loss of IL-13 does not simply prevent the inflammatory response, but instead has a more specific antifibrotic role. It has been suggested that IL-13 could exert its fibrotic effect by TGF-γ (Lee et al., J. Exp. Med. 2001 194: 809-821). However, in this FITC model, the expression of TGF-γ was not reduced in mice with gene knockdown of IL-13. It can be expected that interieucin 4 exerts an effect similar to IL-13, since both act through the same receptor. IL-4 is significantly up-regulated in the lungs of mice with bleomycin-induced pulmonary fibrosis (Gharaee-Kermani et al., Cytokine 2001 15: 138-147).

However, by comparing bleomycin-induced pulmonary fibrosis in C57BL6 / J mice overexpressing IL-4, with IL-4 gene knockdown and wild-type, Izbicki et al. (Am. J. Phvsiol, Lunq Cell Mol, Phvsiol 2002 283 (5): L1110-L1116) found no evidence that IL-4 was involved in the pulmonary fibrosis. Fibrosis was not reduced in IL-4 gene knockouts, and mice overexpressing IL-4 had increased levels of fibrosis. The levels of cytosine IL-13 in BAL are significantly elevated in patients with a variety of forms of pulmonary fibrosis, although with considerable variability. The expression of IL-13 is significantly regulated positively in alveolar macrophages obtained from patients with pulmonary fibrosis. The strongest clinical evidence comes from research at the University of Michigan. Jakubzick and colleagues have studied the gene expression of IL-13 and IL-4 and their receptors in surgical lung biopsies of patients with pulmonary fibrosis. Gene expression of IL-13 is markedly higher in lung samples affected by IPF than in normal lung or other pulmonary fibrotic conditions. Fibroblasts cultured from patients with IPF / NIU show high expression of the IL-13 and IL-4 receptor, compared to tissue and fibroblast biopsies obtained from patients with normal lungs or other forms of pulmonary fibrosis. In particular, fibroblastic foci, which are presumably the epicenter of pathological activity, stain particularly strongly for these receptors (Jakubzick et al., J. Immunol 2003 171: 2684-2693; Jakubzick et al., Am. J. Pathol 2003 162: 1475-1486; Jakubzick et al., Am. J. Pathol. 2004 164 (6): 1989-2001; Jakubzick et al., Immunol. Res. 2004 30 (3): 339-349; Jakubzick et al., J. Clin. Pathol. 200457: 477-486). There is good in vitro evidence that Th2 cytokines in general, and IL-13 in particular, promote a profibrotic phenotype. In at least two animal models, it has been shown that chemically induced fibrosis can be reduced by eliminating IL-13 (in gene knockouts or by anti-IL-13 antibodies). Some evidence indicates that IL-13 is more important in promoting pulmonary fibrosis than IL-4. Clinical evidence of the role of IL-13 in pulmonary fibrosis suggests that IL-13 and its receptors are not regulated in the lungs of patients with IPF. A growing body of data suggests an important role for IL-13-based therapies for the treatment of a variety of fibrotic conditions, including schistosomiasis-induced liver fibrosis and various forms of pulmonary fibrosis (eg, IPF [discussed elsewhere], scleroderma ). Experiments in which IL-4 and IL-13 were independently inhibited, identified IL-13 as the dominant effector cytosine of fibrosis in several models (Chiaramonte et al., J. Clin, Invest, 1999; 104: 777-785). Blease et al J. Immunol. 2001; 166: 5219; Kumar et al. Clin. Exp. Allergy 2002; 32: 1104).

In schistosomiasis, although the egg-induced inflammatory response was not affected by the blockade of IL-13, the Collagen deposition was reduced by more than 85% in chronically infected animals (Chiaramonte et al J. Clin. Invest., 1999; 104: 777; Chiaramonte et al. Hepatology 2001; 34: 273) despite the continuous and non-reduced production of IL-4. The amino acid sequence for hlL-13 is exposed as SEC NO ID 9. (This is the mature protein sequence, ie no signal sequence is present). A polynucleotide encoding hIL-13 is exposed in the SEC NO ID 10. (This is the DNA sequence of the mature protein sequence, ie no signal sequence is present). All references to patents and patent literature disclosed in the present description (including any patent application for which this application claims priority) are expressly and entirely incorporated herein by reference.

Recently, vaccines have been described that produce immune responses against IL-13 for the treatment of asthma (WO 02/070711). A role for IL-13 in sensitizing the skin to environmental allergens has also recently been described (Herrick et al., The Journal of Immunology, 2003, 170: 2488-2495). The present invention provides an antibody that binds to hIL-13 and inhibits the binding of hIL-13 to both chains of hIL-13R, namely, IL-13Ra1 and IL-13Ra2.

Brief Description of the Invention Therefore, the present invention provides an antibody or antigen-binding fragment thereof that specifically binds to hIL-13 and neutralizes the activity of hIL-13. The present invention provides an antibody or antigen-binding fragment thereof that specifically binds to hIL-13 and comprises a CDRH3 which is a variant of the sequence set forth in SEQ ID NO 3 or a variant in which one or two residues of amino acids within the CDRH3 of the variant differ from the amino acid residue in the corresponding position in SEQ ID NO. 3. In one embodiment of the present invention, these differences in amino acid residues are conservative substitutions. The term "specifically binds", as used throughout the present descriptive with respect to antibodies and antigen-binding fragments thereof of the invention, means that the antibody binds to hIL-13 with null or insignificant binding to other human proteins and, in particular, to human IL-4. The term, however, does not exclude the fact that the antibodies of the invention can also be cross-reactive with Cynomolgus IL-13. The term "neutralizes", as used throughout the present descriptive with respect to antibodies and antigen-binding fragments thereof, means that the biological activity of IL-13 is reduced in the presence of the antibodies and antigen-binding fragments of the present invention compared to the activity of IL-13 in the absence of the antibodies and antigen-binding fragments thereof. Neutralization levels can be measured in various ways, for example, by using assays as indicated in the following examples, for example, in a TF-1 cell proliferation assay that can be carried out, for example, as described in FIG. described in Example 3.3-3.5. The neutralization of IL-13 in this assay is measured by evaluating the proliferation of reduced TF-1 cells in the presence of neutralizing antibody. If an antibody or antigen-binding fragment thereof is capable of neutralization, then this is indicative of inhibition of the interaction between hIL-13 and its receptor. Antibodies that are considered to have neutralizing activity against human IL-13 would have a DN50 of less than 100 μg / ml, Or less than 80 μg / ml in the TF-1 cell proliferation assay as indicated in example 3.3, 3.4 or 3.5. In an alternative aspect of the present invention, there are provided antibodies or antigen-binding fragments thereof having neutralizing activity equivalent to the antibodies exemplified herein, for example, antibodies that retain the neutralizing activity of H2L1 in the proliferation assay. of TF-1 cells as indicated in example 3.3, 3.4 or 3.5. As used herein, the term "modulates" means inhibition of the binding of IL-13 to its receptor, and / or blockade of the interaction between IL-13 and its receptor, thus decoupling the signaling pathway h I L-13 / h I L-13R. This may be inhibition and / or blocking of either or both of IL-13Ra1 and IL-13Ra2. The receptor h I L-13 as used herein means one or both of these receptors. The inhibition of the binding of IL-13 to its receptor can be measured in several ways, for example, by using the assays indicated in the following examples, for example, an ELISA procedure such as that described in Example 6.5 and 6.6. The antibodies and antigen-binding fragments thereof of the present invention may be therapeutic antibodies and antigen-binding fragments thereof.specifically, suitable for use in therapy. In one aspect, there is provided an antibody or antigen-binding fragment thereof that specifically binds to hIL-13, and comprises a CDRH3 comprising the sequence set forth in SEQ ID NO 3. In one embodiment, the antibody or fragment of antigen binding of the present invention neutralizes human IL-13. In another embodiment, the antibody or antigen-binding fragment of the present invention modulates the binding of human L-13 to its receptor. In another aspect of the present invention, there is provided an antibody or antigen-binding fragment thereof that binds specifically to h I L-13 and modulates the interaction between h I L-13 and ML-13R. In certain embodiments, the antibodies of the invention inhibit at least the interaction between h I L-13 and hIL-13R, but may also block the interaction between h I L-13 and hIL-13R, thereby decoupling the signaling pathway h I L-13 / h I L-13R. In another embodiment, the present invention provides an antibody or antigen-binding fragment wherein the CDRH3 comprises the sequence of SEQ ID NO. 3. In a further embodiment, the antibody or antigen-binding fragment thereof of the present invention comprises additionally one or more of the following sequences CDRH2: SEC NO ID 2, CDRH1: SEC NO ID 1, CDRL1: SEC NO ID 4, CDRL2: SEC NO ID 5 and CDRL3: SEQ ID NO. 6. In a further embodiment, the present invention further comprises these CDR sequences in the context of a human framework, for example, in the form of a humanized antibody or fragment thereof. In another aspect of the present invention, there is provided an antibody or antigen-binding fragment thereof that specifically binds to hIL-13, and comprises the following CDRs: CDRH1: SEC NO ID 1 CDRH2: SEC NO ID 2 CDRH3: SEC NO ID 3 CDRL1: SEC NO ID 4 CDRL2: SEC NO ID 5 CDRL3: SEQ ID NO. 6 In one embodiment of the present invention, one or more of the CDRs of the antibody or antigen-binding fragment can comprise variants of the CDRs indicated in the sequences listed above. Each CDR variant will comprise one or two amino acid residues that differ from the amino acid residue in the corresponding position in the sequence listed above. Substitutions in the amino acid residues may be conservative substitutions, for example, substituting a hydrophobic amino acid for an alternative hydrophobic amino acid, for example, substituting leucine for valine or isoleucine. Throughout this specification, the amino acid residues in the antibody sequences are numbered according to the Kabat scheme. Similarly, the terms "CDR", "CDRL1", "CDRL2", "CDRL3", "CDRH1", "CDRH2", "CDRH3" follow the Kabat numbering system as set forth in Kabat et al .; "Sequences of proteins of Immunological Interest" NIH, 1987, with the exception that position 30 of the heavy chain is taken as part of a CDR. As used herein, the term "comprising" and "comprises" incorporates "constituted by". In another aspect of the invention, there is provided an antibody or antigen-binding fragment thereof comprising a VH domain comprising the exposed sequence in SEQ ID NO 7 and a VL domain comprising the sequence set forth in SEQ ID NO: 8. In another aspect of the invention, there is provided a VH domain isolated from an antibody comprising the sequence selected from the group consisting of SEQ ID NOs. ID 7, 11, 12, 13 and 14. In one embodiment, the VH domain isolated from an antibody is constituted or is essentially constituted by a VH domain isolated from an antibody selected from the group consisting of SEQ ID NO: 7, 11, 12 , 13 and 14. In another aspect of the invention, there is provided an antibody or antigen-binding fragment thereof comprising a VH domain selected from the group consisting of SEQ ID NO: 7, 11, 12, 13 and 14. In another aspect of the invention, there is provided an antibody that binds specifically to hIL-13 and inhibits at least the interaction between h I L-13 and hIL-13R, the antibody comprising a heavy chain of SEQ ID NO: 18 and a light chain selected from group constituted by SEC NO ID 22, 23 and 24. In another aspect of the invention, there is provided an antibody that specifically binds AH I L-13 and inhibits at least the interaction between h I L-13 and hlL-13 R, the antibody comprising a heavy chain of SEC NO ID 19 and a light chain selected from the group consisting of SEQ ID NO 22, 23 and 24.

In another aspect of the invention, there is provided an antibody that binds specifically to hIL-13 and inhibits at least the interaction between h I L-13 and hIL-13R, the antibody comprising a heavy chain of SEQ ID NO 20 and a chain light selected from the group constituted by SEC NO ID 22, 23 and 24. In another aspect of the invention, there is provided an antibody that binds specifically to hl L-13 and inhibits at least the interaction between h I L-13 and hlL-13R, the antibody comprising a heavy chain of SEC NO. ID 21 and a light chain selected from the group consisting of SEQ ID NO 22, 23 and 24. In another aspect of the invention, there is provided an antibody or antigen-binding fragment thereof that inhibits antibody binding, comprising a heavy chain of SEC NO ID 18 and a light chain of SEC NO ID 22 to hlL-13. According to the present invention, a humanized antibody is provided, the antibody comprising a VH domain of SEQ ID NO: 11 and a V L domain selected from the group consisting of SEQ ID NO: 15, 16 and 17. According to the present invention , a humanized antibody is provided, the antibody comprising a domain VH of SEC NO ID 12 and a VL domain selected from the group constituted by SEQ ID NOs 15, 16 and 17. According to the present invention, a humanized antibody, the antibody comprising a VH domain of SEQ ID NO 13 and a V L domain selected from the group consisting of SEQ ID NOs 15, 16 and 17. In accordance with the present invention, a humanized antibody is provided, the antibody comprising a VH domain of SEC NO ID 14 and a VL domain selected from the group consisting of SEQ ID NOs 15, 16 and 17. According to the present invention, there is provided an antibody or antigen-binding fragment thereof which binds to the peptides indicated in SEQ ID NO: 90, 99, 102, 103, 105, 106, 107, 108, 109, 110, 111, 112 and 114, but does not bind to the peptides indicated in SEQ ID NOs 100, 101, 104 and 113, wherein the binding is defined as having a binding activity equivalent to the antibodies exemplified herein, for example, antibodies that retain a binding activity similar to the binding of 3G4 to human I L-13 peptides in the ELISA assay as indicated in Example 6.4. In another aspect of the invention, there is provided a method of treating a human patient afflicted with a disease or disorder responsive to the modulation of the interaction between h I L-13 and hIL-13R (such as asthma, COPD, allergic rhinitis, atopic dermatitis), the method comprising the step of administering to the patient a therapeutically effective amount of the antibody or antigen-binding fragment thereof as described herein.

The use of an antibody of the invention in the manufacture of a medicament for the treatment of a disease or disorder responsive to the modulation of the interaction between h I L-13 and hIL-13R is also provided. In a further aspect, the invention provides a method of selecting an anti-IL-13 antibody suitable for use in therapy, the method comprising i) providing an antibody that specifically binds to IL-13Ra1, ii) determining whether the antibody is specifically binds to IL-13Ra2, and select an antibody that binds in step ii) for further development. Detailed Description of the Invention The antibodies of the present invention can be intact antibodies or fragments thereof; human, chimeric or humanized antibodies; and mono- or bispecific. 1. Antibody Structures 1.1 Intact Antibodies Intact antibodies include heteromultimeric glycoproteins comprising at least two heavy and two light chains. Apart from IgM, the intact antibodies are usually heterotetrameric glycoproteins of approximately 150 kDa, composed of two identical light chains (L) and two identical heavy (H) chains. Typically, each light chain is attached to a heavy chain by a covalent disulfide bond, while the number of bonds d isulfide between the heavy chains of different isotypes of immunoglobulin varies. Each heavy and light chain also has intrachain disulfide bridges. Each heavy chain has a variable dominance (VH) at one end followed by a series of constant regions. Each light chain has a variable domain (VL) and a constant region at its other end; the constant region of the light chain is aligned with the first constant region of the heavy chain and the variable domain of the light chain is aligned with the variable domain of the heavy chain. The light chains of antibodies of most vertebrate species can be assigned to one of the two types called kappa and lambda based on the amino acid sequence of the constant region. Depending on the amino acid sequence of the constant region of their heavy chains, human antibodies can be assigned to five different classes: IgA, IgD, IgE, IgG and IgM. IgG and IgA can further be subdivided into subclasses IgG 1, IgG2, IgG3 and IgG4; e lgA1 and lgA2. There are species variants in mouse and rat that have at least lgG2a, lgG2b. The variable dominance of the antibody confers a specificity of binding to the antibody with certain regions that have a particular variability called complementarity determining regions (C DR). The most conserved portions of the variable region are called conserved framework regions (FR). The variable domains of the intact heavy and light chains comprise each four FR connected by three CDRs. The CDRs in each chain are held together in close proximity by the FR regions, and with the CDRs from the other chain contribute to the formation of the antigen-binding site of the antibodies. The constant regions are not directly involved in the binding of the antibody to the antigen, but exhibit various effector functions such as participation in antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis by binding to the FCY receptor, half-life / elimination rate by the Fe neonatal receptor (FcRn) and complement-dependent cytotoxicity by the C1q component of the complement cascade. In one embodiment, therefore, an intact antibody is provided which binds specifically to hIL-13, the antibody modulating the interaction between h I L-13 and hIL-13R, for example, the antibody inhibits the interaction between h I L -13 and its receiver. The intact antibody may comprise a constant region of any isotype or subclass thereof described above. In one embodiment, the antibody is of the IgG isotype, particularly IgG 1. The antibody can be rat, mouse, rabbit, primate or human. In a typical embodiment, the antibody is primate (such as Cynomolgus, catrhin monkey or great ape, see, for example, WO99 / 55369, WO93 / 02108) or human. In another embodiment, an intact antibody is provided isolated comprising a CDRH3 of SEQ ID NO 3. In another embodiment, there is provided an intact antibody comprising a variable region comprising CDRs of SEQ ID NO: 1, 2, 3, 4, 5 and 6. In another embodiment, provides an isolated murine intact antibody or antigen-binding fragment thereof comprising a VH domain comprising the sequence SEQ ID NO: 7 and a V L domain of SEQ ID NO: 8 sequence. 1.1.2 Human antibodies Human antibodies can be produced by a series of procedures known to those skilled in the art. Human antibodies can be prepared by the hybridoma method using human myeloma cell lines or mouse-human heteromyeloma, see Kozbor J. Immunol. 133, 3001, (1984) and Brodeur, "Monoclonal Antibody Production Techniques and Applications," p. 51-63 (Marcel Dekker Ine, 1987). Alternative methods include the use of phage libraries or transgenic mice, using both human V region repertoires (see Winter G, (1994), Annu, Rev. Immunol.12, 433-455, Green LL (1999), JL Immunol Methods 231. 11-23). Several strains of transgenic mice are now available in which the mouse immunoglobulin loci have been replaced by human immunoglobulin gene segments (see Tomizuka K, (2000) PNAS 97, 722-727; Fishwild D.M (1996) Nature Biotechnol. 14, 845-851, Méndez MJ, 1997, Nature Genetics. 15, 146-156). Upon exposure to antigen, the mice are able to produce a repertoire of human antibodies from which antibodies of interest can be selected. Of particular importance is the Trimer system ™ (see Eren R et al., (1998) Immunology 93: 154-161), in which human lymphocytes are transplanted into irradiated mice, the selected lymphocyte antibody system (Selected Lymphocyte Antíbody System (SLAM, see Babcook et al., PNAS (1996) 93: 7843-7848)), in which human (or other) lymphocytes are efficiently passed through a mass combined in vitro antibody generation procedure, followed of unconverted limiting dilution and selection procedure and Xenomouse II ™ (Abgenix Inc). An alternative approach is available in Morphotek Ine, using Morphodoma ™ technology. Phage display technology can be used to produce human antibodies (and fragments thereof), see MeCafferty; Nature 348, 552-553 (1990) and Griffiths AD et al. (1994) EMBO 13: 3245-3260. According to this technique, the V domain genes of the antibody are cloned in phase into a major or minor protein cover gene of a filamentous bacteriophage such as M13 or fd, and they are presented (usually with the aid of an auxiliary phage) in form of functional antibody fragments on the surface of the phage particle. Selections based on the functional properties of the antibody result in the selection of the gene encoding the antibody that exhibits those properties. The phage display technique can be used to select antigen-specific antibodies from libraries prepared from human B cells taken from individuals afflicted with a disease or disorder described above or, alternatively, from non-immunized human donors (see Marks; J. Mol. Bio. 222, 581-597, 1991). When an intact human antibody comprising an Fe domain is desired, it is necessary to reclon the derived fragment presented in phage in a mammalian expression vector containing the desired constant regions and which establishes stable expression cell lines. The affinity maturation technique (Marks; Bio / technol. , 779-783 (1992)) can be used to improve binding affinity, in which the affinity of the primary human antibody is improved by sequentially replacing the V regions of the H and L chains by naturally occurring variants and selecting based on the improved union affinities. Variants of this technique, such as "epitope imprint", are now available, see WO 93/06213. See also Waterhouse; Nucí Acids Res. 21. 2265-2266 (1993). Thus, in another embodiment, an isolated human intact antibody or antigen-binding fragment of the same that binds specifically to h I L-13 and modulates the interaction between h I L-13 and hlL-13R, for example, in which it inhibits the interaction between h I L-13 and its receptor. In another aspect, there is provided an isolated human intact antibody or antigen-binding fragment thereof comprising a CDRH3 of SEQ ID NO 3 which specifically binds AH I L-13 and modulates the interaction between h I L-13 and hLL- 13R, for example, in which it inhibits the interaction between h I L-13 and its receptor. In another aspect, there is provided an isolated human intact antibody or antigen-binding fragment thereof comprising a variable region comprising CDRs of SEQ ID NO: 1, 2, 3, 4, 5 and 6 as defined above. 1.2 Chimeric and humanized antibodies The use of intact non-human antibodies in the treatment of human diseases or disorders carries with it the potential of now well-established immunogenicity problems, ie, the patient's immune system can recognize the intact non-human antibody as foreign and mount a neutralizing response. This is particularly evident after multiple administration of the non-human antibody to a human patient. Various techniques have been developed over the years to overcome these problems, and generally involve reducing the composition of non-human amino acid sequences in the intact antibody, retaining the relative ease of obtaining non-human antibodies from an animal immunized, for example, mouse, rat or rabbit. Two approaches have been widely used to achieve this. The first are chimeric antibodies, which generally comprise a non-human variable domain (eg, rodent such as mouse) fused to a human constant region. Because the antigen binding site of an antibody is located within the variable regions of the chimeric antibody, it retains its binding affinity for the antigen but acquires the effector functions of the human constant region and, therefore, is capable of perform effector functions such as those described above. Chimeric antibodies are typically produced using recombinant DNA methods. DNA encoding the antibodies (e.g., cDNA) is isolated and sequenced using conventional methods (e.g., using oligonucleotide probes that are capable of specifically binding to genes encoding the H and L chains of the antibody of the invention, e.g., DNA encoding SEQ ID NO 1, 2, 3, 4, 5 and 6 described above). Hybridoma cells serve as a typical source of DNA. Once isolated, the DNA is arranged in expression vectors that are then transfected into host cells such as E. coli cells, COS cells, CHO cells or myeloma cells, which otherwise do not produce immunoglobulin protein, to obtain the synthesis of the antibody. The DNA can be modified by substituting the coding sequence of the L chains and Human H the corresponding non-human H and L constant regions (for example murine), see, for example Morrison; PNAS 81, 6851 (1984). The second approach involves the generation of humanized antibodies in which the non-human content of the antibody is reduced by humanizing the variable regions. Two techniques of humanization have gained popularity. The first is the humanization by CDR grafting. The CDRs form loops near the N terminus of the antibody, where they form a surface mounted on a structure provided by the framework regions conserved. The specificity of antigen binding of the antibody is defined mainly by the topography and by the chemical characteristics of its CDR surface. These features are determined in turn by the conformation of the individual CDRs, by the relative arrangement of the CDRs and by the nature and arrangement of the side chains of the residues comprising the CDRs. A large reduction in immunogenicity can be achieved by grafting only the CDRs of non-human (e.g., murine) antibodies ("donor" antibodies) to human framework frameworks ("acceptor framework") and human constant regions (see Jones et al. (1986). ) Nature 321, 522-525 and Verhoeyen M et al (1988) Science 239. 1534-1536). However, the CDR graft, per se, may not result in complete retention of the antigen-binding properties, and is frequently that some framework residues (sometimes referred to as "back-mutations") of the donor antibody have to be retained in the humanized molecule to recover a significant antigen binding affinity (see Queen C et al (1989) PNAS 86, 10.029-10.033 , Co, M et al. (1991) Nature 351, 501-502). In this case, the human V regions that show the highest sequence homology with the non-human donor antibody are chosen from a database to provide the human framework (FR). The selection of human FRs can be made from human or individual human consensus antibodies. When necessary, key residues of the donor antibody are substituted in the human acceptor framework to preserve the CDR conformations. The computer modeling of the antibody can be used to help identify the structurally important residues, see WO99 / 48523. As an alternative, humanization can be achieved by a "coating" process. A statistical analysis of the single and murine immunoglobulin heavy and light chain variable regions revealed that the precise patterns of exposed residues are different in human and murine antibodies, and most individual surface positions have a strong preference for a small number of different residues (see Padlan EA et al (1991) Mol Immunol 28, 489-498 and Pedersen JT et al (1994) J. Mol. Biol. 235; 959-973). Therefore, it is possible to reduce the immunogenicity of a non-human Fv by replacing the exposed residues in their conserved framework regions which differ from those usually found in human antibodies. Because protein antigenicity can be correlated with accessibility to the surface, replacement of surface debris may be sufficient to return the variable region of the mouse "invisible" to the human immune system (see also Mark GE et al. (1994). ) in "Handbook of Experimental Pharmacology vol 113: The pharmacology of monoclonal Antibodies", Springer-Verlag, pp. 105-134). This method of humanization is designated as "coating" because only the surface of the antibody is altered, the support residues remaining intact. The expert will be aware that there are other procedures for the humanization of antibodies that are available in the literature. Thus, another embodiment of the invention provides a chimeric antibody comprising a non-human variable domain (eg, rodent) fused to a human constant region (which can be of IgG isotype, eg, IgG1) that binds specifically there I L-13 and modulates the interaction between h I L-13 and hlL-13R, for example, in which it inhibits the interaction between hIL-13 and its receptor. In another embodiment, a chimeric antibody comprising a non-human variable region (e.g. rodent) and a human constant region (which may be of an IgG isotype, eg, IgG1) that specifically binds to IL-13, the antibody additionally comprising a CDRH3 of SEQ ID NO 3. The antibodies may additionally comprise a constant region human isotype IgG, for example, IgG1. In another embodiment, there is a chimeric antibody comprising a non-human variable region (e.g., rodent) and a human constant region (which may be of an IgG isotype, e.g., IgG 1) that specifically binds ah I L- 13, comprising the CDRs of SEQ ID NO: 1, 2, 3, 4, 5 and 6. In another embodiment, a chimeric antibody comprising a VH domain of SEQ ID NO: 7 and a VL domain of SEQ ID NO: 8 is provided. and a human constant region of an IgG isotype, e.g., IgG1, which specifically binds AH I L-13 and modulates the interaction between h I L-13 and hIL-13R, for example, in which it inhibits the interaction between hlL-13 and its receptor. In another embodiment, a humanized antibody or antigen-binding fragment thereof is provided which specifically binds AH I L-13 and modulates the interaction between h I L-13 and hIL-13R, for example, in which it inhibits the interaction between hlL-13 and its receptor. In another embodiment, a humanized antibody or antigen-binding fragment thereof which binds specifically to h I L-13 and comprises a CDRH3 of SEQ ID NO 3 is provided. The antibodies may comprise a region human constant of IgG isotype, for example, IgG1. In another embodiment, there is provided a humanized antibody or antigen-binding fragment thereof which specifically binds AH I L-13 and comprises CDRs of SEQ ID NO: 1, 2, 3, 4, 5 and 6. The antibodies may comprise a human constant region of IgG isotype, for example, IgG1. According to the present invention, a humanized antibody is provided, the antibody comprising a VH domain selected from the group of: SEQ ID NO: 11 and, a V L domain selected from the group of SEQ ID NOs 15, 16, 17. The antibodies may comprising a human constant region of IgG isotype, e.g., IgG1. According to the present invention, a humanized antibody is provided, the antibody comprising a VH domain selected from the group of SEQ ID NO: 12 and a V L domain selected from the group of SEQ ID NO: 15, 16, 17. The antibodies may comprise a human constant region of IgG isotype, e.g., IgG1. According to the present invention, a humanized antibody is provided, the antibody comprising a VH domain selected from the group of SEQ ID NO: 13, and a V L domain selected from the group of SEQ ID NO: 15, 16, 17. The antibodies may comprise a human constant region of IgG isotype, e.g., IgG1. According to the present invention, a humanized antibody, the antibody comprising a VH domain selected from the group of SEQ ID NO: 14, and a V L domain selected from the group of SEQ ID NOs 15, 16, 17. The antibodies may comprise a human constant region of IgG isotype, for example , lgG1. In another embodiment, a humanized antibody is provided, the antibody comprising a VH domain of SEQ ID NO 11 and a VL domain of SEQ ID NO: 15. In another embodiment, a humanized antibody is provided, the antibody comprising a SE VH domain.

NO ID 12 and a VL domain of SEQ ID NO. 15. In another embodiment, a humanized antibody is provided, the antibody comprising a VH domain of SEQ ID NO 13 and a VL domain of SEQ ID NO. 15. In another embodiment, a humanized antibody, the antibody comprising a VH domain of SEQ ID NO: 14 and a VL domain of SEQ ID NO: 15. In another embodiment, a humanized antibody is provided, the antibody comprising a VH domain of SEQ ID NO: 11 and a V L domain of SEQ ID NO. 16. In another embodiment, a humanized antibody is provided, the antibody comprising a VH domain of SEQ ID NO: 12 and a V L domain of SEQ ID NO: 16. In another embodiment, a humanized antibody is provided, the antibody comprising a SEC VH domain NO ID 13 and a VL domain of SEQ ID NO: 16. In another embodiment, a humanized antibody is provided, the antibody comprising a VH domain of SEQ ID NO: 14 and a V L domain of SEQ ID NO: 16. In another embodiment, a humanized antibody, the antibody comprising a VH domain of SEQ ID NO 11 and a VL domain of SEQ ID NO: 17. In another embodiment, a humanized antibody is provided, the antibody comprising a VH domain of SEQ ID NO 12 and a V L domain of SEQ ID NO. 17. In another embodiment, a humanized antibody is provided, the antibody comprising a VH domain of SEQ ID NO: 13 and a V L domain of SEQ ID NO: 17. In another embodiment, a humanized antibody is provided, the antibody comprising a SEC VH domain NO ID 14 and a VL domain of SEQ ID NO. 17. In another embodiment, a humanized antibody or antigen-binding fragment thereof is provided that specifically binds to hIL-13, wherein the antibody or fragment thereof comprises CDRH3 of SEQ ID NO 3, optionally further comprising one or more CDRs of SEQ ID NO: 1, 2, 4, 5 and 6, wherein one or more of the residues selected from the group consisting of the 10, 30, 67, 69 position , 71, 73 and 93 of the frame of the human acceptor heavy chain and one or both of the remains in positions 76 and 98 of the framework of the human acceptor light chain are substituted by the corresponding residues found in the donor antibody framework from which CDRH3 is derived (which is indicated in SEQ ID NO: 7). In another embodiment, a humanized antibody or antigen-binding fragment thereof that specifically binds to hIL-13 is provided, wherein the antibody or fragment thereof comprises CDRH3 of SEQ ID NO: 3, optionally further comprising one or more CDR of SEC NO ID 1, 2, 4, 5 and 6, wherein the framework of the human heavy chain comprises one or more (e.g., all) of the following residues (or conservative substitution thereof): Position Remainder 10 D 30 I 67 A 69 L 71 A 73 K 93 T and a light chain framework comprising any or both of the following residues (or a conservative substitution thereof): 76 N 98 L It will be apparent to those skilled in the art that the term "derivative" is intended to define not only the source in the sense of physical origin for the material, but also to define the material that is structurally identical (in terms of primary amino acid sequence). ) to the material, but that does not originate from the reference source. Thus "residues found in the donor antibody from which CDRH3 is derived" do not necessarily have to be purified from the donor antibody. It is well recognized in the art that certain amino acid substitutions are considered to be "conservative". The amino acids are divided into groups based on common properties of the side chain, and substitutions within groups that maintain all or substantially all of the binding affinity of the antibody of the invention or of the antigen-binding fragment thereof are considered as conservative substitutions. , see table 1: Table 1 According to the present invention, there is provided a humanized antibody comprising a heavy chain selected from the group consisting of SEQ ID NO: 18, 19, 20, 21 and a light chain selected from the group consisting of SEQ ID NO 22, 23, 24. In one embodiment of the invention, there is provided a humanized antibody that specifically binds AH I L-13, which comprises a heavy chain of SEC NO. ID 18 and a light chain of SEQ ID NO. 22. In one embodiment of the invention, there is provided a humanized antibody that specifically binds to hIL-13, which comprises a heavy chain of SEQ ID NO: 19 and a light chain of SEC NO. ID 22. In one embodiment of the invention, there is provided a humanized antibody that specifically binds to hIL-13, comprising a heavy chain of SEQ ID NO: 20 and a light chain of SEQ ID NO: 22. In one embodiment of the invention , a humanized antibody is provided that binds specifically to hIL-13, which comprises a heavy chain of SEQ ID NO: 21 and a light chain of SEQ ID NO: 22. In one embodiment of the invention, a humanized antibody that binds is provided specifically ah I L-1 3, comprising a heavy chain of SEQ ID NO: 18 and a light chain of SEQ ID NO: 23.

In one embodiment of the invention, there is provided a humanized antibody that specifically binds to hIL-13, which comprises a heavy chain of SEQ ID NO: 19 and a light chain of SEQ ID NO: 23. In one embodiment of the invention, it is provided a humanized antibody that specifically binds ah I L-13, which comprises a heavy chain of SEQ ID NO: 20 and a light chain of SEQ ID NO: 23. In one embodiment of the invention, a humanized antibody is provided that binds specifically to hIL-13, comprising a heavy chain of SEQ ID NO: 21 and a light chain of SEQ ID NO. 23. In one embodiment of the invention, a humanized antibody is provided that binds specifically to hL L-13, which comprises a chain of SEC NO ID 18 and a light chain of SEQ ID NO. 24. In one embodiment of the invention, there is provided a humanized antibody that specifically binds AH I L-13, comprising a heavy chain of SEQ ID NO. 19 and a light chain of SEC NO ID 24. In one embodiment of the invention, there is provided a humanized antibody that specifically binds to hIL-13, which comprises a heavy chain of SEQ ID NO: 20 and a light chain of SEQ ID NO: 24. In one embodiment of the invention, it is provided a humanized antibody that specifically binds to hIL-13, comprising a heavy chain of SEQ ID NO: 21 and a light chain of SEQ ID NO: 24. In one embodiment of the present invention, a human or humanized heavy chain variable region is provided comprising each of the CDRs listed in SEQ ID NO. 1-3. In another embodiment of the present invention, a humanized heavy chain variable region comprising the CDRs listed in SEQ ID NO. 1-3 within the major sequence of a human heavy chain variable region is provided. In yet another embodiment, the humanized heavy chain variable region comprises the CDRs listed in SEQ ID NO. 1-3 within an acceptor antibody framework having more than 40% identity in the framework regions conserved, or more than one 50%, or more than 60%, or more than 65% identity with the heavy chain variable region of the murine 3G4 donor antibody (SEQ ID NO: 7). In one aspect of the present invention, the antibodies comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 44, which additionally comprises a series of substitutions at one or more of positions 10, 30, 67, 69 , 71, 73, 93 (Kabat numbering system); wherein each substituted amino acid residue is replaced by the amino acid residue in the equivalent position in SEQ ID NO 7 (the variable chain region) heavy of the donor antibody 3G4) and the number of substitutions is between 0 and 7. In other modalities, the number of substitutions is 0, or 1, or 2, or 3, or 4, or 5, or 6, or 7. In One embodiment of the present invention provides a human or humanized light chain variable region comprising each of the CDRs listed in SEQ ID NOs. 4-6. In another embodiment of the present invention there is provided a humanized light chain variable region comprising the CDRs listed in SEQ ID NO: 4-6 within the major sequence of a human light chain variable region. In yet another embodiment, the humanized light chain variable region comprises the CDRs listed in SEQ ID NO: 4-6 within an acceptor antibody framework that is more than 40% > of identity in the framework regions conserved, or more than 50%, or more than 60%, or more than 65% identity with the heavy chain variable region of the donor antibody 3G4 murine (SEC NO ID 8). In one aspect of the present invention, the antibodies comprise a light chain variable region comprising the amino acid sequence of SEQ ID NO: 45, which additionally comprises a series of substitutions at one or more of positions 76, 98 (number system Kabat); wherein each substituted amino acid residue is replaced by the amino acid residue at the equivalent position in SEQ ID NO 8 (the light chain variable region of donor antibody 3G4) and the number of substitutions is between 0 and 2. In other embodiments, the number of substitutions is 0 or 1 or 2. 1.3 Bispecific Antibodies A bispecific antibody is an antibody that has binding specificities for at least two different epitopes. The methods of preparing the antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the coexpression of two H-chain L pairs of immunoglobulin, in which the two H chains have different binding specificities, see Millstein et al., Nature 305 537-539 ( 1983), WO93 / 08829 and Traunecker et al. EMBO. 10, 1991, 3655-3659. Due to the random distribution of the H and L chains, a potential mixture of ten different antibody structures is produced, of which only one has the desired binding specificity. An alternative approach involves merging the variable domains with the desired binding specificities with the constant region of the heavy chain comprising at least part of the hinge region, CH2 and CH3 regions. It is preferred to have the CH1 region containing the necessary site for binding of the light chain present in at least one of the fusions. The DNA encoding these fusions, and if desired the L chain, are inserted into separate expression vectors and then cotransfected into a suitable host organism. It is possible, however, to insert the sequences of coding for two or the three strings in an expression vector. In a preferred approach, the bispecific antibody is composed of an H chain with a first binding specificity in one arm and a pair of H-L chains, which provides a second binding specificity in the other arm, see WO94 / 04690. See also Suresh et al. Methods in Enzvmolov 121.210, 1986. In one embodiment of the invention, a bispecific antibody is provided, wherein at least one antibody binding specificity is for hIL-13, wherein the antibody modulates the interaction between h I L- 13 and IL-13R, for example, in which it inhibits the interaction between h I L-13 and its receptor. The antibodies may additionally comprise a human constant region of IgG isotype, e.g., IgG1. In some embodiments, the bispecific therapeutic antibody has a first binding specificity for h I L-13 and modulates the interaction between h I L-13 and hlL-13 R, for example, in which it inhibits the interaction between h I L-13 its receptor, and a second binding specificity for hIL-4 and modulates the interaction between hIL-4 and a hIL-4 receptor, for example, in which it inhibits the interaction between hIL-4 and its receptor. In one embodiment of the invention, a bispecific antibody is provided in which at least one binding specificity of the antibody is by hIL-13, wherein the antibody comprises a CDRH3 of SEQ ID NO 3. The antibodies can further comprising a human constant region of IgG isotype, e.g., IgG1. In one embodiment of the invention, a bispecific antibody is provided, wherein at least one binding specificity of the antibody is for hIL-13, wherein the antibody comprises at least CDR of SEQ ID NO: 1, 2, 3, 4 , 5 and 6. The antibodies can additionally comprise a human constant region of IgG isotype, for example, IgG1. 1.4 Antibody fragments In certain embodiments of the invention, antibody fragments are provided that modulate the interaction between h I L-13 and hIL-13R, for example, in which the fragments inhibit the interaction between h I L-13 and its receiver. The fragments can be functional antigen-binding fragments of intact and / or humanized and / or chimeric antibodies such as fragments.

Fab, Fab ', F (ab') 2, Fv, ScFv of the antibodies described above. Traditionally, the fragments are produced by proteolytic digestion of intact antibodies by, for example, digestion with papain (see, for example, WO 94/29348), but can be produced directly from recombinantly transformed host cells. For the production of ScFv, see Bird et al .; (1988) Science, 242, 423-426. In addition, antibody fragments can be produced using a variety of engineering techniques as described below.

The Fv fragments seem to have lower interaction energy of their two chains than the Fab fragments. To establish the association of the VH and VL domains, they have been linked to peptides (Bird et al., (1988) Science 242, 423-426, Huston et al., PNAS 85, 5879-5883), disulfide bridges (Glockshuber and col., (1990) Biochemistrv. 29, 1362-1367) and "outgoing und" mutations (Zhu ef al (1997), Protein Sci .. 6, 781-788). ScFv fragments can be produced by methods well known to those skilled in the art, see Whitlow et al. (1991) Methods companion Methods Enzymol. 2, 97-105 and Huston et al. (1993) Int. Rev. Immunol. 10, 195-217. ScFv can be produced in bacterial cells such as E. coli, but they are more preferably produced in eukaryotic cells. It is a disadvantage of ScFv the monovalence of the product, which prevents an increased avidity due to the polyvalent union, and its short half-life. Attempts to overcome these problems include divalent (ScFv ') 2 produced from ScFV containing an additional C-terminal cysteine by chemical coupling (Adams et al (1993) Can. Res. 53, 4026-4034 and McCartney et al. (1995) Protein Eng. 8, 301-314) or by spontaneous site-specific dimerization of ScFv containing an unpaired C-terminal cysteine residue (see Kipriyanov et al (1995) Cell. Biophvs 26, 187-204 ). Alternatively, ScFv can be forced to form multimers by shortening the peptide linker to 3 to 12 residues to form "diabodies", see Holliger et al. PNAS (1993), 90, 6444- 6448. Further reducing the linkage can result in scFV trimers ("triabodies", see Kortt et al (1997) Protein Eng. 10, 423-433) and tetramers ("tetrabodies", see Le Gall et al (1999) FEBS Lett 453, 164-168). The construction of divalent ScFV molecules can also be achieved by genetic fusion with protein dimerizing motifs to form "miniantibodies" (see Pack et al (1992) Biochemistry 31, 1579-1584) and "minibodies" (see Hu et al. 1996), Cancer Res. 56, 3055-3061). ScFv-Sc-Fv series ((ScFV) 2) can also be produced by linking two units ScFv through a third peptide linker, see Kurucz et al. (1995) J. Immol. 154, 4576-4582. Bispecific diabodies can be produced by the non-covalent association of two single-chain fusion products consisting of one VH domain of one antibody linked by a short linker to the VL domain of another antibody, see Kipriyanov et al. (1998), Int. J. Can. 77,763-772. The stability of bispecific diabodies can be enhanced by the introduction of disulphide bridges or "outgoing to und" mutations as described above, or by the formation of single-stranded diabodies (ScDb) in which two hybrid ScFv fragments are connected by a peptide linker , see Kontermann et al. (1999) J. Immunol. Methods 226 179-188. Tetravalent bispecific molecules are available, for example, by fusing a ScFv fragment with the CH3 domain of a IgG molecule or with a Fab fragment through the hinge region, see Coloma et al. (1997) Nature Biotechnol. 15, 159-163. Alternatively, tetravalent bispecific molecules have been created by the fusion of bispecific single chain diabodies (see Alt et al., (1999) FEBS Lett 454, 90-94). Minor tetravalent bispecific molecules may also be formed by dimerization of any of the ScFv-ScFv series with a linker containing a helix-loop-helix motif (DiBi miniantibodies, see Muller et al (1998) FEBS Lett 432, 45-49 ) or a single-chain molecule comprising four variable antibody domains (VH and VL) in an orientation that prevents intramolecular pairing (serial diabody, see Kipriyanov et al., (1999) J. Mol. Biol.293.41-56). The bispecific F (ab ') 2 fragments can be created by chemical coupling of Fab' fragments or by heterodimerization by leucine zippers (see Shalaby et al., (1992) J. Exp. Med. 175, 217-225 and Kostelny et al. (1992), J. Immunol., 148, 1547-1553). Also available are isolated VH and VL domains (Domantis pie), see documents US 6,248,516; US 6,291,158; US 6,172,197. In one embodiment, an antibody fragment (e.g., ScFv, Fab, Fab ', F (ab') 2), or an antibody fragment engineered as described above, which specifically binds ah I L- is provided. 13 and modulates the interaction between h I L-13 and hlL-13R, for example, in the that the fragments inhibit the interaction between h I L-13 and its receptor. The antibody fragment may comprise a CDRH3 comprising the sequence of SEQ ID NO: 3, optionally together with additional CDRs comprising one or more of the sequences indicated in SEQ ID NO: 1, 2, 4, 5 and 6. It may be ScFv comprising the VH and VL regions of the antibodies of the present invention. For example, a ScFv may comprise SEQ ID NO: 12 and 15 or, for example, may comprise SEQ ID NO: 13 and 15. This could be done by the polynucleotides according to the invention, for example, the sequences indicated in SEQ ID NO. 93 and 94 or, for example, by the sequences set forth in SEQ ID NOs 28 and 31. In one embodiment of the invention, a ScFv is provided which comprises a protein encoded by the sequences set forth in SEQ ID NOs 93 and 94. 1.5 Heteroconjugate Antibodies Heteroconjugate antibodies also form one embodiment of the present invention. Heteroconjugate antibodies are composed of two covalently bound antibodies formed using any convenient crosslinking method. See, for example, US 4,676,980. 1.6 Other modifications. It is believed that the interaction between the Fe region of an antibody and various Fe (FcyR) receptors mediates the effector functions of the antibody, including antibody-dependent cellular cytotoxicity (ADCC), complement fixation, phagocytosis, and antibody half-life / elimination. Various modifications can be made in the Fe region of the antibodies of the invention, depending on the desired property. For example, specific mutations in the Fe region are detailed to render non-lytic an antibody that would otherwise be lytic in EP 0629240B1 and EP 0307434B2, or a wild-type receptor binding epitope can be incorporated into the antibody to increase the serum half-life, see US 5,739,277. There are currently five recognized human Fcy receptors, FcyR (I), FcyRIla, FcyRIIb, Fc? Rllla and neonatal FcRn. Shields et al., (2001) J. Biol. Chem. 276. 6591-6604 demonstrated that a common set of IgG1 residues is involved in the binding of all FcyR, whereas FcyRIl and FcyRIII use different sites outside this common set. A group of IgG1 residues reduced binding to all FcyR when altered to alanine: Pro-238, Asp-265, Asp-270, Asn-297 and Pro-239. All are in the CH2 domain of IgG and agglomerated near the hinge that binds CH1 and CH2. Although FcyRI uses only the common set of lgG1 residues for binding, FcyRIl and Fc? RIII interact with different residues in addition to the common set. Alteration of some residues reduced binding only to FcyRIl (eg, Arg-292) or to FcyRIII (eg, Glu-293). Some variants showed an improved binding to FcyRIl or FcyRIII, but did not affect the binding to the other receptor (for example, Ser-267Ala improved binding to FcyRIl, but binding to FcyRIII was not affected). Other variants exhibited improved binding to FcyRIl or FcyRIII with reduction of binding to the other receptor (eg, Ser-298Ala improved binding to FcyRIII and reduced binding to FcyRIl). For Fc? Rllla, the best lgG1 binding variants had alanine substitutions combined in Ser-298, Glu-333 and Lys-334. The neonatal FcRn receptor is thought to be involved both in the elimination of antibodies and in transcytosis through tissues (see Junghans R.P (1997) Immunol. Res. 16, 29-57 and Gh et al. (2000) Annu. Rev. Immunol. 18, 739-766). Residues of human IgG1 determined by direct interaction with human FcRn include Ile253, Ser254, Lys288, Thr307, Gln311, Asn434 and His435. Changes in any of these positions described in this example may enable an increased serum half-life and / or altered effector properties of the antibodies of the invention. Other modifications include glycosylation variants of the antibodies of the invention. The glycosylation of antibodies at positions conserved in their constant regions is known to have a profound effect on the function of antibodies, particularly effector functioning such as those described above, see, for example, Boyd et al. (1996), Mol. Immunol. 32. 1311-1318. Variations in glycosylation of antibodies or antigen-binding fragments are contemplated of the same as those of the present invention in which one or more carbohydrate moieties are added, substituted, deleted or modified. The introduction of an asparagine-X-serine or asparagine-X-threonine motif creates a potential site for enzymatic binding of carbohydrate moieties and, therefore, can be used to manipulate the glycosylation of an antibody. In Raju et al. (2001) Biochemistry 40, 8868-8876, the terminal sialization of a TNFR-IgG immunoadhesin was increased by a process of regalactosylation and / or resialization using beta-1,4-galactosyltransferase and / or alpha-2,3-sialyltransferase. It is believed that increasing the terminal sialization increases the half-life of the immunoglobulin. Antibodies, like most glycoproteins, are typically produced in the form of a mixture of glycoforms. This mixture is particularly evident when antibodies are produced in eukaryotic cells, particularly mammalian ones. A variety of procedures have been developed to manufacture defined glycoforms, see Zhang et al. Science (2004), 303, 371, Sears et al., Science. (2001) 291, 2344, Wacker et al. (2002) Science. 298 1790, Davis et al. (2002) Chem.Rev. 102, 579, Hang et al. (2001) Acc. Chem. Res. 34, 727. Thus, the invention contemplates a plurality of (monoclonal) antibodies (which may be of the IgG isotype, for example, IgG1) as described herein comprising a defined number (for example, 7 or less, for example, 5 or less, such as two or one) glycoform (s) of the antibodies or fragments of antigen binding thereof. Additional embodiments of the invention include antibodies of the invention or antigen-binding fragments thereof coupled to a non-protein polymer such as polyethylene glycol (PEG), polypropylene glycol or polyoxyalkylene. The conjugation of proteins to PEG is a technique established to increase the half-life of proteins, as well as reduce the antigenicity and immunogenicity of proteins. The use of PEGylation with different molecular weights and styles (linear or branched) with intact antibodies, as well as Fab 'fragments, has been investigated, see Koumenis I.L. and col. (2000) Int. J. Pharmaceut. 198: 83-95. 2. Production methods The antibodies of the invention can be produced in the form of a polyclonal population, but are more preferably produced in the form of a monoclonal population (which is a substantially homogeneous population of identical antibodies directed against a specific antigen binding site). Of course, it will be apparent to those skilled in the art that a population involves more than one antibody entity. The antibodies of the present invention can be produced in transgenic organisms such as goats (see Pollock et al (1999), J. Immunol Methods 231: 147-157), chickens (see Morrow KJJ (2000) Genet, Eng. News 20 : 1-55, mice (see Pollock et al.) Or plants (see Doran PM, (2000) Curr. Opinion Biotechnol. 11, 199-204, Ma JK-C (1998), Nat. Med. 4; 601-606, Baez J et al., BioPharm (2000) 13: 50-54, Stoger E et al .; (2000) Plant Mol. Biol. 42: 583-590). The antibodies can also be produced by chemical synthesis, however, the antibodies of the invention are typically produced using recombinant cell culture technology well known to those skilled in the art. A polynucleotide encoding the antibody is isolated and inserted into a replicable vector such as a plasmid for cloning (amplification) or additional expression. The glutamate synthetase system is a useful expression system (such as that sold by Lonza Biologics), particularly when the host cell is CHO or NSO (see below). The polynucleotide encoding the antibody is easily isolated and sequenced using conventional procedures (e.g., oligonucleotide probes). Vectors that can be used include plasmid, virus, phage, transposons, minichromosomes, of which plasmids are a typical embodiment. Usually, the vectors additionally include a signal sequence, an origin of replication, one or more marker genes, an enhancer element, promoter and transcription terminator sequences operatively linked to the light and / or heavy chain polynucleotide to facilitate expression. The polynucleotide encoding the light and heavy chains can be inserted into separate vectors and transfected into the same host cell or, if desired, both the heavy chain and the light chain can be inserted into the same vector for transfection in the host cell. Therefore, according to one aspect of the present invention, there is provided a method of constructing a vector encoding the light and / or heavy chains of an antibody or antigen-binding fragment thereof of the invention, the method comprising inserting into a vector a polynucleotide encoding a light chain and / or heavy chain of an antibody of the invention. In another aspect of the invention, there is provided a polynucleotide that encodes a murine VH domain comprising the sequence set forth as SEQ ID NO: 25. In another aspect of the invention, there is provided a polynucleotide encoding a murine VL domain comprising the exposed sequence as SEQ ID NO. 26. In another embodiment, there is provided a polynucleotide encoding a VH domain comprising the sequence selected from the group consisting of SEQ ID NO: 27, 28, 29, 30. In another embodiment, a polynucleotide encoding a VL domain comprising the sequence selected from the group consisting of SEQ ID NO: 31, 32, 33. According to the present invention, a polynucleotide encoding a heavy chain of the invention is provided, the polynucleotide being selected from the group consisting of SEC NO ID 34, 35, 36, 37.

According to the present invention, a polynucleotide encoding a light chain of the invention is provided, the polynucleotide being selected from the group consisting of SEQ ID NOs 38, 39, 40. It will be immediately apparent to those skilled in the art that, due to In addition to the redundancy of the genetic code, polynucleotides alternative to those disclosed herein (particularly those codon optimized for expression in a given host cell) that will encode the polypeptides of the invention are also available. 3.1 Signal Sequences The antibodies of the present invention can be produced in the form of a fusion protein with a heterologous signal sequence having a specific cleavage site at the N terminus of the mature protein. The signal sequence should be recognized and processed by the host cell. For prokaryotic host cells, the signal sequence may be a leader sequence of alkaline phosphatase, penicillinase or thermostable enterotoxin II. For yeast secretion, the signal sequences may be a leader sequence of yeast invertase, leader-factor sequence or acid phosphatase leader sequences, see, for example, WO90 / 13646. In mammalian cell systems, viral secretory leader sequences are available such as herpes simplex gD signal and a native immunoglobulin signal sequence.

Typically, the signal sequence is linked in frame to the DNA encoding the antibody of the invention. 3.2 Origin of replication The origins of replication are well known in the art, with pBR322 suitable for most gram-negative bacteria, plasmid 2 μ for most yeasts, and various viral origins such as SV40, polyoma, adenovirus, VSV or BPV for most mammalian cells. Generally, the origin of replication component is not necessary for mammalian expression vectors, but SV40 can be used, since it contains the early promoter. 3. 3 Selection marker Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, eg, ampicillin, neomycin, methotrexate or tetracycline or (b) supplement auxotrophic deficiencies or supply nutrients not available in complex media. The selection scheme may involve stopping the growth of the host cell. Cells that have been successfully transformed with the genes encoding the antibody of the present invention survive due, for example, to the drug resistance conferred by the selection maker. Another example is the so-called DHFR selection marker, in which the transformants are cultured in the presence of methotrexate. In typical embodiments, cells are cultured in the presence of increasing amounts of methotrexate to amplify the number of copies of the exogenous gene of interest. CHO cells are a cell line particularly useful for the selection of DHFR. The glutamate synthetase expression system (Lonza Biologics) is an additional example. It is a suitable selection gene for use in yeast the trp 1 gene, see Stinchcomb et al. Nature 282. 38, 1 979. 3.4 Promoters Suitable promoters for expressing antibodies of the invention are operably linked to DNA / polynucleotide encoding the antibody. Promoters for prokaryotic hosts include the phoA promoter, the beta-lactamase and lactose promoter systems, promoters of alkaline phosphatase, tryptophan and hybrids such as Tac. Promoters suitable for expression in yeast cells include 3-phosphoglycerate kinase or other glycolytic enzymes, for example, enolase, glyceraldehyde-3-phosphate dehydrogenase, hexoquase, pyruvate decarboxylase, phosphofructokinase, glucose-6-phosphate isomerase. , 3-phosphoglycerate mutase and glucokinase. The inducible yeast promoters include alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, metallothionein and enzymes responsible for the metabolism of nitrogen or the utilization of maltose / galactose. Promoters for expression in mammalian cell systems include viral promoters such as polyoma promoter, fowl pox and adenovirus (e.g., adenovirus 2), bovine papillomavirus, avian sarcoma virus, cytomegalovirus (in particular, the immediate early gene promoter), retrovirus, hepatitis B virus, actin, Rous sarcoma virus (RSV) and the early or late simian virus 40. Of course, the choice of the promoter is based in adequate compatibility with the host cell used for expression. Therefore, in one embodiment, a first plasmid comprising an RSV promoter and / or SV40 and / or CMV, DNA encoding the V region of the light chain (VL) of the invention, the KC region along with markers is provided. of selection of resistance to neomycin and ampicillin, and a second plasmid comprising an RSV or SV40 promoter, DNA encoding the heavy chain V region (VH) of the invention, DNA encoding the constant region? 1, resistance markers to DHFR and ampicillin. 3.5 Enhancer Element Where appropriate, for example for expression in higher eukaryotes, an enhancer element operably linked to the promoter element in a vector can be used. Suitable mammalian enhancer sequences include globin enhancing elements, elastase, albumin, fetoprotein and insulin. Alternatively, a eukaryotic cell virus enhancing element such as SV40 enhancer (in bp 100-270), cytomegalovirus early promoter enhancer, polyoma enhancer, baculoviral enhancer or murine lgG2a locus (see WO04 / 009823). The enhancer is preferably located in the vector at a site upstream of the promoter. 3.5.5 Polyadenylation signals In eukaryotic systems, polyadenylation signals are operably linked to DNA / polynucleotide encoding the antibody of this invention. The signals are typically located 3 'of the open reading frame. In mammalian systems, non-limiting examples include signals derived from growth hormones, elongation factor 1-a and viral genes (e.g., SV40) or long retroviral terminal repeats. In yeast systems, non-limiting examples of polyadenylation / termination signals include those derived from the genes phosphoglycerate kinase (PGK) and alcohol dehydrogenase 1 (ADH). In prokaryotic systems, polyadenylation signals are typically not necessary, and instead it is common to use shorter and more defined terminator sequences. Of course, the choice of polyadenylation / termination sequences is based on adequate compatibility with the host cell used for expression. 3.6 Host Cells Suitable host cells for cloning or expressing vectors encoding antibodies of the invention are prokaryotic, yeast or higher eukaryotic cells. Suitable prokaryotic cells include eubacteria, for example, enterobacteria such as Escherichia, for example, E. coli (for example, ATCC 31,446; 31,537; 27,325), Enterobacter, Erwinia, Klebsiella Proteus, Salmonella, for example, Salmonella typhimurium, Serratia, for example, Serratia marcescans and Shigella, as well as bacilli such as B. subtilis and B. licheniformis (see DD 266,710), Pseudomonas such as P. aeruginosa and Streptomyces. Of the yeast host cells, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Kluyveromyces (eg, ATCC 16,045, 12,424, 24,178, 56,500), Yarrowia (EP 402,226), Pichia are also contemplated.

Pastoris (EP183.070, see also Peng et al., J. Biotechnol., 108 (2004) 185-192), Candida, Trichoderma reesia (EP244.234, Penicillin, Tolypocladium and Aspergillus such as A. nidulans and A. niger. the prokaryotic and yeast host cells are specifically contemplated by the invention, however the host cells of the present invention are preferably higher eukaryotic cells.The suitable higher eukaryotic host cells include mammalian cells such as COS-1 (ATCC No. CRL 1650 ) COS-7 (ATCC CRL 1651), line 293 of human embryonic kidney, newborn hamster kidney cells (BHK) (ATCC CRL.1632), BHK570 (ATCC No. CRL 10314), 293 (ATCC No. CRL 1573), Chinese hamster ovary CHO (eg, CHO-K1, ATCC No. CCL 61), DHFR-CHO cell line such as DG44 (see Urlaub et al., (1986) Somatic Cell Mol.Genet.125, 555-556)), particularly those CHO cell lines adapted for suspension culture, mouse Sertoli cells, monkey kidney cells, African green monkey kidney (ATCC CRL-1587), HELA cells, canine kidney cells (ATCC CCL 34), human lung cells (ATCC CCL 75), Hep G2 and myeloma or lymphoma cells, eg NSO (see US 5,807,715), Sp2 / 0, YO. Thus, in one embodiment of the invention there is provided a stably transformed host cell comprising a vector encoding a heavy chain and / or light chain of the antibody or antigen-binding fragment thereof as described herein. Preferably, the host cells comprise a first vector encoding the light chain and a second vector encoding the heavy chain.

Bacterial fermentation Bacterial systems are particularly suitable for the expression of antibody fragments. The fragments are located intracellularly or within the periplasm. Insoluble periplasmic proteins can be extracted and refolded to form active proteins according to procedures known to those skilled in the art, see Sánchez et al. (1999) X_ Biotechnol. 72, 13-20 and Cupit PM et al. (1999) Lett. Appl. Microbiol .. 29, 273-277. 3. 7 Cell culture methods. Host cells transformed with vectors encoding the antibodies of the invention or antigen-binding fragments thereof can be cultured by any method known to those skilled in the art. The host cells can be grown in centrifugal flasks, roller cans or hollow fiber systems, but it is preferred for large scale production to use particularly stirred tank reactors for suspension cultures. Preferably, the stirred tanks are adapted for aeration using, for example, traps, deflectors or low shear propellers. For bubble columns and reactors with air agitation, direct aeration can be used with air or oxygen bubbles. When the host cells are cultured in a serum-free culture medium, it is preferred that the medium be supplemented with a cellular protective agent such as Pluronic F-68 to help prevent cell damage as a result of the aeration process. Depending on the characteristics of the host cell, microcarriers can be used as growth substrates for anchor-dependent cell lines, or the cells can be adapted to suspension culture (which is typical). The culture of host cells, particularly invertebrate host cells, can utilize a variety of operational modes such as batch feeding, processing in repeated batches (see Drapeau et al. (1994) Cvtotechnology 15: 103-109), extended batch process or culture by perfusion. Although recombinantly transformed mammalian host cells can be cultured in serum-containing medium such as fetal calf serum (FCS), it is preferred that the host cells are coated in serum-free synthetic medium as disclosed in Keen et al. cabbage. (1995) Cvtotechnology 1 7: 153-163, or commercially available media such as ProCHO-C DM or Utratra ™ (Cambrex NJ, USA), supplemented if necessary with a power source such as glucose and factors of synthetic growth such as recombinant insulin. Serum-free culture of host cells may require that those cells be adapted to grow in serum-free conditions. An adaptation approach is to culture the host cells in serum-containing medium and repeatedly exchange 80% of the culture medium with serum-free media, so that the host cells learn to adapt to serum-free conditions (see, for example, example, Scharfenberg K et al (1995) in "Animal Cell technology: Developments to the 21st century" (Beuvery E.C. et al., pages 619-623, Kluwer Academic Publishers). Antibodies of the invention secreted into the medium can be recovered and purified using a variety of techniques to provide a degree of purification suitable for the intended use. For example, the use of antibodies of the invention for the treatment of human patients demands at least 95% purity, more typically 98% or 99% or higher purity (compared to the crude culture medium). In the first case, the cellular waste is typically removed from the culture media using centrifugation, followed by a clarification step of the supernatant using, for example, microfiltration, ultrafiltration and / or depth filtration. A variety of other techniques are available such as dialysis and gel electrophoresis and chromatographic techniques such as (HA); affinity chromatography on hydroxyapatite (which optionally involves an affinity labeling system such as polyhistidine) and / or hydrophobic interaction chromatography (HIC, see US 5,429,746). In one embodiment, the antibodies of the invention, after various clarification steps, are captured using affinity chromatography with protein A or G followed by additional chromatography steps such as ion exchange and / or HA chromatography, anion exchange or cation exchange chromatography. , exclusion by size and precipitation with ammonium sulfate. Typically, various steps of virus removal (eg, nanofiltration using, for example, a DV-20 filter) are also used. After these various steps, a purified (preferably monoclonal) preparation comprising at least 75 mg / ml or more, eg, 100 mg / ml or more of the antibody of the invention or antigen-binding fragment thereof, is provided, and for the both form one embodiment of the invention. Suitably, the preparations are substantially free of aggregated forms of antibodies of the invention. 4. Pharmaceutical Compositions Purified preparations of antibodies of the invention (particularly monoclonal preparations) as described above can be incorporated into pharmaceutical compositions for use in the treatment of human diseases and disorders such as atopic diseases, for example, asthma, allergic rhinitis, COPD. Typically, the compositions comprise a pharmaceutically acceptable carrier known and claimed for acceptable pharmaceutical practice, see, for example, "Remingtons Pharmaceutical Sciences", 16th edition, (1980), Mack Publishing Co. Examples of vehicles include sterilized vehicle such as saline solution, Ringer's solution or dextrose solution, buffered with suitable buffers at a p'H within a range of 5 to 8. The pharmaceutical compositions for injection (e.g., intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular or intraportal) or continuous infusion are suitably free of visible particulate material and can comprise between 0.1 ng and 100 mg of antibody, preferably between 5 mg and 25 mg of antibody. The procedures for the preparation of the pharmaceutical compositions are well known to those skilled in the art. In one modality, the Pharmaceutical compositions comprise between 0.1 ng and 100 mg of antibodies of the invention in unit dosage form, optionally together with instructions for use. The pharmaceutical compositions of the invention may be lyophilized for reconstitution prior to administration according to procedures well known or apparent to those skilled in the art. When embodiments of the invention comprise antibodies of the invention with an IgG1 isotype, a copper chelator such as citrate (eg, sodium citrate) or EDTA or histidine can be added to the pharmaceutical composition to reduce the degree of copper-mediated degradation. of antibodies of this isotype, see EP0612251. The anti-h I L-3 treatment can be administered orally, by inhalation, topically (for example, intraocular, intranasal, rectal, in skin wounds). The effective dosages and treatment regimens for administering the antibody of the invention are generally determined empirically, and depend on factors such as the age, weight and state of health of the patient and the disease or disorder to be treated. The factors are within the reach of the attending physician. A guide for the selection of appropriate doses can be found, for example, in Smith et al. (1977) "Antibodies in human diagnosis and therapy", Raven Press, New York, but in general will be between 1 mg and 1000 mg.

Depending on the disease or disorder to be treated (but particularly asthma), the pharmaceutical compositions comprising a therapeutically effective amount of the antibody of the invention can be used simultaneously, separately or sequentially with an effective amount of another drug such as anti-aging agents. inflammatories (eg, corticosteroids or an NSAID), anticholinergic agents (particularly M1 / M2 / M3 receptor antagonists), β2 adrenoreceptor agonists, anti-infective agents (eg, antibiotics, antivirals), antihistamines or PDE4 inhibitor.

Examples of β2 adrenoreceptor agonists include salmeterol, salbutamol, formoterol, salmefamol, fenoterol, terbutaline. Preferred long acting ß2 adrenoceptor agonists include those described in WO02 / 66422A, WO02 / 270490, WO02 / 076933, WO03 / 024439 and WO03 / 072539. Suitable corticosteroids include methylprednisolone, prednisolone, dexamethasone, fluticasone propionate, S-fluoromethyl ester of 6a, 9a-difluoro-a - [(2-furanylcarbonyl) oxy] -11β-h id roxy-16a-methyl-3- oxo-and rosta- 1, 4-dien-17β-carbothioic acid, S- (2-oxotetrahydrofuran-3S-yl) acid ester 6a, 9a-difluoro-11β-hydroxy-16a-methyl-3-oxo-α-propionyloxyandrosta-1,4-diene-17β-carbothioic acid, beclomethasone esters (e.g. 17-propionate ester or ester 17, 21-dipropionate), budesonide, flunisolide, mometasone esters (eg, furoate ester), triamcinolone acetonide, rofleponide, ciclesonide (16a, 17 - [[(f?) - cyclohexy I methylene] bis (oxy)] - 11?, 21-dihydroxy pregna-1,4-diene-3,20-dione), butyxocort propionate, RPR- 106541 and ST-126. Preferred corticosteroids include fluticasone propionate, S-fluoromethyl ester of 6a, 9a-difluoro-11β-hydroxy-16a-methyl-a - [(4-methyl-1,3-thiazol-5-carbaryl) oxy ] -3-oxoandrosta-1, 4-dien-17β-carbothioic acid and S-fluoromethyl ester of 6a, 9a-difluoro-a - [(2-fura nyl carbonyl) oxy] -11β-hydroxy-16a-methyl -3-oxoandrosta-1,4-dien-17β-carbothioic, more preferably S-fluoromethyl ester of 6a, 9a-difluoro-a - [(2-furanylcarbonyl) oxy] -11β-hydroxy-16a-met i l-3-oxoand rosta-1,4-dien-17β-carbothioic acid. Non-steroidal compounds that have glucocorticoid agonism that may possess transrepression selectivity versus transactivation and that may be useful in combination therapy include those covered in the following patents: WO03 / 082827, WO01 / 10143, WO98 / 54159, WO04 / 005229, WO04 / 009016, WO04 / 009017, WO04 / 018429, WO03 / 104195, WO03 / 082787, WO03 / 082280, WO03 / 059899, WO03 / 101932, WO02 / 02565, WO01 / 16128, WO00 / 66590, WO03 / 086294, WO04 / 026248, WO03 / 061651, WO03 / 08277. Suitable antiinflammatory agents include non-steroidal anti-inflammatory drugs (NSAIDs). Suitable NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (eg, theophylline, PDE4 inhibitors or mixed inhibitors of PDE3 / PDE4), leukotriene antagonists, inhibitors of leukotriene synthesis (eg, montelukast), NOS inhibitors, tryptase and elastase inhibitors, beta 2 integrin antagonists and adenosine receptor agonists or antagonists (eg, adenosine agonists 2a), cytosine antagonists (eg, chemokine antagonists such as a CCR3 antagonist) or inhibitors of cytosine synthesis, or 5-lipoxygenase inhibitors. Other suitable β2-adrenoreceptor agonists include salmeterol (for example, in the form of the xinafoate), salbutamol (for example, in the form of the sulfate or free base), formoterol (for example, in the form of the fumarate), fenoterol or terbutaline and salts of the same. A NOS (inducible nitric oxide synthase inhibitor) is preferred for oral administration. Suitable NOS inhibitors include those disclosed in WO93 / 13055, WO98 / 30537, WO02 / 50021, WO95 / 34534 and WO99 / 62875. Suitable CCR3 inhibitors include those disclosed in WO02 / 26722. Of particular interest is the use of antibodies of the invention in combination with a phosphodiesterase 4 (PDE4) inhibitor. The specific PDE4 inhibitor useful in this aspect of the invention can be any compound that is known to inhibit the PDE4 enzyme or that is found to act as an inhibitor of PDE4, and which are only PDE4 inhibitors, not compounds that inhibit other members of the PDE family, such as PDE3 and PDE5, as well as PDE4. Compounds of interest include c / 's-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid, 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) ) cyclohexan-1-one and c / s- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol]. In addition, c / s-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid (also known as cilomilast) and its salts, esters, prodrugs or physical forms are described in U.S. Pat. 5,552,438 issued September 3, 1996; this patent and the compounds disclosed are hereby incorporated by reference in their entirety. AWD-12-281 by Elbion (Hofgen, N. et al. "15th EFMC Int. Symp. Med. Chem." (September 6-10, Edinburgh) 1998, Abst P.98; Cat. No. 247584020-9); a 9-benzyladenine derivative called NCS-613 (INSERM); D-4418 of Chiroscience and Schering-Plow; a benzodiazepine inhibitor of PDE4 identified as CI-1018 (PD-168787) and attributed to Pfizer; a benzodioxol derivative disclosed by Kyowa Hakko in WO99 / 16766; K-34 of Kyowa Hakko; V-11294A by Napp (Landells, LJ et al., Resp. J. [Annu. Cong. Eur. Resp. Soc. (September 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst. P2393); roflumilast (reference no. CAS 162401-32-3) and a phthalazinone (WO99 / 47505, whose description is incorporated herein by reference) by Byk-Gulden; pumafentrin, (-) - p - [(4aR *, 10oS *) - 9-ethoxy-1, 2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [c] [1, 6] -naphyridin-6-yl] -? /, N-diisopropylbenzamide, which is a mixed inhibitor of PDE3 / PDE4 which has been prepared and published by Byk-Gulden, now Altana; arophylline under development by Almirall-Prodesfarma; VM554 / UM565 from Vernalis; or T-440 (Tanabe Seiyaku, Fuji, K. and col. J Pharmacol Exp Ther.1998, 284 (1): 162), and T2585. Additional compounds of interest are disclosed in published international patent application WO04 / 024728 (Glaxo Group Ltd), PCT / EP2003 / 014867 (Glaxo Group Ltd) and PCT / EP2004 / 005494 (Glaxo Group Ltd). Suitable anticholinergic agents are those compounds which act as antagonists at muscarinic receptors, in particular those compounds which are antagonists of the M1 or M3 receptors, dual antagonists of the M ^ / M3 or M2 / M3 receptors, or panantagonists of the M receptors. ? / M2 / M3. Exemplary compounds for administration by inhalation include ipratropium (e.g., in the form of the bromide, CAS 22254-24-6, marketed under the name Atrovent), oxitropium (e.g., in the form of the bromide, CAS 30286-75-0) and tiotropium (for example, in the form of the bromide, CAS 136310-93-5, marketed under the name Spiriva). Also of interest are revatropathy (eg, in the form of the hydrobromide, CAS 262586-79-8) and LAS-34273, which is given to be known in WO01 / 04118. Exemplary compounds for oral administration include pirenzepine (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or CAS 133099-07-7 for the hydrobromide marketed under the name Enablex), oxybutynin (CAS 5633-20- 5, marketed under the name Ditropan), terodiline (CAS 15793-40-5), tolterodine (CAS 124937-51-5, or CAS 124937-52-6 for tartrate, marketed under the name Detrol), otilonium (for example, in the form of the bromide, CAS 26095-59-0, marketed under the name Spasmomen), trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1, or CAS 242478-38-2 for succinate, also known as YM-905 and marketed under the name of Vesicare). Other suitable anticholinergic agents include compounds of formula (XXI) which are disclosed in U.S. Pat. 60/487981: wherein the preferred orientation of the alkyl chain attached to the tropane ring is endo; R31 and R32 are independently selected from the group consisting of straight or branched chain lower alkyl groups preferably having 1 to 6 carbon atoms, cycloalkyl groups having 5 to 6 carbon atoms, carbon, cycloalkylalkyl having 6 to 10 carbon atoms, 2-thienyl, 2-pyridyl, phenyl, phenyl substituted with an alkyl group having not more than 4 carbon atoms and phenyl substituted with an alkoxy group having not more than 4 carbon atoms; X 'represents an anion associated with the positive charge of the atom of N. X "may be, but without limitation, chloride, bromide, iodide, sulfate, benzenesulfonate and toluenesulfonate, including, for example: (3-e / c) bromide /o)-3-(2,2-di-2-tienleletenl )-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane; (3-epdo) -3- (2-bromide , 2-diphenylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane; (3-ep o) -3- (2,2-diphenylethenyl) -8,8-dimethyl-8-methylbenzenesulfonate -azoniabicyclo [3.2.1] octane; (3-e? do) -8,8-dimethyl-3- [2-phenyl-2- (2-thienyl) ethenyl] -8-azoniabicyclo [3.2.1] bromide octane; and / or (3-e7cfo) -8,8-dimethyl-3- [2-phenyl-2- (2-pyridinyl) ethenyl] -8-azoniabicyclo [3.2.1] octane bromide Suitable anticholinergic agents Additional compounds include compounds of formula (XXII) or (XXIII), which are disclosed in U.S. patent application 60/511009: (XXIII) in which: the indicated H atom is in the exo position; R41"represents an anion associated with the positive charge of the atom of N. R1" may be, but is not limited to, chloride, bromide, iodide, sulfate, benzenesulfonate and toluenesulfonate; R42 and R43 are independently selected from the group consisting of straight or branched chain lower alkyl groups (preferably having from 1 to 6 carbon atoms), cycloalkyl groups (having from 5 to 6 carbon atoms), cycloalkylalkyl (having 6 to 6 carbon atoms), to 10 carbon atoms), heterocycloalkyl (having 5 to 6 carbon atoms) and N or O as heteroatom, heterocycloalkylalkyl (having 6 to 10 carbon atoms) and N or O as heteroatom, aryl, optionally substituted aryl, heteroaryl and optionally substituted heteroaryl; R44 is selected from the group consisting of alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms-cycloalkyl of 3 to 12 carbon atoms carbon, alkyl of 1 to 6 carbon atoms-heterocycloalkyl of 3 to 7 carbon atoms, aryl, heteroaryl, alkyl of 1 to 6 carbon atoms-aryl, alkyl of 1 to 6 carbon atoms-heteroaryl, -OR45, - CH2OR45, -CH2OH, -CN, -CF3, -CH2O (CO) R46, -CO2R47, -CH2NH2, -CH2N (R7) SO2R45, -SO2N (R47) (R48), -CON (R47) (R48), -CH2N (R48) CO (R46), -CH2N (R48) SO2 (R46), -CH2N (R8) CO2 (R45), -CH2N (R 8) CONH (R47); R 45 is selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-cycloalkyl of 3 to 12 carbon atoms, alkyl of 1 to 6 carbon atoms-heterocycloalkyl of 3 to 7 carbon atoms carbon, alkyl of 1 to 6 carbon atoms-aryl, alkyl of 1 to 6 carbon atoms-heteroaryl; R46 is selected from the group consisting of alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms-cycloalkyl of 3 to 12 carbon atoms carbon, alkyl of 1 to 6 carbon atoms-heterocycloalkyl of 3 to 7 carbon atoms, aryl, heteroaryl, alkyl of 1 to 6 carbon atoms-aryl, alkyl of 1 to 6 carbon atoms-heteroaryl; R47 and. R48 are independently selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms-cycloalkyl of 3 to 12 carbon atoms, alkyl of 1 to 6 carbon atoms-heterocycloalkyl of 3 to 7 carbon atoms, alkyl of 1 to 6 carbon atoms-aryl, and alkyl of 1 to 6 carbon atoms-heteroaryl including, for example: iodide of (endo) -3- (2-methoxy-2,2-dithiophen-2-ylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane; 3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2.2- diphenylpropionitrile; (endo) -8-methyl-3- (2,2,2-triphenylethyl) -8-azabicyclo [3.2.1] octane; 3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropionamide; 3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropionic acid; iodide of (endo) -3- (2-cyano-2,2-diphenylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane; (endo) -3- (2-cyano-2,2-diphenylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane bromide; 3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropan-1-ol; ? / - benzyl-3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropionamide; iodide of (endo) -3- (2-carbamoyl-2,2-diphenylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane; 1-Benzyl-3- [3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropyl] -urea; 1-ethyl-3- [3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropyl] -urea; ? / - [3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropyl-acetamide; ? / - [3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropyl] -benzamide; 3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-dithiophene-2- Ipropionitrile; iodide (endo) -3- (2-cyano-2,2-dithiophen-2-ylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane; ? / - [3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropyl] -benzenesulfonamide; [3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropyl] urea; ? / - [3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropyl] -methanesulfonamide; and / or (endo) -3- bromide. { 2,2-diphenyl-3 - [(1-phenylmethanoyl) amino] propyl} -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane. More preferred compounds useful in the present invention include: (endo) -3- (2-methoxy-2,2-dithiophene-2-ylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane iodide; iodide of (endo) -3- (2-cyano-2,2-diphenylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane; (endo) -3- (2-cyano-2,2-diphenylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane bromide; iodide of (endo) -3- (2-carbamoyl-2,2-diphenylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane; iodide (endo) -3- (2-cyano-2,2-dithiophen-2-ylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane; and / or (endo) -3- bromide. { 2,2-diphenyl-3 - [(1- phenylmethanoyl) amino] propyl} -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane. Suitable antihistamines (also referred to as H1 receptor antagonists) include any one or more of the numerous known antagonists that inhibit H1 receptors and are safe for human use. First generation antagonists include derivatives of ethanolamines, ethylenediamines and alkylamines, for example, diphenylhydramine, pyrilamine, clemastine, chlorpheniramine. Second-generation antagonists, which are non-sedating, include loratidine, desloratidine, terfenadine, astemizole, acrivastine, azelastine, levocetirizine, fexofenadine and cetirizine. Examples of preferred antihistamines include loratidine, desloratidine, fexofenadine and cetirizine. Other contemplated combinations include the use of antibodies of the invention in combination with an anti-IL-4 agent (e.g., anti-IL-4 antibody such as pascolizumab) and / or anti-IL-5 agent (e.g. -IL-5 such as mepolizumab) and / or anti-IgE agent (eg, anti-IgE antibody such as omalizumab (Xolair ™) or talizumab). Conveniently, a pharmaceutical composition comprising a kit of antibody portions of the invention or antigen-binding fragment thereof together with the other medicaments, optionally together with instructions for use, is also contemplated by the present invention.

The invention further contemplates a pharmaceutical composition comprising a therapeutically effective amount of monoclonal therapeutic antibody or antigen-binding fragment thereof as described herein for use in the treatment of diseases responsive to the modulation of the interaction between hIL-13 and hlL-13R. According to the present invention, a pharmaceutical composition comprising a therapeutically effective amount of a monoclonal humanized therapeutic antibody is provided., the antibody comprising a VH domain selected from the group consisting of SEQ ID NO: 11, 12, 13, 14 and a VL domain selected from the group consisting of SEQ ID NO: 15, 16, 17. According to the present invention, provides a pharmaceutical composition comprising a monoclonal antibody comprising a heavy chain selected from the group consisting of SEQ ID NOs 18, 19, 20, 21 and a light chain selected from the group consisting of SEQ ID NOs 22, 23, 24. According to the present invention, there is provided a pharmaceutical composition comprising a monoclonal antibody comprising a heavy chain of SEQ ID NO: 18 and a light chain of SEQ ID NO: 22, and a pharmaceutically acceptable carrier. According to the present invention, a A pharmaceutical composition comprising a monoclonal antibody comprising (or essentially consisting of) a heavy chain of SEQ ID NO: 18 and a light chain of SEQ ID NO: 22, and a pharmaceutically acceptable carrier. According to the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a monoclonal antibody population, the antibody comprising a heavy chain of SEQ ID NO: 18 and a light chain of SEQ ID NO: 22. In accordance with the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a monoclonal antibody population, the antibody comprising a heavy chain of SEQ ID NO. 18 and a light chain of SEQ ID NO. 23. According to the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a monoclonal antibody population, the antibody comprising a heavy chain of SEC NO. ID 18 and a light chain of SEQ ID NO. 24. In accordance with the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount therapeutically of a monoclonal antibody population, the antibody comprising a heavy chain of SEQ ID NO: 19 and a light chain of SEQ ID NO: 22. In accordance with the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an Therapeutically effective of a monoclonal antibody population, the antibody comprising a heavy chain of SEQ ID NO. 19 and a light chain of SEQ ID NO. 23. In accordance with the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a monoclonal antibody population, the antibody comprising a heavy chain of SEC NO. ID 19 and a light chain of SEQ ID NO. 24 In accordance with the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a monoclonal antibody population, the antibody comprising a heavy chain of SEC NO. ID and a light chain of SEQ ID NO. 22. According to the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a monoclonal antibody population, the antibody comprising a heavy chain of SEQ ID NO: 20 and a light chain of SEQ ID NO: 23. In accordance with the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of an antibody monoclonal population. , the antibody comprising a heavy chain of SEC NO ID and a light chain of SEQ ID NO. 24. According to the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a monoclonal antibody population, the antibody comprising a heavy chain of SEC NO. ID 21 and a light chain of SEQ ID NO. 22. According to the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a monoclonal antibody population, the antibody comprising a heavy chain of SEC NO. ID 21 and a light chain of SEQ ID NO. 23. According to the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a monoclonal antibody population, the antibody comprising a SEC heavy chain. NO ID 21 and a light chain of SEC NO ID 24. 5. Clinical uses. The antibodies of the invention can be used in the treatment of atopic diseases / disorders and chronic inflammatory diseases / disorders. Of particular interest is its use in the treatment of asthma, such as allergic asthma, particularly severe asthma (which is asthma which is insensitive to current treatment, including corticosteroids administered systemically, see Busse WW et al., J Allergy Clin. Immunol 2000, 106: 1033-1042), "difficult" asthma (defined as the asthmatic phenotype characterized by inability to achieve control despite the maximum recommended doses of prescribed inhaled steroids, see Barnes PJ (1998), Eur Respir J 12: 1208- 1218), "labile" asthma (defines a subgroup of patients with severe unstable asthma who maintain a wide variability of maximum expiratory flow (PEF) despite high doses of inhaled steroids, see Ayres JG et al (1998) Thorax 58: 315-321), nocturnal asthma, premenstrual asthma, steroid-resistant asthma (see Woodcock AJ (1993) Eur. Respir. J. 6: 743-747), steroid-dependent asthma (defined as asthma that can be controlled only with high doses). from steroi oral), asthma induced by aspirin, adult onset asthma, pediatric asthma. The antibodies of the invention can be used to prevent, reduce the frequency or mitigate the effects of acute asthmatic episodes (asthmatic state). The antibodies of the invention can also be used to reduce the dosage needed (in terms of amount administered or frequency of dosing) of other drugs used in the treatment of asthma. For example, the antibodies of the invention can be used to reduce the dosage necessary for asthma steroid treatment such as corticosteroid treatment ("steroid saving"). Other diseases or disorders that can be treated with antibodies of the invention include atopic dermatitis, allergic rhinitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), eosinophilic esophagitis, fibrotic diseases or disorders such as idiopathic pulmonary fibrosis, progressive systemic sclerosis (scleroderma). , liver fibrosis, hepatic granulomas, schistosomiasis, leishmaniasis and cell cycle regulation diseases, for example, Hodgkins disease, B-cell chronic lymphocytic leukemia. Additional diseases or disorders that can be treated with antibodies of the invention in the background of the invention above. In one embodiment of the invention, there is provided a method of treating a human patient afflicted with an asthmatic condition that is refractory to treatment with corticosteroids, the method comprising the step of administering to the patient a therapeutically effective amount of an antibody of the invention. In another embodiment, a method of prevention of an acute asthmatic attack in a human patient, the method comprising the step of administering to the patient a therapeutically effective amount of an antibody of the invention. In another embodiment, a method of reducing the frequency and / or mitigating the effects of an acute asthmatic attack in a human patient is provided, the method comprising the step of administering to the patient a therapeutically effective amount of an antibody of the invention. . In another embodiment of the invention, a method of shunting the response of T helper cells to a Th1 type response after an inflammatory and / or allergic attack in a human patient is provided, the method comprising administering to the patient a therapeutically effective amount of an antibody or antigen-binding fragment thereof of the invention. In another embodiment of the invention, there is provided a method of treating a human patient having the variant h I L-13 Q130, the asthma patient being afflicted, such as severe asthma, the method comprising the step of administering to the patient a Therapeutically effective amount of an antibody or antigen-binding fragment thereof of the invention. Although the present invention has been described mainly in relation to the treatment of diseases or disorders In humans, the present invention may also have applications in the treatment of similar diseases or disorders in non-human mammals. The present invention is now described by way of example only. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 Sandwich ELISA illustrating the binding of mouse monoclonal antibody 3G4 to human IL-13 expressed in recombinant E. coli at increasing concentrations. Figure 2a Neutralization assay illustrating the ability of the mouse monoclonal antibody 3G4 at increasing concentrations to inhibit the bioactivity of human IL-13 expressed in recombinant E. coli in a TF-1 cell proliferation assay. Figure 2b Neutralization assay illustrating the ability of chimeric 3G4 at increasing concentrations to inhibit the bioactivity of human IL-13 expressed in recombinant E. coli in a TF-1 cell proliferation assay. Figure 3 Neutralization assay illustrating the ability of the mouse monoclonal antibody 3G4 (and chimeric 3G4) at increasing concentrations to inhibit the bioactivity of Cynomolgus IL-13 expressed in recombinant E. coli in an assay of proliferation of TF-1 cells. The curve marked "Campath" is obtained using humanized anti-CD52 antibody alemtuzumab, which acts as an irrelevant antibody control in this experiment. The line marked 'anti-hlL13 poly' is that obtained using a neutralizing anti-IL-13 polyclonal preparation (R & D Systems, catalog number AF-213-NA) as a positive control. Figure 4 Neutralization assay illustrating the ability of the mouse monoclonal antibody 3G4 (and chimeric 3G4) at increasing concentrations to inhibit the bioactivity of human expressed L-13 in mammal (CHO cell) in a TF-1 cell proliferation assay . Campath and anti-hIL13 are control reagents as described above. Figure 5 Neutralization assay illustrating the ability of the mouse monoclonal antibody 3G4 (chimeric 3G4) at increasing concentrations to inhibit the bioactivity of human I L-13 Q130 expressed in recombinant E. coli in a TF-1 cell proliferation assay. Campath and anti-hIL13 are control reagents as described above. Figure 6 An epitope mapping ELISA for determining the binding epitope for mouse monoclonal antibody 3G4 to human IL-13 and Cynomolgus.

Figure 7a An epitope mapping ELISA for identifying the fine binding specificity of mouse monoclonal antibody 3G4 to human I L-13. Figure 7b An epitope mapping ELISA for identifying the fine-binding specificity of mouse monoclonal antibody 3G4 to Cynomolgus IL-13. Figure 8 An epitope mapping ELISA for determining the key amino acid residues necessary to bind the mouse monoclonal antibody 3G4 to human IL-13. Figure 9 An epitope mapping ELISA for determining the key amino acid residues necessary to bind the mouse monoclonal antibody 3G4 to human IL-13. Figure 10 sandwich ELISA illustrating the binding of chimeric mouse 3G4, 3G4 monoclonal antibody and humanized mAbs H2L1, H3L1 to human IL-13 expressed in recombinant E. coli at increasing concentrations. Figure 11 Neutralization assay illustrating the capacity of the mouse monoclonal antibody 3G4, chimeric 3G4 and the humanized mAbs H2L1, H3L1 at increasing concentrations for inhibit the bioactivity of human IL-13 expressed in recombinant E. coli in a TF-1 cell proliferation assay. Figure 12 Neutralization assay illustrating the ability of chimeric mouse 3G4, 3G4 monoclonal antibody and humanized mAbs H2L1, H3L1 at increasing concentrations to inhibit the bioactivity of Cynomolgus I L-13 expressed in recombinant E. coli in a proliferation assay of TF-1 cells. Figure 13 Neutralization assay illustrating the capacity of the mouse monoclonal antibody 3G4, chimeric 3G4 and the humanized mAbs H2L1, H3L1 at increasing concentrations of inhibiting the bioactivity of human IL-13 expressed in mammalian (CHO cells) in a TF-1 cell proliferation assay. Figure 14 Neutralization assay illustrating the ability of chimeric 3G4, 3G4 mouse montfclonal antibody and humanized mAbs H2L1, H3L1 at increasing concentrations to inhibit the bioactivity of human IL-13 Q130 expressed in recombinant E. coli in a proliferation assay of TF-1 cells. Figure 15 sandwich ELISA demonstrating that the mouse monoclonal antibody 3G4, chimeric 3G4 and the humanized mAbs H2L1, H3L1 do not bind to human IL-4 expressed in recombinant E. coli.

Figure 16 Sandwich ELISA demonstrating that chimeric mouse 3G4, 3G4 monoclonal antibody and humanized mAbs H2L1, H3L1 do not bind to human IL-5 expressed in recombinant E. coli. Figure 17 Direct binding ELISA demonstrating that mouse monoclonal antibody 3G4, chimeric 3G4 and humanized mAbs H2L1, H3L1 do not bind to human GM-CSF. Figure 18 sandwich ELISA illustrating the binding of chimeric mouse 3G4, 3G4 monoclonal antibody and humanized mAbs H2L1, H3L1 to native human IL-13 at increasing concentrations. Figure 19 ELISA illustrating the ability of chimeric mouse 3G4, 3G4 monoclonal antibody and humanized mAbs H2L1, H3L1 at increasing concentrations to inhibit the binding of human I L-13 expressed in recombinant E. coli to the α1 chain of the human receptor. I L-13 human. Figure 20 ELISA illustrating the ability of chimeric 3G4, 3G4 mouse monoclonal antibody and humanized mAbs H2L1, H3L1 at increasing concentrations to inhibit the binding of human L-13 expressed in recombinant E. coli to the IL receptor chain at 2. -13 human.

Examples 1. Generation of monoclonal antibodies and characterization of monoclonal antibody 3g4 Five SJ L mice were immunized by intraperitoneal injection each with 2 μg of recombinant human L-13 derived from E. coli (Cambridge Bioscience, Cat. CH-01 3). Spleen cells were removed from mice and B lymphocytes were fused with mouse myeloma cells derived from P3X cells, using PEG 1500 (Boehringer) to generate hybridomas. Individual hybridoma cell lines were cloned by limiting dilution (E Harlow and D Lane). Wells containing individual colonies were microscopically identified and the activity of the supernatants was assayed. The cells of the most active clones were expanded for cryopreservation, production of antibodies, etc. Initially, the hybridizing supernatants were examined for binding activity against a human L-13 protein labeled with recombinant det-1 expressed in E. coli (prepared in the laboratory) in a sandwich assay format. A secondary examination of these positives was completed using a BIAcore ™ procedure to detect binding to human protein I L-1 3 labeled with det-1. The ability to neutralize the bioactivity of recombinant human I L-1 3 expressed in E. coli (Cambridge Bioscience, Cat. No. H-013) in a TF-1 cell assay was then tested in samples of these hybridomas.

The positives identified were subcloned from the neutralizing bioassay of human IL-13 by limiting dilution to generate stable monoclonal cell lines. Immunoglobulins were purified from these hybridomas, grown in cell factories under serum-free conditions, using immobilized protein A columns. These purified mAbs were retested in the same three assay systems. The 3G4 monoclonal antibody was identified as a potent antibody that neutralized the bioactivity of human IL-13. The 3G4 antibody has the amino acid sequence of the VH region as indicated in SEQ ID NO. 7. The 3G4 antibody has the amino acid sequence of the V region as indicated in SEQ ID NO. 8. A chimeric antibody was constructed variable regions of the murine monoclonal antibody 3G4 and grafting these in wild type C regions of human IgG1 / k. A human signal sequence (as shown in SEQ ID NO 43) was used in the construction of these constructs. This chimeric antibody was named 3G4C. 1. 1 Recombinant human IL-13 binding expressed in E. coli 3G4 bound to recombinant human L-13 expressed in E. coli in a sandwich ELISA, the procedure was carried out as described in Example 6.1 (see Figure 1). 1. 2. Neutralization of human IL-13 and recombinant Cynomolgus expressed in E. coli in a proliferation bioassay of TF-1 cells. TF-1 cells proliferate in response to human IL-13 and Cynomolgus IL-13. A bioassay was developed to evaluate the neutralization capacity of a mAb at nti-1 L-13 in the proliferation of TF-1 cells induced by human I L-13 and Cynomolgus. The procedure was carried out as described in Example 6.2. The amino acid sequence and a cDNA sequence of Cynomolgus IL-13 (which does not include the signal sequence) are set forth as SEQ ID NO 41 and SEQ ID NO 42, respectively. 3G4 neutralized the bioactivity of recombinant human IL-13 in a TF-1 cell bioassay (see Figure 2a). 3G4 neutralized the bioactivity of Cynomolgus IL-13 less potently than human IL-13 (see Figure 3). An average value of DN50 of 0.13 μg / ml was calculated for the neutralization of approximately 10 ng / ml bioactivity of recombinant human IL-13 expressed in E. coli in a TF-1 cell bioassay by the monoclonal antibody 3G4. A DN50 value of 29 μg / ml was calculated for the neutralization of approximately 10 ng / ml bioactivity of I L-13 of recombinant Cynomolgus expressed in E. coli in a TF-1 cell bioassay by the monoclonal antibody 3G4. [He DN50 value (neutralization dose) is the concentration of monoclonal antibody necessary to reduce the proliferation of TF-1 cells by 50% in response to a fixed concentration of IL-13]. 1.3. Neutralization of human IL-13 expressed in a mammal (CHO cell) in a TF-1 cell proliferation bioassay. The neutralizing ability of the human IL-13 monoclonal antibody 3G4 expressed from CHO cells in a TF-1 cell proliferation assay was evaluated. The procedure was carried out as described in Example 6.2. 3G4 neutralized human IL-13 expressed in mammal more potently than a commercially available anti-human IL-13 polyclonal reagent. A DN50 value of 0.31 μg / ml was calculated for the neutralization of -20 ng / ml of human IL-13 expressed in a mammal in a TF-1 cell bioassay by the monoclonal antibody 3G4. See Figure 4. 1.4. Neutralization of recombinant human IL-13 Q130 variant in a TF-1 cell proliferation bioassay The neutralization capacity of the recombinant human IL-13 Q130 monoclonal antibody 3G4 expressed in E. coli (Peprotech, Cat. No. 200) was evaluated. -13A) in a TF-1 cell proliferation assay. The procedure was carried out as described in Example 6.2. 3G4 neutralized human IL-13 Q130 more potently than a polyclonal anti-l L-13 reagent human available commercially. A DN50 value of 0.025 μg / ml was calculated for the neutralization of -60 ng / ml of bioactivity of human IL-13 Q130 in a TF-1 cell bioassay by the monoclonal antibody 3G4. See Figure 5. 1.5 BIAcore ™ Analysis Affinity of the 3G4 mouse mAb was assessed by human I L-13 and recombinant Cynomolgus by BIAcore ™ analysis (surface plasmon resonance). See Table 2. BIAcore ™ analyzes were performed using anti-mouse IgG capture. An anti-mouse IgG antibody was coupled to a CM5 chip by primary amine coupling according to the manufacturers' recommendation. Original 3G4 mouse mAb was then captured on this surface and either human or Cynomolgus IL-13 was passed over it at defined concentrations. The surface was regenerated back to anti-mouse IgG surface using weak acid elution conditions, this did not significantly affect the ability to capture antibody for a subsequent I L-13 binding event. This work was carried out in Biacore 3000, it was analyzed using the evaluation software of the machine and the data were analyzed using the 1: 1 union model. Human IL-13 binding data was generated using human I L-13 labeled with Det-1 expressed in recombinant E. coli, as well as a commercial reagent of unlabeled human L-13 expressed in recombinant E. coli (supplied by Peprotech). I L-13 of Cynomolgus expressed in recombinant E. coli was generated in GSK. All Biacore processes were carried out at 25 ° C. Table 2. Biacore 3000 data for binding of original 3G4 mouse mAb to human IL-13 and Cynomolgus For human IL-13 labeled with Det-1, the data were produced from 2 independent experiments, both processes being carried out in duplicate. The data are presented as the mean and standard deviation (in parentheses) of these results. For human IL-13 (supplied by Peprotech) and Cynomolgus IL-13 (prepared in GSK), the data are the result of an experiment carried out in duplicate. For the data described above, the duplicates were analyzed together providing a value for the process. These data indicate that the 3G4 mouse mAb has a very high binding affinity for human IL-13, the binding affinity of the 3G4 mouse mAb for Cynomolgus IL-13 is less potent in comparison. 2. Humanization of clone 3G4 2.1 Sequence analysis A comparison was made between the sequences of the variable regions of 3G4 and other murine and human immunoglobulin sequences. This was done using the FASTA and BLAST programs and through inspection. The following framework residues in 3G4 were identified as potentially important in the design of a CDR (humanized) version of the antibody: Position 3G4 VH 10 D 30 I 93 T The position is according to the Kabat and COI numbering system. Position 3G4 VL 98 L An adequate human acceptor framework was identified for 3G4 VH: SEC NO ID 44 An adequate human acceptor framework was identified for V of 3G4: SEC NO ID 45. In SEC NO ID 44, CRDH1 and H2 are present and CDRH3 is represented by XXXXXXXXXX. In SEC NO ID 45, CRDL1 and L2 are present and CDRL3 is represented by XXXXXXXXX. In CDR grafting, it is typical to require one or more framework residues from the donor antibody to be included in place of their orthologs in the acceptor frames to obtain a satisfactory binding. In addition to those listed above, the following murine framework residues were also considered for possible retention in a humanized antibody design.

Position (No. Kabat) VH of 3G4 Human VH 10 D E 30 I T 67 A V 69 L M 71 A R 73 K T 93 T A Position (No. Kabat) VL of 3G4 of human VL mouse 76 N S 98 L F Four humanized VH constructs with different backmotions were designed to obtain a humanized antibody with satisfactory activity. They are numbered H1 to H4.

H1 is constituted by a CDR graft of the VH CDRs of 3G4 in the specific acceptor sequence. Additionally, H1 contains the murine moiety in position 30 (isoleucine). This is outside Kabat's definition of CDR, but within the definition of H1 from Chothia's CDR. In this case, this waste is considered to be part of the CDR instead of a true frame backmowing. H2 is identical to H1, but with a back-mutation in which the amino acid in position 93 is threonine instead of alanine. H3 is identical to H2, but with an additional back-mutation in which the amino acid at position 10 is aspartic acid instead of glutamic acid. H4 is identical to H3, but contains four additional retromutations at positions 67 (alanine instead of valine), 69 (leucine instead of methionine), 71 (alanine instead of arginine) and 73 (lysine instead of threonine). Three humanized VL constructs with different backmutations were designed to obtain a humanized antibody with satisfactory activity. These are numbered L1 to L3. L1 is constituted by a CDR graft of the VL CDRs of 3G4 in the specified acceptor sequence, using the Kabat definition of CDR. L2 is identical to L1, but with a back-mutation in which the amino acid at position 98 is leucine instead of phenylalanine.

L3 is identical to L2, but with an additional back-mutation in which the amino acid in position 76 is asparagine instead of serine. Humanized VH Construct H1: SEC NO ID 11 Humanized VH H2 construct: SEC NO ID 12 Humanized V H construct H3: SEC NO ID 13 Humanized V H construct H4: SEC NO ID 14 Humanized VL construct L1: SEC NO ID 15 Humanized VL construct L2: SEC NO ID 16 Humanized VL construct L3: SEC NO ID 17 2.2 Humanization of 3G4 Humanized VH and VL constructs were prepared by de novo accumulation of overlapping oligonucleotides including restriction sites for vector cloning of expression of mammal Rld and Rln, as well as a human signal sequence. Restriction sites were introduced Hind lll and Spe I as a framework of the VH domain that contains the human signal sequence (SEC NO ID 43) for cloning in Rld which contains the constant region of wild type human 1. The restriction sites Hind lll and BsiW I were introduced as a framework of the VL domain containing the human signal sequence for cloning in Rln containing the human kappa constant region. This is essentially as described in WO 2004/014953. 3. Expression and characterization of humanized antibodies Humanized VH constructs (H1, H2, H3 and H4) and two humanized VL constructs (L1 and L2) were prepared in mammalian expression vectors Rld hC? 1wt and Rln hO ?. Light chain heavy plasmid combinations (H1L1, H1L2, H2L1, H2L2, H3L1, H3L2, H4L1, H4L2) were transiently cotransfected in CHO cells and expressed on a small scale, providing eight different humanized antibodies.

It was analyzed in the antibodies produced in the supernatant of CHO cells and subsequent batches of purified antibodies the activity in ELISA binding to human L-13, in the neutralization bioassay of human IL-13, and binding to human IL-13 by BIAcore ™. The eight humanized mAbs showed binding and / or neutralization of human I L-13 in each of these assays. H2L1 and H3L1 were selected for further analysis due to the better performance in the neutralization bioassay of human IL-13 and binding to human I L-13 by BIAcore ™, offering a limited number of backmutations. 3. 1 Binding to recombinant human IL-13 expressed in E. coli 3G4C, H2L1 and H3L1 bound to recombinant human IL-13 expressed in E. coli in a sandwich ELISA with similar profiles. The procedure was carried out as described in Example 6.1A. Table 3 shows the average values of ED50 (see also Figure 10). [The ED50 (effective dose) is the concentration of antibody needed for half-maximal binding to I L-13 in this ELISA] 7ab / a 3 It has also been shown that 3G4, 3G4C, H2L1, and H3L1 inhibit the binding of human IL-13 to human I L-13 receptor chains (IL13Ra1 and IL13Ra2) by ELISA. This procedure was carried out as described in Example 6.5 and 6.6. Figure 19 shows the data demonstrating the inhibition of IL13Ra1 binding. Table 4 shows the average IC50 values for the inhibition of IL13Ra2 binding. [Cl50 is the concentration of mAb necessary to inhibit the binding of a fixed amount of human I L-13 to IL13Ra2 in a fifty%]. Table 4 Figure 19 illustrates that 3G4, 3G4, H2L1 and H3L1 inhibit the binding of human I L-13 to IL13Ra1 with similar potency. Figure 20 illustrates that 3G4, 3G4C, H2L1 and H3L1 inhibit the binding of human I L-13 to IL13Ra2 with similar potency. 3.2 Binding to native human IL-13 The HDLM-2 cell line (a cell line similar to Reed-Steinberg, originally derived from bone marrow), prepares human I L-13 and uses it autocrine for growth. This native human IL-13 is secreted in the supernatant of HDLM-2 cells. This was used to evaluate the binding of 3G4, 3G4C, H2L1 and H3L1 to native human IL-13 using a procedure as described in Example 6.1B. Using ELISA, the four antibodies bound to native human IL-13 in the supernatant of HDLM2 cells with a performance very similar to that of the 3G4 mAb original. See Figure 18. 3.3 Neutralization of human IL-13 and recombinant Cynomolgus expressed in E. coli in a TF-1 cell proliferation bioassay. 3G4, 3G4C, H2L1 and H3L1 neutralized the bioactivity of human IL-13 and recombinant Cynomolgus expressed in E. coli. The procedure was carried out as described in Example 6.2A. 3G4, 3G4C, H2L1 and H3L1 neutralized the bioactivity of IL-13 of recombinant Cynomolgus expressed in E. coli less potently than that of human IL-13 [DN50 (neutralizing dose) is the concentration of mAb necessary to reduce the proliferation of TF cells -1 by 50% in response to a fixed concentration of I L-13]. See table 5 below and figures 11 and 12. Table 5 The mean value of DN50 for 3G4 was 0.049 μg / ml, calculated for the neutralization of approximately 10 ng / ml bioactivity of recombinant human L-13 expressed in E. coli in the TF-1 assay. The results in table 5 are the average of four separate repetitions. The value obtained is comparable, although approximately twice less, than the value of DN50 obtained above (see example 1.2). The neutralization level of human IL-13 expressed in E. coli achieved for the original 3G4 mouse mAb is comparable to that achieved by chimeric 3G4. The potency of H2L1 and H3L1 were reduced compared to both the original 3G4 mouse and the chimeric 3G4 mAb. The mean value of DN50 for original 3G4 is 34 μg / ml. This was calculated for the neutralization of approximately 10 ng / ml of bioactivity of recombinant Cynomolgus IL-13 expressed in E. coli in the TF-1 assay. This value was similar to the value previously reported for the original 3G4 (see example 1.2). H2L1 and H3L1 also showed a similar potency to 3G4 against Cynomolgus IL-13. 3.4 Neutralization of human IL-13 expressed in a mammal (CHO cells) in a TF-1 cell proliferation bioassay The neutralization capacity of the human IL-134, 3G4C, H2L1, and H3L1 monoclonal antibody expressed in CHO cells was evaluated in a TF-cell proliferation assay 1 according to the procedure indicated in Example 6.2A. 3G4, 3G4C, H2L1 and H3L1 neutralized the bioactivity of human IL-13 expressed in recombinant CHO (see Table 6 and Figure 13). [DN50 (neutralizing dose) is the concentration of mAb necessary to reduce the proliferation of TF-1 cells by 50% in response to a fixed concentration of I L-13] Table 6 The mean value of DN50 for original 3G4 was 0.05 μg / ml.

This was calculated for the neutralization of -10 ng / ml human I L-13 expressed in a mammal in a TF-1 cell bioassay. This value differs from that obtained previously (see example 1.3). However, the amount of human IL-13 used to stimulate the proliferation of TF-1 cells in these experiments was lower than previously used (10 ng / ml). The level of neutralization of human IL-13 expressed in CHO achieved by the original 3G4 mAb was slightly better than the level for 3G4C. The potencies of H2L1 and H3L1 were reduced in comparison with both the original 3G4 mAb and the chimeric 3G4. 3. 5 Neutralization of the recombinant human IL-13 Q130 variant in a TF-1 cell proliferation bioassay. The neutralization capacity of 3G4, 3G4C, H2L1 and H3L1 of recombinant human I L-13 Q130 expressed in E. coli was evaluated in a TF-1 cell proliferation assay. The procedure was carried out as described in Example 6.2A.

A DN50 value of 0.274 μg / ml was obtained. This differs from the DN50 value previously obtained (see example 1.4). This test was repeated several times to confirm these values of DN50. The quality of the human commercial IL-13 Q130 preparation used in both sets of experiments (carried out at different times) may explain the differences observed for these two data sets.

Table 7 indicates the powers of 3G4C, H2L1 and H3L1, which were all similar. See also Figure 14.

Table 7 3. 6 BIAcore ™ Analysis Affinity of 3G4C, H2L1 and H3L1 was evaluated by human I L-13 and recombinant Cynomolgus by BIAcore ™ analysis. See Tables 8, 9 and 10. Analyzes were carried out using protein A capture. Briefly, protein A was coupled onto a CM5 chip by primary amine coupling according to the manufacturer's recommendations. The chimeric antibody or humanized antibodies were then captured on this surface and either human or Cynomolgus IL-13 were passed over it at defined concentrations. The surface to protein A surface was regenerated again using acid elution conditions weak, this did not significantly affect the ability to capture antibody for a subsequent IL-13 binding event. The work was carried out on Biacore 3000 and T100 Biacore machines, the data were analyzed using the evaluation software of the machines and fitted to a 1: 1 union model. The data differed slightly between the two machines, although the differences observed between the binding kinetics of the chimeric and humanized antibodies to human IL-13 were similar for both machines. The binding data for human I L-13 conformed well to the 1: 1 model for all the constructs, however, the fit for I L-13 binding of Cynomolgus was worse, raising the possibility that the actual values could be slightly worse (for example, a difference of 2-3 times) than those reported due to this worse adjustment and the difficulty of the analyzes. The data were generated using human IL-13 or non-labeled recombinant Cynomolgus (prepared in GSK). All Biacore processes were carried out at 25 ° C. Table 8: Biacore 3000 data for the binding of chimeric and humanized antibodies to human IL-13 For chimeric 3G4, the data were produced from 4 independent experiments (two of which were carried out in duplicate, each duplicate being analyzed separately). For the humanized mAbs H2L1 and H3L1, the data were produced from two independent experiments carried out in duplicate (each duplicate being analyzed separately). The data are presented as mean and standard deviation (in parentheses) of these results. Table 9: T100 data for the binding of chimeric and humanized antibodies to human IL-13 Data were produced from 2 independent experiments, and presented as mean and standard deviation (in parentheses) of these results.

The chimeric antibody 3G4 and the humanized mAbs H2L1 and H3L1 bind with high affinity to human IL-13, and these data are comparable with the binding affinity of the original 3G4 mouse mAb to human I L-13.

Table 10: T100 data for the binding of chimeric and humanized antibodies to Cynomolgus IL-13 The data was produced from an individual experiment. The chimeric antibody 3G4 and the humanized mAbs H2L1 and H3L1 bind to Cynomolgus IL-13 with a lower affinity compared to their binding affinity for human I L-13. 3.7 Specificity of 3G4C, H2L1 and H3L1 for binding to human IL-13. The specificities of 3G4C, H2L1 and H3L1 were evaluated by human IL-13 by analysis of the cross-reactivity potential against human IL-4, human IL-5 and human GM-CSF in binding ELISA. These procedures were carried out as described in section 6.7, 6.8 and 6.9, respectively. See Figures 15, 16 and 17. These mAbs were found to be specific for I L-13 binding, without cross-reactivity for human IL-4, human IL-5 or human GM-CSF at mAb concentrations up to 30 μg / ml. 3G4 chimerical seemed to show certain binding by human IL-5 at 30 μg / ml, this is probably due to a pipetting error, since no observation was made for humanized mAbs H2L1 and H3L1 at a similar concentration. 4. Cartography of 3g4 epitopes using biotinylated peptides A series of epitope mapping experiments were performed to determine which amino acid residues in I L-13 were required for the binding of the mouse mAb 3G4. 4.1 Thick mapping of the binding epitope of mouse mAb 3G4 to human IL-13 and Cynomolgus Peptides of 16 biotinylated units displaced in 4 were synthesized to map the location of the binding epitope recognized by mouse mAb 3G4 to human IL-13 and of Cynomolgus. An ELISA procedure was used as described in Example 6.3 to detect the binding of immobilized biotinylated peptide to the original mouse mAb 3G4. Details of the custom-designed peptides of 16 units: 88 x 16 units, displaced by 4 (supplied by Mimotopes, Australia). Format: Peptides 25 and 44 = Biotin-SGSG-PEPTIDE-acid Peptides 2-24 and 27-43 = Biotin-SGSG-PEPTIDE-amide No. Hydro PM Term-N Sequence Term-C 2 0.42 2,311.66 Biotin- SEC NO ID 46 -NH2 3 0.27 2,453.82 Biotin- SEC NO ID 47 -NH2 4 0.38 2,326.70 Biotin- SEC NO ID 48 -NH2 0.31 2,231.58 Biotin- SEC NO ID 49 -NH2 6 0.43 2,289.66 Biotin- SEC NO ID 50 -NH2 7 0.59 2,190.57 Biotin- SEC NO ID 51 -NH2 8 0.57 2,260.64 Biotin- SEC NO ID 52 -NH2 9 0.62 * '2,255.64 Biotin- SEC NO ID 53 -NH2 0.51 2,197.56 Biotin- SEC NO ID 54 -NH2 11 0.56 2,144.52 Biotin- SEC NO ID 55 -NH2 12 0.46 2,090.38 Biotin- SEC NO ID 56 -NH2 13 0.29 2,219.54 Biotin- SEC NO ID 57 -NH2 14 0.29 2,180.53 Biotin- SEC NO ID 58 -NH2 0.36 2,318.70 Biotin- SEC NO ID 59 -NH2 16 0.32 2,303,73 Biotin- SEC NO ID 60 -NH2 17 0.47 2,209.57 Biotin- SEC NO ID 61 -NH2 18 0.48 2,257.60 Biotin- SEC NO ID 62 -NH2 19 0.17 2,273.57 Biotin- SEC NO ID 63 -NH2 0.27 2,300.60 Biotin- SEC NO ID 64 -NH2 21 0.29 2,383.77 Biotin- SEC NO ID 65 -NH2 22 0.35 2,401,83 Biotin- SEC NO ID 66 -NH2 23 0.45 2,407.92 Biotin- SEC NO ID 67 -NH2 24 0.42 2,541.08 Biotin- SEC NO ID 68 -NH2 0.33 2,513.97 Biotin- SEC NO ID 69 -OH 27 0.42 2,283.64 Biotin- SEC NO ID 70 -NH2 28 0.27 2,425.81 Biotin- SEC NO ID 71 -NH2 29 0.57 2,228.57 Biotin- SEC NO ID 72 -NH2 0.62 * 2,223.57 Biotin- SEC NO ID 73 -NH2 31 0.51 2,165.49 Biotin- SEC NO ID 74 -NH2 32 0.56 2,112.45 Biotin- SEC NO ID 75 -NH2 33 0.27 2,207.56 Biotin- SEC NO ID 76 -NH2 34 0.33 2,345.73 Biotin- SEC NO ID 77 -NH2 35 0.29 2,330.76 Biotin- SEC NO ID 78 -NH2 36 0.45 2,236.60 Biotin- SEC NO ID 79 -NH2 37 0.43 2,276.64 Biotin- SEC NO ID 80 -NH2 38 0.12 2,292.62 Biotin- SEC NO ID 81 -NH2 39 0.22 2,319.64 Biotin- SEC NO ID 82 -NH2 40 0.24 2, 402.82 Biotin- SEC NO ID 83 -NH2 41 0.33 2,387.80 Biotin- SEC NO ID 84 -NH2 42 0.43 2,393.90 Biotin- SEC NO ID 85 -NH2 43 0.39 2,527.05 Biotin- SEC NO ID 86- NH2 44 0.35 2,471.88 Biotin- SEC NO ID 87 -OH (* indicates a high hydrophobic value) The results indicate that the 3G4 mouse mAb bound to the two peptides shown below (see also Figure 6). Peptide 25: DLLLHLKKLFREGRFN (SEQ ID NO 88) Peptide 44: DLLVHLKKLFREGQFN (SEQ ID NO 89) Peptide 25 is derived from human I L-13. Peptide 44 is derived from Cynomolgus IL-13.

NB: BLACK indicates differences of remains between human I L-13 and Cynomolgus IL-13 ortholog. 4.2 Fine mapping of the binding epitope of mouse mAb 3G4 to human IL-13 and of Cynomolgus using biotinylated peptides The minimal binding epitope was determined for mouse mAb 3G4 to human I L-13 using a set of peptides based on the peptide sequence QFVKDLLLHLKKLFREGRFN (SEC NO ID 90). The peptides were obtained with an amino acid sequentially removed from the N or C terminus of this original peptide sequence to define the precise linear binding epitope for the mouse mAb 3G4. A similar approach was taken to map the IL-13 binding of Cynomolgus. An ELISA procedure (carried out as described in Example 6.4) was used to detect the binding of immobilized biotinylated peptide to the original mouse mAb 3G4 (Figures 7a and 7b). The results indicate that the original 3G4 mouse mAb binds to the minimal amino acid epitope LLHLKKLFREG (SEQ ID NO 91) in the C-terminal region of human L-13. However, the two amino acids (D and L) located adjacent to the N-terminus of the previous peptide sequence (in the sequence of human IL-13) may also be important for binding, since the binding signal is enhanced when these remains are present. Similarly, the three amino acids (R, F and N) located adjacent to the C-terminal end of the above peptide sequence (in the sequence of human I L-13) may also be important for binding, since the binding signal is lost when residues R and F are present, but the Binding signal is recovered when the N moiety is present. Similar results were obtained for the binding of the mouse mAb 3G4 to the set of peptides I L-13 of Cynomolgus. The results indicate that the original 3G4 mouse mAb binds to the minimal amino acid epitope LLVHLKKLFREG (SEQ ID NO 98) in the C-terminal region of I L-13 of Cynomolgus. However, amino acid 1 (D) located adjacent to the N-terminus of the above peptide sequence (in the I-13 sequence of Cynomolgus) may also be important for binding, since the binding signal is enhanced when this residue is present. Similarly, the 3 amino acids (Q, F, and N) located adjacent to the C-terminal end of the previous peptide sequence (in the sequence of I L-13 of Cynomolgus) may also be important for binding, since the signal binding is lost when the Q and F residues are present, but the binding signal is recovered when the remainder N. is present. 4.3 Analysis of alanine of the epitope binding to mouse mAb 3G4 using biotinylated peptides To identify the key residues involved in the interaction of human IL-13 with mouse mAb 3G4, an alanine analysis approach was adopted using the original peptide sequence QFVKDLLLHLKKLFREGRFN (SEC NO ID 90). For this analysis, the peptides indicated in Table 11 (AnaSpec Ine) were obtained, in which an amino acid was sequentially replaced by an alanine residue at each amino acid position in the LKKLFRE (SEQ ID NO: 92) portion of the original epitope QFVKDLLLHLKKLFREGRFN (SEC NO ID 90). Table 11 An ELISA procedure (similar to that indicated in Example 6.4) was used to detect the binding of immobilized biotinylated peptide to the original 3G4 mouse mAb (see Figure 8). These data confirm that the key amino acid residues involved in the interaction of the original 3G4 mouse mAb with human IL-13 are, at least, arginine (R) at position 107, lysine (K) at position 103, and lysine (K) ) at position 104. The numbering of these is as described above in WO2006 / 003407. Since the above analysis had analyzed only the LKKLFRE (SEQ ID NO. 92) portion of the minimal binding epitope, an additional set of peptides was obtained as indicated in Table 12 (Mimotopes) to expand the alanine analysis study to the other amino acid residues in the minimal binding epitope. Table 12: An ELISA procedure (similar to that used in Example 6.4) was used again to detect the binding of immobilized biotinylated peptide to the original 3G4 mouse mAb. See Figure 9 (in this experiment, the peptide QFVKDLLLHLKKLFREGRFN (SEC NO ID 90) is the positive control that demonstrates maximum binding, and the peptide QFVKDLLLHLKKLFAEGRFN (SEC NO ID 104) is the negative control that shows minimal binding). These data suggest that the phenylalanine moiety (F) at position 111 is also important for the interaction of the original 3G4 mouse mAb with human L-13. The numbering of this rest is as described above in the document WO2006 / 003407. 5. Efficacy of a humanized anti-IL-13 mAb in the asthma model in Cynomolgus This example is predictive. The model of pulmonary bronchoconstriction induced by Ascaris suum (A. suum) in Cynomolgus monkeys (Macaca fascicularis) is widely recognized as the most similar and relevant non-clinical model for asthma in humans (Patterson R, et al Trans. Assoc. Am. Phvsicians 1980 93: 317-325; Patterson R, et al., J. Lab. Clin. Med. 1983 101: 864-872). In this model, animals that have an innate pulmonary sensitivity to A. suum to nebulized A. suum are exposed to induce an asthmatic response. This asthmatic response can be characterized by measuring the airway hyperreactivity (HVR), the cellular infiltration measured in the bronchoalveolar lavage fluid (BAL) and the serum levels of IgE. The experimental procedures are similar to those described above by Mauser P, et al. in Am. J. Resp. Crit. Care Med. 1995 204: 467-472 and by Evanoff H, et al. in Immunologic They investigated 199221: 39. This study uses 30 preselected animals for entry that have demonstrated a positive bronchoconstrictive response to a specific dose of A. suum antigen. A. suum is administered at the optimal response dose (DRO) for each animal. It is a predetermined dose of A. suum that produces an increase in RP (lung resistance) of at least 40% and a reduction in DDIN (dynamic compliance) of at least 35% by aerosol inhalation (for a single dose) given during 15 aspirations using a nebulizer). The study takes place in 2 phases. During phase 1, HVR is evaluated in response to the application of intravenous (iv) histamine (ie, a dose of histamine sufficient to induce an increase in PR of at least 30% above the baseline (PC30 )) both before (evaluation of baseline lung function on day 1) and after (on day 11) of administering antigen of A. suum (on days 9 and 10, when A. suum is administered at an optimal predetermined dose for each animal by aerosol inhalation). Phase 2 is identical to phase 1 except that the animals are treated with antibody (see below), each antibody is administered as 3 doses of approximately 30 mg / kg administered by i.v. on days 1, 5 and 9. Group 1 (n = 12): A humanized anti-IL-13 monoclonal antibody (30 mg / kg) Group 2 (n = 12): A humanized anti-IL-13 monoclonal antibody (30 mg / kg) and pascolizumab (humanized anti-IL-4 monoclonal antibody, 30 mg / kg) Group 3 (n = 6): Negative control treatment with vehicle only The HVR readings of phases 1 and 2 are calculated by taking readings of pressure and air flow, pulmonary resistance (RP) and dynamic compliance (DD | N) in response to histamine, using the mechanical pulmonary system of Buxco. The maximum percentage change from baseline compared to after exposure to A. suum antigen [for pulmonary resistance (RP) and dynamic compliance (C IN)] for phases 1 and 2 is compared, specifically, with or without treatment of antibody, and these data are used to evaluate the HVR phenotype. In addition, BAL samples are taken on days 1 and 11 in phases 1 and 2, to measure cellular infiltration and, in particular, eosinophilia. Serum samples are also taken to control IgE levels. 6.1. Human IL-13 or Cynomolgus binding ELISA This assay describes an ELISA that detects the binding of an antibody to human L-13 or Cynomolgus. It is an ELISA sandwich format. 6.1.1 Materials 1. Nunc Immunoplate 1 F96 Maxisorp (Life Technologies, 4-39454A) 2. Human IL-13 (expressed in E. coli from Cambridge Biosciences, Cat. No. CH1-013) 3. Cynomolgus IL-13 (prepared by GlaxoSmithkline) 4. polyclonal goat anti-human L-13 polyclonal antibody (R + D Systems, Cat. No. AF-213-NA) . Anti-human IgG-HRP (Sigma, Cat No. A-6029) 6. Anti-mouse IgG-HRP (Sigma, Cat No. A-9309) 7. Carbonate / bicarbonate buffer (Sigma, cat. C-3041) 8. TBST [Tris buffered saline solution (6.06 g Tris + 8.06 g NaCI + 0.2 g KCl + H2O to 1 I) + 0.05% Tween 20] 9. BSA (Sigma A-7030) 10. OPD (Sigma, Cat. No. P-9187) 11. acid sulfuric. 6.1.2 Procedure 1. The blocking solution is 3% BSA + TBST 2. The washing solution is TBST 3. "Nunc Maxisorp" ELISA plates are coated with 50 μl of goat anti-human IL-13 polyclonal antibody 5 μg / ml (R + D Systems, cat # AF-213-NA, prepared at a stock concentration of 500 μg / ml according to the manufacturer's instructions, and stored in aliquots at -20 ° C) in carbonate buffer / bicarbonate (Sigma; Cat No. C-3041, prepared according to the manufacturer's instructions), covered with a plate sealer and incubated overnight at 4 ° C. 4. Block with 100 μl of 3% BSA / TBST, incubate at tpa for 1 h. 5. Wash X3 in TBST (at least 200 μl of washing solution per well and per wash). 6. 20 ng per well are added (in a volume of 50 μl) of human IL-13 (Cambridge Bioscience, Cat. No. CH1-013, prepared at a stock concentration of 100 ng / μl according to the manufacturer's instructions, and stored in aliquots at -20 ° C) or 20 ng per well of I Cynomolgus L-13, in blocking solution, and incubated at room temperature for 1 h. 7. Wash X3 in TBST. 8. Add 50 μl of antibody sample (titrated to obtain the titre data title, if necessary) in blocking solution, incubate at tpa for 1 h. 9. Wash X3 in TBST. 10. For the chimeric 3G4 antibody or humanized antibody, binding is detected using 50 μl per well of anti-human IgG-HRP (Sigma, Cat. No. A-6029) at a 1/2000 dilution in blocking solution for 1 has tpa. For the mouse monoclonal antibody 3G4, binding is detected using 50 μl per well of anti-mouse IgG-HRP (Sigma, Cat. No. A-9309) at a 1/1000 dilution in blocking solution for 1 hr. . 11. Wash X3 in TBST. 12. It is developed with 100 μl of OPD (Sigma, Cat No. P-9187. Prepared according to the manufacturers instructions), stopped with 50 μl of 3 M H2SO, read at an absorbance of 490 nm. The development time is -12 minutes. 6.1A Human IL-13 binding ELISA This assay describes an ELISA that detects the binding of a antibody to human IL-13. It is a sandwich ELISA format and differs only slightly from that described in Example 6.1. 6.1 A.1 Materials 1. 96-well ElA Costar plate (Corning Costar No. cat. 3369) 2. Human I-L-13 (Peprotech, Cat. No. 200-13) 3. Polyclonal goat anti-l L antibody -13 human (R + D Systems, Cat. No. AF-213-NA) 4. Anti-human kappa-HRP light chain (Sigma, Cat. No. A7164) 5. Carbonate / bicarbonate buffer (Sigma, Cat. C-3041) 6. TBST [Tris buffered saline solution (6.06 g Tris + 8.06 g NaCl + 0.2 g KCl + H2O up to 1 I) + 0.05% Tween 20] 7. BSA (Sigma A-7030) 8. OPD (Sigma, Cat No. P-9187) 9. Sulfuric acid 6.1 A.2 Procedure 1. The blocking solution is 3% BSA + TBST 2. The washing solution is TBST 3. "Costar E1A / RIA" ELISA plates are coated with 50 μl of 5 μg / ml goat anti-human IL-13 polyclonal antibody (R + D) Systems, No. cat. AF-213-NA. Prepared at a stock concentration of 500 μg / ml according to the manufacturer's instructions, and stored in aliquots at -20 ° C) in buffer carbonate / bicarbonate (Sigma; Cat No. C-3041, prepared according to the manufacturer's instructions), covered with a plate sealer and incubated overnight at 4 ° C. 4. Block with 100 μl of 3% BSA / TBST at tpa for 1 h or at least overnight at 4 ° C. 5. Wash X2 in TBST (at least 200 μl of washing solution per well and per wash). 6. 20 ng per well (in a volume of 50 μl) of human I L-13 (Peprotech No. cat 200-13) are added. (Prepared at a stock concentration of 100 ng / μl according to the manufacturer's instructions, and stored in aliquots at -20 ° C), diluted in blocking solution and incubated at room temperature for 1 h 7. X2 is washed in TBST . 8. Add 50 μl of antibody sample (titrated to obtain the titre data title, if necessary) in blocking solution, incubate at tpa for 1 h. 9. X2 is washed in TBST. 10. For chimeric 3G4 antibody or humanized antibody, binding is detected using 50 μl per well of anti-human kappa-HRP light chain (Sigma, Cat. No. A7164) at a 1/2000 dilution in blocking solution for 1 h tpa. 11. Wash X2 in TBST. 12. It is developed with 100 μl of OPD (Sigma, Cat No. P-9187, prepared according to the manufacturer's instructions), stop with 50 μl of 3 M H2SO4 and read at an absorbance of 490 nm. 6.1 B Native human IL-13 binding ELISA This assay describes an ELISA that detects the binding of an antibody to native human L-13. It is in an ELISA sandwich format. 6.1B.1 Materials I. Nunc Immunoplate 1 F96 Maxisorp (Life Technologies, 4-39454A) 2. Native human L-13 (supernatant of HDLM-2 cells) 3. Anti-human IL-13 antibody (Pharmingen, No. cat 554570) 4. Biotinylated human anti-IL-13 antibody (Pharmingen, Cat No. 555054) 5. Streptavidin-HRP (Sigma Cat. No. E2886) 6. Carbonate / bicarbonate buffer (Sigma, cat. -3041) 7. RPMI + 20% FBS + 2 mM glutamine 8. PBST (PBS + 0.05% Tween 20) 9. BSA (Sigma A-7030) 10. OPD (Sigma, Cat. No. P-9187) II . Sulfuric acid 6.1 B.2 Procedure 1. The blocking solution is 1% BSA in PBST 2. The washing solution is PBST 3. "Nunc Maxisorp" ELISA plates are coated with 50 μl of chimeric or humanized 3G4 antibody 5 μg / ml or anti-human IL-13 antibody at 2 μg / ml dilution (Pharmingen Cat. No. 554570 ) in carbonate / bicarbonate buffer, cover with a plate sealer and incubate overnight at 4 ° C. 4. Block with 200 μl of 1% BSA / PBST and incubate at room temperature for 1 h. 5. Wash X3 in PBST. 6. Add 50 μl of native IL-13 present in HDLM2 supernatant sample (titrated), dilute in RPMI + 20% FBS + 2 mM glutamine solution, incubate at tpa for 1 h. 7. Wash X3 in PBST. 8. Add 50 ul per well of 1 μg / ml biotinylated anti-human IL-13 antibody (Pharmingen, Cat No. 555054), dilute in PBST + 1% BSA, incubate at tpa for 1 h ^ 9 Wash X3 in PBST. 10. Add 50 μl per well of streptavidin-HRP conjugate at a 1/1000 dilution, dilute in PBST + 1% BSA. It is incubated for 1 hour at room temperature. 11. Wash x3 in TBST 12. Run with 100 μl per well of OPD (Sigma, No. .cat.P-9187. Prepared according to the manufacturer's instructions), stop with 50 μl per well of 3M H2SO4, it reads at an absorbance of 490 nm. 6.2. Neutralization Bioassay of IL-13 (TF-1 Cell Proliferation Assay) This is an I L-13 bioassay that can be used to determine the neutralizing capacity of an anti-IL-13 antibody. The procedure described below uses human I L-13 or recombinant Cynomolgus. Human expressed human IL-13 or variant human IL-13 Q130 can also be used in this assay. 6.2.1 Materials 1. TF-1 cell line (TF-1 cell line obtained in laboratory, NB, version available from ATCC) 2. 96-well tissue culture plates (Invitrogen) 3. Human IL-13 (Cambridge Bioscience , No. cat. CH1-013) 4. CelITiter 96 non-radioactive cell proliferation assay (Promega, Cat. No. G4000) 6.2.2 Procedure 1. Method for measuring the capacity of a human anti-I L-13 mAb neutralize the bioactivity of human IL-13 or Recombinant cynomolgus in a TF-1 cell bioassay. 2. This assay is performed on 96-well sterile tissue culture plates (Invitrogen) under sterile conditions. All tests are carried out in triplicate. 3. Human I L-13 is pre-incubated 10 ng / ml (Cambridge Bioscience, No. cat. CH1-013 Peparated to a stock concentration of 100 ng / μl according to the manufacturer's instructions using sterile techniques in a tissue culture hood of class 2, stored in small aliquots at -20 ° C) or I L-13 of Cynomolgus 10 ng / ml (generated in GSK) with various dilutions of anti-human L-13 mAb (diluted from 6 μg / ml in 3-fold dilutions to 0.025 μg / ml) in a total volume of 50 μl for 1 hour at 37 ° C. Also included are positive control wells that have I L-13 present, but not anti-human L-13 mAb. In addition, the negative control wells will not have IL-13 or anti-human L-13 mAb present. A sterile 96-well round-bottom low protein binding plate is used for this preincubation. (Note that the concentration of IL-13 and anti-human L-3 mAb will be reduced by half at a later stage when cells are added). 4. 50 μl of TF-1 cells are seeded at 2 × 10 5 per ml in a sterile 96-well tissue culture plate. After 1 hour of preincubation, IL-13 and the sample of anti-human IL-13 mAb are added to the cells. The final assay volume of 100 μl, containing various dilutions of anti-human L-13 mAb, recombinant IL-13 and TF-1 cells, is incubated at 37 ° C for -70 hours in a humidified CO2 incubator. 5. At -66 h, the wells are examined to confirm that they are sterile and that no bacterial contamination has occurred. 6. Add 15 μl of MTT substrate sterilized by per well filtration (Cat No. G4000, Promega, prepared according to the manufacturer's instructions) during the final 4 hours of incubation. 7. Stop the reaction with 100 μl of stop solution (provided in the MTT kit) to solubilize the metabolized formazan blue product. Leave for at least 2 hours, then pipette in and out to help dissolve the crystals. Alternatively, cover with a plate sealer and leave at 4 ° C overnight, then pipette in and out the next day (this is easier in terms of pipetting). 8. The absorbance of the solution in each well is read in a 96-well plate reader at a wavelength of 570 nm. 9. The ability of the human anti-L-13 mAb to neutralize the bioactivity of human IL-13 or Cynomolgus is expressed as the concentration of anti-human IL-13 mAb necessary to neutralize the bioactivity of a defined amount of I L -13 human or Cynomolgus (5 ng / ml) by 50% (= DN50). The less concentration is necessary, the more powerful the neutralization capacity. 6.2. A IL-13 neutralization bioassay (TF-1 cell proliferation assay) This is a bioassay of IL-13 that can be used to determine the neutralization capacity of an anti-HIV antibody.

IL-13. The procedure described below uses human I L-13 and recombinant Cynomolgus. Human expressed human L-13 or variant of human IL-13 Q130 can also be used in this assay. Note that this procedure differs only slightly from that described in Example 6.2 6.2. A.1 Materials 1. TF-1 cell line (TF-1 cell line obtained in the laboratory, NB, version available from ATCC) 2. 96-well tissue culture plates (Corning costar, Cat. No. 3596) 3. I human L-13 (Peprotech, No. cat 200-13) 4. Human IL-13 (expressed in CHO cells) generated in GSK. 5. Variant Q130 of human I L-13 (Peprotech, Cat. No. 200-13A) 6. Cynomolgus IL-13 (generated in GSK). 7. Polyclonal human anti-IL-13 antibody (R & D Systems AF-213-NA) 8. 96-well tissue culture plates (Corning costar, Cat. No. 3790) 9. Cell non-radioactive cell proliferation assay 96 (Promega, No. cat. G4000) 6.2. A.2 Procedure 1. Procedure to measure the capacity of an anti-mAb Human IL-13 neutralize the bioactivity of human IL-13 and recombinant Cynomolgus in a TF-1 cell bioassay. 2. This assay is performed in 96-well sterile tissue culture plates (Corning costar, Cat No. 3596) under sterile conditions. All tests are carried out in triplicate. 3. Human IL-13 10 ng / ml (Peprotech, Cat. No. 200-13), or human L-13 expressed in 10 ng / ml CHO (generated in GSK) or Q130 variant of I L-13 is preincubated. human serum 60 ng / ml (Peprotech, Cat. No. 200-13A), or I L-13 Cynomolgus 10 ng / ml (generated in GSK), commercial Ab are prepared at a stock concentration according to the manufacturer's instructions using techniques Sterile in tissue culture hood of class 2, are stored in small aliquots at -20 ° C. With various dilutions of anti-human L-13 mAb (diluted from 6 μg / ml or 2 μg / ml or 180 μg / ml in 3-fold dilutions up to 0.025 μg / ml or 0.008 μg / ml or 0.74 μg / ml) ml, respectively) in a total volume of 50 μl for 1 hour at 37 ° C. Positive control wells having I L-13 present but not anti-human L-13 mAb will also be included. In addition, the negative control wells will not have I L-13 or anti-human IL-13 mAb present. A sterile, low-protein round bottom 96-well plate is used for this preincubation (Corning cost, Cat. No. 3790). (Note that the concentration of I L-13 and anti-human IL-13 mAb will be reduced by half at a later stage when add cells). 4. 50 μl of TF-1 cells are seeded at 2 × 10 5 per ml in a 96-well sterile tissue culture plate (Corning costar, Cat. No. 3596). After 1 hour of pre-incubation, the I L-13 and the sample of anti-human L-13 mAb are added to the cells. The final assay volume of 100 μl, containing various dilutions of anti-human L-13 mAb, recombinant I L-13 and TF-1 cells, is incubated at 37 ° C for 3 days in a humidified CO2 incubator. 5. The wells are examined to confirm that they are sterile and that no bacterial contamination has occurred. 6. Add 15 μl of MTT substrate per well (Cat No. G4000, Promega) during the final 4 hours of incubation. 7. Stop the reaction with 100 μl of stop solution (provided in the MTT kit) to solubilize the metabolized formazan blue product. It is left for at least 2 hours at RT, then the plates are shaken on a plate shaker for -30 min. Alternatively, cover with a plate sealer and leave at 4 ° C overnight, then shake the plates on a plate shaker for -30 min. The absorbance of the solution is read in each well of a 96-well plate reader at 570 nm wavelength. 8. The ability of the human anti-human IL-13 mAb to neutralize the bioactivity of human I L-13 and Cynomolgus is expressed as the concentration of anti-human L-13 mAb required for neutralize the bioactivity of a defined amount of human IL-13 or Cynomolgus by 50% (= DN50). The lower the concentration required, the more potent the neutralization capacity. 6.3. Thick Epitope Mapping ELISA This assay describes an ELISA that detects the binding of mouse mAbs 3G4 to human IL-13 or Cynomolgus peptides. 6.3.1 Materials 1. Nunc Immunoplate 1 F96 Maxisorp (Life Technologies, 4-39454A) 2. ImmunoPure © Streptavidin (Pierce, Cat. No. 21125) 3. PBST (Phosphate buffered saline + 0.05% Tween 20) 4 BSA (Sigma A-7030) 5. Peptides of 16 units of human IL-13 and Cynomolgus, displacement = 4 (custom order of Mimotopes) 6. Peptides of 20 positive and negative control units (supplied with the custom order of Mimotopes) 7. 3G4 mouse mAb 8. Ab control (supplied with the customized order of Mimotopes) 9. Rabbit anti-mouse Ig-HRP conjugate (DAKO, Code No. P0260) 10. OPD (Sigma, Cat No. P-9187) 11. Sulfuric acid 3 M 6. 3.2 Procedure 1. The blocking solution is 3% BSA + PBST. 2. The wash solution is PBST. 3. "Nunc Maxisorp" ELISA plates are coated with 100 μl of ImmunoPure® 5 μg / ml streptavidin (Pierce, Cat. No. 21125 prepared at a stock concentration of 1 mg / ml according to the manufacturer's instructions, and stored in aliquots a + 4 ° C) using PBST as a diluent. They are incubated overnight at 37 ° C, allowing the solution to dry. 4. Block with 200 μl of 3% BSA / PBST. Plate sealer is added and incubated on top for 1 h. 5. Wash X3 in PBST (at least 200 μl of washing solution per well and per wash). 6. In duplicate and using PBST as a diluent, add 100 μl per well (except control wells) or 1,000-fold dilutions of each peptide (dissolved according to the manufacturer's instructions in 200 μl of 40% acetonitrile, 60% water, then aliquots are taken at 10-fold dilutions in the same solvent and stored at -20 ° C). 7. In the control wells, in duplicate and using PBST as a diluent, 100 μl per well of 10-fold dilutions of control peptides (dissolved according to the manufacturer's instructions in 1 ml of 40% acetonitrile and 60% water) are added per well. stored at -20 ° C). Plate sealer is added and incubated at tpa for 1 hr on a vibrating table. 8. X3 is washed in PBST (at least 200 μl of washing solution per well and per wash). 9. Add 100 μl per well (except control wells) of mouse mAb 1.506 μg / ml in PBST. 10. Add 100 μl per well to the control wells only, at 4, 16 and 32 fold dilutions of the control antibody (used as supplied by the manufacturer and stored at -20 ° C) using PBST as a diluent. Plate sealer is added and incubated at tpa (temperature and ambient pressure) for 1 h on a vibrating table. 11. Wash X3 in PBST (at least 200 μl of wash solution per well and per wash). 12. Add 100 μl per 2000-fold dilution well of rabbit anti-mouse Ig-HRP conjugate (DAKO, No. code P0260, used as supplied, stored at + 4 ° C) using PBST as diluent. Plate sealer is added and incubated at tpa for 1 hr on a vibrating table. 13. Wash X3 in PBST (at least 200 μl of washing solution per well and per wash). 14. It is developed with 100 μl of OPD (Sigma, Cat No. P-9187 Prepared according to the manufacturer's instructions), stopped with 50 μl of 3 M H2SO4, read at an absorbance of 490 nm. The development time is -10 minutes. 6.4. Epitope thin mapping ELISA This assay describes an ELISA that detects the binding of mAb 3G4 to peptides of human IL-13 or of Cynomolgus. 6.4.1 Materials 1. Nunc Immunoplate 1 F96 Maxisorp (Life Technologies, 4-39454A) 2. ImmunoPure © Streptavidin (Pierce, Cat. No. 21125) 3. PBST (Phosphate buffered saline + 0.05% Tween 20) 4 BSA (Sigma A-7030) 5. Peptides net partial window of human IL-13 and Cynomolgus (of 14 units, truncated by an amino acid each time from both N and C-terminal ends; custom order of Mimotopes) 6. Peptide of 16 positive control units (supplied with the previous order of Mimotopes) 7. mAb 3G4 (prepared in laboratory) 8. Goat anti-mouse IgG-HRP conjugate antibody (specific for Fc) ) (Sigma A-9309) 9. OPD (Sigma, Cat No. P-9187) 10. 3 M Sulfuric acid 6.4.2 Procedure 1. The blocking solution is 3% BSA + PBST. 2. The wash solution is PBST. 3. "Nunc Maxisorp" ELISA plates are coated with 100 μl of ImmunoPure® 5 μg / ml streptavidin in ultrapure water (Pierce, Cat. No. 21125, prepared at a stock concentration of 1 mg / ml according to the manufacturer's instructions, and stored at + 4 ° C). It is incubated overnight at + 37 ° C. 4. Block with 200 μl of 3% BSA in PBST. Plate sealer is added and incubated overnight at + 4 ° C. 5. Wash X3 in PBST (at least 200 μl of washing solution per well and per wash). 6. In duplicate, using 3% BSA in PBST as a diluent, add 100 μl per well of 1,000-fold dilutions of each peptide (dissolved according to the manufacturer's instructions in 200 μl of 40% acetonitrile and 60% water and stored at -20 ° C). Plate sealer is added and incubated at room temperature for 1 hour on a vibrating table. 7. Wash X3 in PBST (at least 200 μl of wash solution per well and per wash). 8. Add 100 μl per well of 3G43 μg / ml diluted in 3% BSA in PBST. Plate sealer is added and incubated at room temperature for 1 hour on a vibrating table. 9. Wash X3 in PBST (at least 200 μl of washing solution per well and per wash). 10. Add 100 μl per 1000-fold dilution well of goat anti-mouse IgG-HRP conjugated antibody (Sigma A-9309 used as supplied, stored at + 4 ° C) using 3% BSA in PBST as diluent . Plate sealer is added and incubated at room temperature for 1 hour on a vibrating table. 11. X3 is washed in PBST (at least 200 μl of washing solution per well and per wash). 12. It is developed with 100 μl of OPD (Sigma, Cat No. P-9187, prepared according to the manufacturer's instructions), stopped with 50 μl of 3 M H2SO, read at an absorbance of 490 nm. The development time is -10 minutes. 6.5 ELISA binding of human IL-13 to the human IL-13Ra1 chain This ELISA determines whether an antibody can inhibit the binding of human IL-13 to the human IL13Ra1 chain. 6.5.1 Materials 1. Nunc Immunoplate 1 F96 Maxisorp (Life Technologies, 4-39454A) 2. Human IL13Ra1-Fc (R & D Systems, Cat. No. 146-IR) 3. I Human L-13 (prepared in the laboratory ) 4. Biotinylated human anti-IL-13 antibody (R & D Systems, Cat. No. BAF213) 5. Streptavidin-HRP (Sigma, Cat. No. E2886) 6. Carbonate / bicarbonate buffer (Sigma, Cat. C-3041) 7. TBST [Tris buffered saline solution (6.06 g Tris + 8.06 g NaCl + 0.2 g KCl + H2O up to 1 I) + 0.05% Tween 20] 8. BSA (Sigma A-7030) 9. OPD (Sigma, Cat No. P-9187) 10. Sulfuric acid 6. 5.2 Procedure 1. The blocking solution is 3% BSA + TBST 2. The washing solution is TBST 3. "Nunc Maxisorp" ELISA plates are coated with 50 μl of human IL-13Ra1-Fc 5 ng / μl in carbonate buffer /baking soda.

They are covered with a plate sealer and incubated overnight at 4 ° C. 4. Block with 100 μl of 3% BSA / TBST, incubate at tpa for 1 h. 5. Wash X3 in TBST (at least 200 μl of washing solution per well and per wash). 6. In a total volume of 50 μl, 0.4 ng / μl human IL-13 was preincubated with antibody sample (titrated) in blocking solution for 30 minutes. The pre-incubated sample is added to the recipient coated ELISA plate and incubated at room temperature for 1 h. 7. Wash x3 in TBST 8. Any bound human IL-13 is detected using 50 μl per well of biotinylated anti-human L-13 antibody diluted at 1 μg / ml. It is incubated for 1 hour at room temperature. 9. Wash x3 in TBST 10. Add 50 μl per well of streptavidin-HRP conjugate of 1/1000 dilution. It is incubated for 1 hour at room temperature. 11. Wash x3 in TBST. 12. It is developed with 100 μl per well of OPD (Sigma, No. cat. P-9187, prepared according to the manufacturer's instructions), stopped with 50 μl per well of 3 M H2SO4, read at an absorbance of 490 nm. 6.6 ELISA binding of human IL-13 to the human IL13Ra2 chain This ELISA determines whether an antibody can inhibit the binding of human IL-13 to the human IL13Ra2 chain. 6.6.1 Materials 1. Nunc Immunoplate 1 F96 Maxisorp (Life Technologies, 4-39454A) 2. Human IL13Ra2-Fc (R & D Systems, Cat. No. 614-IR) 3. Human IL-13 (generated in GSK) 4. Biotinylated human anti-IL-13 antibody (R &D Systems , Cat. No. BAF213) 5. Streptavidin-HRP 6. Carbonate / bicarbonate buffer (Sigma, Cat No. C-3041) 7. TBST [Tris buffered saline solution (6.06 g Tris + 8.06 g NaCl + 0.2 g KCl + H2O up to 1 I) + 0.05% Tween 20] 8. BSA (Sigma A-7030) 9. OPD (Sigma, Cat No. P-9187) 10. Sulfuric acid 6.6.2 Procedure 1. The blocking solution is 3% BSA + TBST 2. The washing solution is TBST 3. "Nunc Maxisorp" ELISA plates are coated with 50 μl of 5 ng / μl human IL-13Ra2-Fc in carbonate / bicarbonate buffer. They are covered with a plate sealer and incubated overnight at 4 ° C. 4. Block with 100 μl of 3% BSA / TBST, incubate at tpa for 1 h. 5. Wash X3 in TBST (at least 200 μl of washing solution per well and per wash). 6. In a total volume of 50 μl, human IL-13 0.01 ng / μl was preincubated with antibody sample (titrated) in blocking solution for 60 minutes. The pre-incubated sample is added to the recipient coated ELISA plate and incubated at room temperature for 1 h. 7. Wash X3 in TBST. 8. Any bound human IL-13 is detected using 50 μl per well of biotinylated human anti-L-13 antibody diluted to 0.5 μg / ml. It is incubated for 1 hour at room temperature. 9. Wash x3 in TBST. 10. Add 50 μl per well of streptavidin-HRP conjugate at a 1/1000 dilution. It is incubated for 1 hour at room temperature. 11. Wash x3 in TBST 12. It is developed with 100 μl per well of OPD (Sigma, Cat. No. P-9187, prepared according to the instructions of manufacturer), stop with 50 μl per well of H2SO43 M, read at an absorbance of 490 nm. The development time is -2 minutes. 6.7 Human IL-4 binding ELISA This assay describes an ELISA that detects the binding of an antibody to human IL-4. It is an ELISA sandwich format. 6.7.1 Materials I. Nunc Immunoplate 1 F96 Maxisorp (Life Technologies, 4-39454A) 2. Human IL-4 (R + D Systems, Cat. No. 204IL) 3. Polyclonal goat anti-human IL-4 antibody ( R + D Systems, Cat. No. AF-204-NA) 4. Biotinylated rat anti-human IL-4 antibody (R & D systems, Cat. No. BAF204.) . Anti-mouse IgG-HRP (Dako, Cat No. P0260) 6. Kappa-HRP anti-human light chain (Sigma A7164) 7. Streptavidin-HRP (Sigma, Cat No. E2886) 8. Carbonate / bicarbonate buffer (Sigma, Cat. No. C-3041) 9. TBST [Tris buffered saline solution (6.06 g Tris + 8.06 g NaCl + 0.2 g KCl + H2O up to 1 I) + 0.05% Tween 20] . BSA (Sigma A-7030) II. OPD (Sigma, Cat No. P-9187) 12. Sulfuric acid 6. 7.2 Procedure 1. The blocking solution is 3% BSA in TBST 2. The washing solution is TBST 3. "Nunc Maxisorp" ELISA plates are coated with 50 μl of goat polyclonal anti-human L-4 5 μg antibody. / ml (R + D Systems, No. cat. AF-204-NA, prepared at a stock concentration of 500 μg / ml according to the manufacturer's instructions, and stored in aliquots at -20 ° C) in carbonate / bicarbonate buffer (Sigma, Cat. No. C-3041, prepared according to manufacturer's instructions), cover with a plate sealer and incubate overnight at 4 ° C. 4. Block with 100 μl of 3% BSA / TBST, incubate at room temperature and pressure (tpa) for 1 h. 5. Wash X3 in TBST (at least 200 μl of washing solution per well and per wash). 6. Add 1 ng / ml (in a volume of 50 μl) of human I L-4 in blocking solution and incubate at room temperature for 1 h. 7. Wash X3 in TBST. 8. Add 50 μl of antibody sample (titrated to obtain the titre data title, if necessary) in blocking solution, incubate at tpa for 1 h. As a positive control for binding to human I L-4, a biotinylated human anti-IL-4 monoclonal antibody (titrated) is used. 9. Wash X3 in TBST.

. For the mouse monoclonal antibody 3G4, binding is detected using 50 μl per well of anti-mouse IgG-HRP (Dako, Cat. No. P0260) at a 1/2000 dilution in blocking solution for 1 h at tpa. For chimeric 3G4 antibody or humanized antibody, binding is detected using 50 μl per well of anti-human kappa-HRP light chain (Sigma, Cat. No. Sigma A7164) at a dilution of 1/2000 in blocking solution for 1 has tpa. For positive control, the biotinylated human anti-IL-4 rat monoclonal antibody is detected using a streptavidin-HRP conjugated antibody (Sigma, Cat No. E2886) at 1/1000 dilution in blocking solution for 1 h at tpa. 11. Wash X3 in TBST. 12. It is developed with 100 μl of OPD (Sigma, Cat No. P-9187, prepared according to the manufacturer's instructions), stopped with 50 μl of 3 M H2SO, read at an absorbance of 490 nm. 6.8 Human IL-5 binding ELISA This assay describes an ELISA that detects the binding of an antibody to human IL-5. It is an ELISA in sandwich format. 6.8.1 Materials 1. Nunc Immunoplate 1 F96 Maxisorp (Life Technologies, 4-39454A) 2. Human IL-5 (R + D Systems, Cat. No. 205IL) 3. Human L-5 polyclonal anti-L antibody (R + D Systems, No. cat. AF-205-NA) 4. Mepolizumab anti-human IL-5 (clinical purity in laboratory) 5. Anti-mouse IgG-HRP (Dako, Cat. No. P0260) 6. Kappa-HRP anti-human light chain (Sigma A7164) 7. Carbonate / bicarbonate buffer (Sigma, Cat. No. C-3041) 8. TBST [Tris-buffered saline solution (6.06 g Tris + 8.06 g NaCl + 0.2 g KCl + H2O up to 1 I) + 0.05 % Tween 20] 9. BSA (Sigma A-7030) 10. OPD (Sigma, Cat No. P-9187) 11. Sulfuric acid 6.8.2 Procedure 1. The blocking solution is 3% BSA in TBST 2 The washing solution is TPBST 3. "Nunc Maxisorp" ELISA plates are coated with 50 μl of 5 μg / ml goat anti-human IL-5 polyclonal antibody (R + D Systems, Cat. No. AF-205-NA) , prepared at a stock concentration of 500 μg / ml according to the manufacturer's instructions, and stored in aliquots at -20 ° C) in carbonate / bicarbonate buffer (Sigma, Cat No. C-3041, prepared according to the manufacturer's instructions) , cover with a plate sealer and incubate overnight at 4 ° C. 4. Block with 100 μl of 3% BSA / TBST, incubate at room temperature and pressure (tpa) for 1 h.

. X3 is washed in TBST (at least 200 μl of washing solution per well and per wash). 6. 100 ng / ml (in a volume of 50 μl) of human IL-5 (R + D Systems, Cat. No. 205IL) is added in blocking solution and incubated at room temperature for 1 h. 7. Wash X3 in TBST. 8. Add 50 μl of antibody sample (titrated to obtain the titre data title, if necessary) in blocking solution, incubate at tpa for 1 h. As a positive control for binding to human IL-5, an anti-human L-5 mepolizumab antibody (titrated) is used. 9. Wash X3 in TBST. 10. For the mouse monoclonal antibody 3G4, binding is detected using 50 μl per well of anti-mouse IgG-HRP (Dako, Cat No. P0260) at a 1/2000 dilution in blocking solution for 1 hr at tpa. For a chimeric 3G4 antibody or humanized antibody, and mepolizumab anti-IL-5, binding is detected using 50 μl per well of light chain-anti-human HRP (Sigma, Cat. No. Sigma A7164) at a dilution 1/2000 in solution blocking for 1 ha tpa. 11. Wash X3 in TBST. 12. It is developed with 100 μl of OPD (Sigma, No. cat.P-9187, prepared according to the manufacturer's instructions), stopped with 50 μl of 3 M H2SO, read at an absorbance of 490 nm. 6. 9 Human GM-CSF binding ELISA This assay describes an ELISA that detects the binding of an antibody to human GM-CSF. It is a direct binding ELISA format. 6.9.1 Materials 1. Nunc Immunoplate 1 F96 Maxisorp (Life Technologies, 4-39454A) 2. Human GM-CSF (clinical purity in laboratory) 3. Human anti-GM-CSF monoclonal antibody (R + D Systems, Cat. No. MAB215) 4. Anti-mouse IgG-HRP (Dako, Cat No. P0260) 5. Anti-human kappa-HRP light chain (Sigma A7164) 6. Carbonate / bicarbonate buffer (Sigma, Cat. No. C-3041) 7. PBST (PBS + 0.05% Tween 20) 8. BSA (Sigma A-7030) 9. OPD (Sigma, Cat. No. P-9187) 10. Sulfuric acid 6.9.2 Procedure 1. The blocking solution is 3% BSA in PBST 2. The washing solution is PBST 3. "Nunc Maxisorp" ELISA plates are coated with 50 μl of human GM-CSF dilution 2 μg / ml in PBS, cover with a plate sealer and incubate overnight at 4 ° C. 4. Block with 200 μl of 3% BSA / PBST, incubate ambient temperature and pressure (tpa) for 1 h. 5. Wash X3 in PBST. 6. Add 50 μl of antibody sample (titrated to obtain the titre data title) in blocking solution, incubate at tpa for 1 h. As a positive control for binding to human IL-GM-CSF, human anti-GM-CSF antibody (R & D Systems, Cat. No. antibody MAB215) (titrated) is used. 7. Wash X3 in PBST. 8. For the anti-GM-CSF mouse monoclonal antibody, binding is detected using 50 μl per well of anti-mouse IgG-HRP (Dako, Cat. No. P0260) at a 1/2000 dilution in blocking solution for 1 h tpa. For chimeric 3G4 antibody or humanized antibody, binding is detected using 50 μl per well of anti-human kappa-HRP light chain (Sigma, Cat. No.

Sigma A7164) at a 1/2000 dilution in blocking solution for 1 h at tpa. 9. Wash X3 in PBST. 10. It is developed with 100 μl of OPD (Sigma, Cat No. P-9187, prepared according to the manufacturer's instructions), stopped with 50 μl of 3 M H2SO4, read at an absorbance of 490 nm.

Table 13 Note: The polynucleotide sequence of protein or DNA in SEQ ID numbers from 11 to 24 and 27 to 40 (inclusive) also includes the signal sequence.

SEC NO ID 1 DYEIH SEC NO ID 2 AIDPETGGTAYNQKFKG SEC NO ID 3 ILLYYYPMDY SEC NO ID 4 RASQNISDYLH SEC NO ID 5 YASQSIS SEC NO ID 6 QNGHSFPLT SEC NO ID 7 QVQLQQSGADLVRPGASVTLSCKASGYTFIDYEIHWMKQTPV HGLEWIGAIDPETGGTAYNQKFKGKAILTADKSSSTAYMELRSLTSE DSAVYYCTRILLYYYPMDYWGQGTSVTVSS SEC NO ID 8 DIVMTQSPATLSVTPGDRVSLSCRASQNISDYLHWYQQKSHE SPRLLIKYASQSISGIPSRFSGSGSGSDFTLSINSVEPEDVGVYYCQN GHSFPLTLGAGTKLELK SEC NO ID 9 GPVPPSTALRELIEELVNITQNQKAPLCNGSMVWSINLTAGMY CAALESLINVSGCSAIEKTQRMLSGFCPHKVSAGQFSSLHVRDTKIE VAQFVKDLLLHLKKLFREGRFN SEC NO ID 10 GGCCCTGTGCCTCCCTCTACAGCCCTCAGGGAGCTCATTGA GGAGCTGGTCAACATCACCCAGAACCAGAAGGCTCCGCTCTGCA ATGGCAGCATGGTATGGAGCATCAACCTGACAGCTGGCATGTACT GTGCAGCCCTGGAATCCCTGATCAACGTGTCAGGCTGCAGTGCC ATCGAGAAGACCCAGAGGATGCTGAGCGGATTCTGCCCGCACAA GGTCTCAGCTGGGCAGTTTTCCAGCTTGCATGTCCGAGACACCAA AATCGAGGTGGCCCAGTTTGTAAAGGACCTGCTCTTACATTTAAA GAAACTTTTTCGCGAGGGACGGTTCAACTGA SEC NO ID 11 MGWSCMLFLVATATGVHSQVQLVQSGAEVKKPGASVKVSCKA SGYTFIDYEIHWVRQAPGQGLEWMGAIDPETGGTAYNQKFKGRVTM TTDTSTSTAYMELRSLRSDDTAVYYCARILLYYYPMDYWGQGTLVTV SS SEC NO ID 12 MGWSCIILFLVATATGVHSQVQLVQSGAEVKKPGASVKVSCKA SGYTFIDYEIHWVRQAPGQGLEWMGAIDPETGGTAYNQKFKGRVTM TTDTSTSTAYMELRSLRSDDTAVYYCTRILLYYYPMDYWGQGTLVTV SS SEC NO ID 13 MGWSCIILFLVATATGVHSQVQLVQSGADVKKPGASVKVSCKA SGYTFIDYEIHWVRQAPGQGLEWMGAIDPETGGTAYNQKFKGRVTM TTDTSTSTAYMELRSLRSDDTAVYYCTRILLYYYPMDYWGQGTLVTV SS SEC NO ID 14 MGWSCIILFLVATATGVHSQVQLVQSGADVKKPGASVKVSCKA SGYTFIDYEIHWVRQAPGQGLEWMGAIDPETGGTAYNQKFKGRATL TADKSTSTAYMELRSLRSDDTAVYYCTRILLYYYPMDYWGQGTLVTV H.H SEC NO ID 15 MGWSCIILFLVATATGVHSEIVLTQSPATLSLSPGERATLSCRA SQNISDYLHWYQQKPGQAPRLLIYYASQSISGIPARFSGSGSGTDFT LTISSLEPEDFAVYYCQNGHSFPLTFGGGTKVEIK SEC NO ID 16 MGWSCIILFLVATATGVHSEIVLTQSPATLSLSPGERATLSCRA SQNISDYLHWYQQKPGQAPRLLIYYASQSISGIPARFSGSGSGTDFT LTISSLEPEDFAVYYCQNGHSFPLTLGGGTKVEIK SEC NO ID 17 MGWSCIILFLVATATGVHSEIVLTQSPATLSLSPGERATLSCRA SQNISDYLHWYQQKPGQAPRLLIYYASQSISGIPARFSGSGSGTDFT LTINSLEPEDFAVYYCQNGHSFPLTLGGGTKVEIK SEC NO ID 18 MGWSCIILFLVATAÍGVHSQVQLVQSGAEVKKPGASVKVSCKA SGYTFIDYEIHWVRQAPGQGLEWMGAIDPETGGTAYNQKFKGRVTM TTDTSTSTAYMELRSLRSDDTAVYYCARILLYYYPMDYWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK SEC NO ID 19 MGWSCIILFLVATATGVHSQVQLVQSGAEVKKPGASVKVSCKA SGYTFIDYEIHWVRQAPGQGLEWMGAIDPETGGTAYNQKFKGRVTM TTDTSTSTAYMELRSLRSDDTAVYYCTRILLYYYPMDYWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK SEQ ID NO 20 MGWSCIILFLVATATGVHSQVQLVQSGADVKKPGASVKVSCKA SGYTFIDYEIHWVRQAPGQGLEW ^ / IGAIDPETGGTAYNQKFKGRVTM TTDTSTSTAYMELRSLRSDDTAVYYCTRILLYYYPMDYWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK SEC NO ID 21 MGWSCMLFLVATATGVHSQVQLVQSGADVKKPGASVKVSCKA SGYTFIDYEIHWVRQAPGQGLEWMGAIDPETGGTAYNQKFKGRATL TADKSTSTAYMELRSLRSDDTAVYYCTRILLYYYPMDYWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK SEC NO ID 22 MGWSCIILFLVATATGVHSEIVLTQSPATLSLSPGERATLSCRA SQNISDYLHWYQQKPGQAPRLLIYYASQSISGIPARFSGSGSGTDFT LTISSLEPEDFAVYYCQNGHSFPLTFGGGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGE C SEC NO ID 23 MGWSCIILFLVATATGVHSEIVLTQSPATLSLSPGERATLSCRA SQNISDYLHWYQQKPGQAPRLLIYYASQSISGIPARFSGSGSGTDFT LTISSLEPEDFAVYYCQNGHSFPLTLGGGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGE C SEC NO ID 24 MGWSCIILFLVATATGVHSEIVLTQSPATLSLSPGERATLSCRA SQNISDYLHWYQQKPGQAPRLLIYYASQSISGIPARFSGSGSGTDFT LTINSLEPEDFAVYYCQNGHSFPLTLGGGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGE C SEQ ID NO 25 CAGGTTCAACTGCAGCAGTCTGGGGCTGACCTGGTGAGGC CTGGGGCTTCAGTGACGCTGTCCTGCAAGGCTTCGGGCTACACAT TTATTGACTATGAAATACACTGGATGAAGCAGACACCTGTGCATG GCCTGGAATGGATTGGAGCTATTGATCCTGAAACTGGTGGTACAG CCTATAATCAGAAGTTCAAGGGCAAGGCCATTCTGACTGCAGACA AATCCTCCAGTACAGCCTACATGGAGCTCCGCAGCCTGACATCTG AGGACTCTGCCGTCTATTACTGTACAAGAATTCTCTTATATTACTA TCCTATGGACTACTGGGGTCAAGGGACCTCAGTCACAGTCTCCTC A SEQ ID NO 26 GACATTGTGATGACTCAGTCTCCAGCCACCCTGTCTGTGAC TCCAGGAGATAGAGTCTCTCTTTCCTGCAGGGCCAGCCAGAATAT TAGCGACTACTTACACTGGTATCAACAAAAATCACATGAGTCTCCA AGGCTTCTCATCAAATATGCTTCCCAATCCATCTCTGGGATCCCCT CCAGGTTCAGTGGCAGTGGATCAGGGTCAGATTTCACTCTCAGTA TCAACAGTGTGGAACCTGAAGATGTTGGAGTGTATTACTGTCAAA ATGGTCACAGCTTTCCGCTCACGCTCGGTGCTGGGACCAAGCTG GAGCTGAAA SEC NO ID 27 ATGGGCTGGAGCTGCATCATCCTGTTCCTGGTGGCCACCGC CACCGGCGTGCACAGCCAGGTGCAGCTGGTGCAGAGCGGCGCC GAGGTGAAGAAGCCCGGCGCCAGCGTGAAGGTGAGCTGCAAGGC CAGCGGCTACACCTTCATCGACTACGAGATCCACTGGGTGCGCCA GGCCCCCGGCCAGGGCCTGGAGTGGATGGGCGCCATCGACCCC GAGACCGGCGGCACCGCCTACAACCAGAAGTTCAAGGGCCGCGT GACCATGACCACCGACACCAGCACCAGCACCGCCTACATGGAGC TGCGCAGCCTGCGCAGCGACGACACCGCCGTGTACTACTGCGCC CGCATCCTGCTGTACTACTACCCCATGGACTACTGGGGCCAGGG CACACTAGTCACAGTCTCCTCA SEQ ID NO 28 ATGGGCTGGAGCTGCATCATCCTGTTCCTGGTGGCCACCGC CACCGGCGTGCACAGCCAGGTGCAGCTGGTGCAGAGCGGCGCC GAGGTGAAGAAGCCCGGCGCCAGCGTGAAGGTGAGCTGCAAGGC CAGCGGCTACACCTTCATCGACTACGAGATCCACTGGGTGCGCCA GGCCCCCGGCCAGGGCCTGGAGTGGATGGGCGCCATCGACCCC GAGACCGGCGGCACCGCCTACAACCAGAAGTTCAAGGGCCGCGT GACCATGACCACCGACACCAGCACCAGCACCGCCTACATGGAGC TGCGCAGCCTGCGCAGCGACGACACCGCCGTGTACTACTGCACC CGCATCCTGCTGTACTACTACCCCATGGACTACTGGGGCCAGGG CACACTAGTCACAGTCTCCTCA SEC NO ID 29 ATGGGCTGGCTGCATCATCCTGTTCCTGGTGGCCACCGC CACCGGCGTGCACAGCCAGGTGCAGCTGGTGCAGAGCGGCGCC GACGTGAAGAAGCCCGGCGCCAGCGTGAAGGTGAGCTGCAAGGC CAGCGGCTACACCTTCATCGACTACGAGATCCACTGGGTGCGCCA GGCCCCCGGCCAGGGCCTGGAGTGGATGGGCGCCATCGACCCC GAGACCGGCGGCACCGCCTACAACCAGAAGTTCAAGGGCCGCGT GACCATGACCACCGACACCAGCACCAGCACCGCCTACATGGAGC TGCGCAGCCTGCGCAGCGACGACACCGCCGTGTACTACTGCACC CGCATCCTGCTGTACTACTACCCCATGGACTACTGGGGCCAGGG CACACTAGTCACAGTCTCCTCA SEC NO ID 30 ATGGGCTGGAGCTGCATCATCCTGTTCCTGGTGGCCACCGC CACCGGCGTGCACAGCCAGGTGCAGCTGGTGCAGAGCGGCGCC GACGTGAAGAAGCCCGGCGCCAGCGTGAAGGTGAGCTGCAAGGC CAGCGGCTACACCTTCATCGACTACGAGATCCACTGGGTGCGCCA GGCCCCCGGCCAGGGCCTGGAGTGGATGGGCGCCATCGACCCC GAGACCGGCGGCACCGCCTACAACCAGAAGTTCAAGGGCCGCGC CACCCTGACCGCCGACAAGAGCACCAGCACCGCCTACATGGAGC TGCGCAGCCTGCGCAGCGACGACACCGCCGTGTACTACTGCACC CGCATCCTGCTGTACTACTACCCCATGGACTACTGGGGCCAGGG CACACTAGTCACAGTCTCCTCA SEC NO ID 31 ATGGGCTGGAGCTGCATCATCCTGTTCCTGGTGGCCACCGC CACCGGCGTGCACAGCGAGATCGTGCTGACCCAGAGCCCCGCCA CCCTGAGCCTGAGCCCCGGCGAGCGCGCCACCCTGAGCTGCCG CGCCAGCCAGAACATCAGCGACTACCTGCACTGGTACCAGCAGA AGCCCGGCCAGGCCCCCCGCCTGCTGATCTACTACGCCAGCCAG AGCATCAGCGGCATCCCCGCCCGCTTCAGCGGCAGCGGCAGCGG CACCGACTTCACCCTGACCATCAGCAGCCTGGAGCCCGAGGACT TCGCCGTGTACTACTGCCAGAACGGCCACAGCTTCCCCCTGACCT TCGGCGGCGGCACCAAGGTGGAGATCAAG SEC NO ID 32 ATGGGCTGGAGCTGCATCATCCTGTTCCTGGTGGCCACCGC CACCGGCGTGCACAGCGAGATCGTGCTGACCCAGAGCCCCGCCA CCCTGAGCCTGAGCCCCGGCGAGCGCGCCACCCTGAGCTGCCG CGCCAGCCAGAACATCAGCGACTACCTGCACTGGTACCAGCAGA AGCCCGGCCAGGCCCCCCGCCTGCTGATCTACTACGCCAGCCAG AGCATCAGCGGCATCCCCGCCCGCTTCAGCGGCAGCGGCAGCGG CACCGACTTCACCCTGACCATCAGCAGCCTGGAGCCCGAGGACT TCGCCGTGTACTACTGCCAGAACGGCCACAGCTTCCCCCTGACCC TGGGCGGCGGCACCAAGGTGGAGATCAAG SEC NO ID 33 ATGGGCTGGAGCTGCATCATCCTGTTCCTGGTGGCCACCGC CACCGGCGTGCACAGCGAGATCGTGCTGACCCAGAGCCCCGCCA CCCTGAGCCTGAGCCCCGGCGAGCGCGCCACCCTGAGCTGCCG CGCCAGCCAGAACATCAGCGACTACCTGCACTGGTACCAGCAGA AGCCCGGCCAGGCCCCCCGCCTGCTGATCTACTACGCCAGCCAG AGCATCAGCGGCATCCCCGCCCGCTTCAGCGGCAGCGGCAGCGG CACCGACTTCACCCTGACCATCAACAGCCTGGAGCCCGAGGACTT CGCCGTGTACTACTGCCAGAACGGCCACAGCTTCCCCCTGACCCT GGGCGGCGGCACCAAGGTGGAGATCAAG SEC NO ID 34 ATGGGCTGGAGCTGCATCATCCTGTTCCTGGTGGCCACCGC CACCGGCGTGCACAGCCAGGTGCAGCTGGTGCAGAGCGGCGCC GAGGTGAAGAAGCCCGGCGCCAGCGTGAAGGTGAGCTGCAAGGC CAGCGGCTACACCTTCATCGACTACGAGATCCACTGGGTGCGCCA GGCCCCCGGCCAGGGCCTGGAGTGGATGGGCGCCATCGACCCC GAGACCGGCGGCACCGCCTACAACCAGAAGTTCAAGGGCCGCGT GACCATGACCACCGACACCAGCACCAGCACCGCCTACATGGAGC TGCGCAGCCTGCGCAGCGACGACACCGCCGTGTACTACTGCGCC CGCATCCTGCTGTACTACTACCCCATGGACTACTGGGGCCAGGG CACACTAGTCACAGTCTCCTCAGCCTCCACCAAGGGCCCATCGGT CTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAG CGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACAC CTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAG CGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA TCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGA AAGTTGAGCCCAAATCTTGTGACAAACTACACACATGCCCACCGT GCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCC CCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAG GTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAA GACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACA GGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACC AGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTAC AAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC TACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAA CGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEC NO ID 35 ATGGGCTGGCTGCATCATCCTGTTCCTGGTGGCCACCGC CACCGGCGTGCACAGCCAGGTGCAGCTGGTGCAGAGCGGCGCC GAGGTGAAGAAGCCCGGCGCCAGCGTGAAGGTGAGCTGCAAGGC CAGCGGCTACACCTTCATCGACTACGAGATCCACTGGGTGCGCCA GGCCCCCGGCCAGGGCCTGGAGTGGATGGGCGCCATCGACCCC GAGACCGGCGGCACCGCCTACAACCAGAAGTTCAAGGGCCGCGT GACCATGACCACCGACACCAGCACCAGCACCGCCTACATGGAGC TGCGCAGCCTGCGCAGCGACGACACCGCCGTGTACTACTGCACC CGCATCCTGCTGTACTACTACCCCATGGACTACTGGGGCCAGGG CACACTAGTCACAGTCTCCTCAGCCTCCACCAAGGGCCCATCGGT CTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAG CGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACAC CTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAG CGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA TCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGA AAGTTGAGCCCAAATCTTGTGACAAACTCACACATGCCCACCGT GCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCC CCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAG GTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAA GACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACA GGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACC AGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTAC AAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC TACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAA CGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEC NO ID 36 ATGGGCTGGAGCTGCATCATCCTGTTCCTGGTGGCCACCGC CACCGGCGTGCACAGCCAGGTGCAGCTGGTGCAGAGCGGCGCC GACGTGAAGAAGCCCGGCGCCAGCGTGAAGGTGAGCTGCAAGGC CAGCGGCTACACCTTCATCGACTACGAGATCCACTGGGTGCGCCA GGCCCCCGGCCAGGGCCTGGAGTGGATGGGCGCCATCGACCCC GAGACCGGCGGCACCGCCTACAACCAGAAGTTCAAGGGCCGCGT GACCATGACCACCGACACCAGCACCAGCACCGCCTACATGGAGC TGCGCAGCCTGCGCAGCGACGACACCGCCGTGTACTACTGCACC CGCATCCTGCTGTACTACTACCCCATGGACTACTGGGGCCAGGG CACACTAGTCACAGTCTCCTCAGCCTCCACCAAGGGCCCATCGGT CTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAG CGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACAC CTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAG CGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA TCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGA AAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGT GCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCC CCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAG GTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAA GACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACA GGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACC AGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTAC AAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC TACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAA CGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEC NO ID 37 ATGGGCTGGAGCTGCATCATCCTGTTCCTGGTGGCCACCGC CACCGGCGTGCACAGCCAGGTGCAGCTGGTGCAGAGCGGCGCC GACGTGAAGAAGCCCGGCGCCAGCGTGAAGGTGAGCTGCAAGGC CAGCGGCTACACCTTCATCGACTACGAGATCCACTGGGTGCGCCA GGCCCCCGGCCAGGGCCTGGAGTGGATGGGCGCCATCGACCCC GAGACCGGCGGCACCGCCTACAACCAGAAGTTCAAGGGCCGCGC CACCCTGACCGCCGACAAGAGCACCAGCACCGCCTACATGGAGC TGCGCAGCCTGCGCAGCGACGACACCGCCGTGTACTACTGCACC CGCATCCTGCTGTACTACTACCCCATGGACTACTGGGGCCAGGG CACACTAGTCACAGTCTCCTCAGCCTCCACCAAGGGCCCATCGGT CTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAG CGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACAC CTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAG CGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA TCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGA AAGTTGAGCCCAAATCTTGTGACAAACTACACACATGCCCACCGT GCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCC CCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAG GTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAA GACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACC AGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTAC AAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC TACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAA CGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO 38 ATGGGCTGGAGCTGCATCATCCTGTTCCTGGTGGCCACCGC CACCGGCGTGCACAGCGAGATCGTGCTGACCCAGAGCCCCGCCA CCCTGAGCCTGAGCCCCGGCGAGCGCGCCACCCTGAGCTGCCG CGCCAGCCAGAACATCAGCGACTACCTGCACTGGTACCAGCAGA AGCCCGGCCAGGCCCCCCGCCTGCTGATCTACTACGCCAGCCAG AGCATCAGCGGCATCCCCGCCCGCTTCAGCGGCAGCGGCAGCGG CACCGACTTCACCCTGACCATCAGCAGCCTGGAGCCCGAGGACT TCGCCGTGTACTACTGCCAGAACGGCCACAGCTTCCCCCTGACCT TCGGCGGCGGCACCAAGGTGGAGATCAAGCGTACGGTGGCTGCA CCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTG GAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAG AGGCCAAAGTACAGTGGAAGGTGGACAACGCCCTCCAATCGGGT AACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCAC CTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACG AGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGA GCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG SEC NO ID 39 ATGGGCTGGAGCTGCATCATCCTGTTCCTGGTGGCCACCGC CACCGGCGTGCACAGCGAGATCGTGCTGACCCAGAGCCCCGCCA CCCTGAGCCTGAGCCCCGGCGAGCGCGCCACCCTGAGCTGCCG CGCCAGCCAGAACATCAGCGACTACCTGCACTGGTACCAGCAGA AGCCCGGCCAGGCCCCCCGCCTGCTGATCTACTACGCCAGCCAG AGCATCAGCGGCATCCCCGCCCGCTTCAGCGGCAGCGGCAGCGG CACCGACTTCACCCTGACCATCAGCAGCCTGGAGCCCGAGGACT TCGCCGTGTACTACTGCCAGAACGGCCACAGCTTCCCCCTGACCC TGGGCGGCGGCACCAAGGTGGAGATCAAGCGTACGGTGGCTGCA CCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTG GAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAG AGGCCAAAGTACAGTGGAAGGTGGACAACGCCCTCCAATCGGGT AACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCAC CTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACG AGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGA GCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG SEC NO ID 40 ATGGGCTGGAGCTGCATCATCCTGTTCCTGGTGGCCACCGC CACCGGCGTGCACAGCGAGATCGTGCTGACCCAGAGCCCCGCCA CCCTGAGCCTGAGCCCCGGCGAGCGCGCCACCCTGAGCTGCCG CGCCAGCCAGAACATCAGCGACTACCTGCACTGGTACCAGCAGA AGCCCGGCCAGGCCCCCCGCCTGCTGATCTACTACGCCAGCCAG AGCATCAGCGGCATCCCCGCCCGCTTCAGCGGCAGCGGCAGCGG CACCGACTTCACCCTGACCATCAACAGCCTGGAGCCCGAGGACTT CGCCGTGTACTACTGCCAGAACGGCCACAGCTTCCCCCTGACCCTGGGCGGCGGCACCAAGGTGGAGATCAAGCGTACGGTGGCTGCAC CATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGG AACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGA GGCCAAAGTACAGTGGAAGGTGGACAACGCCCTCCAATCGGGTA ACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACC TACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGA GAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAG CTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG SEQ ID NO 41 SPVPPSTALKELIEELVNITQNQKAPLCNGSMVWSINLTAGVYC AALESLINVSGCSAIEKTQRMLNGFCPHKVSAGQFSSLRVRDTKIEV AQFVKDLLVHLKKLFREGQFN SEQ ID NO 42 AGCCCTGTGCCTCCCTCTACAGCCCTCAAGGAGCTCATTGA GGAGCTGGTCAACATCACCCAGAACCAGAAGGCCCCGCTCTGCA ATGGCAGCATGGTGTGGAGCATCAACCTGACAGCTGGCGTGTACT GTGCAGCCCTGGAATCCCTGATCAACGTGTCAGGCTGCAGTGCC ATCGAGAAGACCCAGAGGATGCTGAACGGATTCTGCCCGCACAA GGTCTCAGCTGGGCAGTTTTCCAGCTTGCGTGTCCGAGACACCAA AATCGAGGTGGCCCAGTTTGTAAAGGACCTGCTCGTACATTTAAA GAAACTTTTTCGCGAGGGACAGTTCAACTGA SEC NO ID 43 MGWSCIILFLVATATGVHS SEQ ID NO 44 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPG QGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLR SDDTAVYYCARXXXXXXXXXXWGQGTLVTVSS SEQ ID NO 45 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQA PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCXXX XXXXXXFGGGTKVEIK SEQ ID NO 46 SGSGPSTALRELIEELVNIT SEC NO ID 47 SGSGLRELIEELVNITQNQK SEC NO ID 48 SGSGIEELVNITQNQKAPLC SEC NO ID 49 SGSGVNITQNQKAPLCNGSM SEC NO ID 50 SGSGQNQKAPLCNGSMVWSI SEC NO ID 51 SGSGAPLCNGSMVWSINLTA SEC NO ID 52 SGSGNGSMVWSINLTAGMYC SEC NO ID 53 SGSGVWSINLTAGMYCAALE SEC NO ID 54 SGSGNLTAGMYCAALESLIN SEC NO ID 55 SGSGGMYCAALESLINVSGC SEC NO ID 56 SGSGAALESLINVSGCSAIE SEC NO ID 57 SGSGSLINVSGCSAIEKTQR SEC NO ID 58 SGSGVSGCSAIEKTQRMLSG SEC NO ID 59 SGSGSAIEKTQRMLSGFCPH SEC NO ID 60 SGSGKTQRMLSGFCPHKVSA SEC NO ID 61 SGSGMLSGFCPHKVSAGQFS SEC NO ID 62 SGSGFCPHKVSAGQFSSLHV SEC NO ID 63 SGSGKVSAGQFSSLHVRDTK SEC NO ID 64 SGSGGQFSSLHVRDTKIEVA SEC NO ID 65 SGSGSLHVRDTKIEVAQFVK SEC NO ID 66 SGSGRDTKIEVAQFVKDLLL SEC NO ID 67 SGSGIEVAQFVKDLLLHLKK SEC NO ID 68 SGSGQFVKDLLLH LKKLFRE SEC NO ID 69 SGSGDLLLHLKKLFREGRFN SEC NO ID 70 SGSGPSTALKELIEELVNIT SEC NO ID 71 SGSGLKELIEELVNITQNQK SEC NO ID 72 SGSGNGSMVWSINLTAGVYC SEC NO ID 73 SGSGVWSINLTAGVYCAALE SEC NO ID 74 SGSGNLTAGVYCAALESLIN SEC NO ID 75 SGSGGVYCAALESLINVSGC SEC NO ID 76 SGSGVSGCSAIEKTQRMLNG SEC NO ID 77 SGSGSAIEKTQRMLNGFCPH SEC NO ID 78 SGSGKTQRMLNGFCPHKVSA SEC NO ID 79 SGSGMLNGFCPHKVSAGQFS SEC NO ID 80 SGSGFCPHKVSAGQFSSLRV SEC NO ID 81 SGSGKVSAGQFSSLRVRDTK SEC NO ID 82 SGSGGQFSSLRVRDTKIEVA SEC NO ID 83 SGSGSLRVRDTKIEVAQFVK SEC NO ID 84 SGSGRDTKIEVAQFVKDLLV SEC NO ID 85 SGSGIEVAQFVKDLLVHLKK SEC NO ID 86 SGSGQFVKDLLVHLKKLFRE SEC NO ID 87 SGSGDLLVHLKKLFREGQFN SEC NO ID 88 DLLLHLKKLFREGRFN SEC NO ID 89 DLLVHLKKLFREGQFN SEC NO ID 90 QFVKDLLLHLKKLFREGRFN SEQ ID NO 91 LLHLKKLFREG SEQ ID NO 92 LKKLFRE SEQ ID NO 93 CAGGTGCAGCTGGTGCAGAGCGGAGCCGAGGTGAAGAAGC CTGGCGCCAGCGTCAAGGTGTCCTGCAAGGCCAGCGGCTACACC TTCATCGACTACGAGATCCACTGGGTGCGGCAGGCTCCTGGACA GGGCCTGGAATGGATGGGCGCCATCGACCCCGAGACAGGCGGC ACCGCCTACAACCAGAAGTTCAAGGGCCGGGTCACCATGACCAC CGACACCAGCACCAGCACCGCCTATATGGAACTGCGGAGCCTGA GAAGCGACGACACCGCCGTGTACTACTGCACCCGGATCCTGCTG TACTACTACCCCATGGACTACTGGGGCCAGGGCACACTAGTCACC GTGAGCAGC SEC NO ID. 94 GAGATCGTGCTGACCCAGAGCCCCGCCACCCTGAGCCTGA GCCCTGGCGAGCGGGCCACCCTGTCCTGCCGGGCCAGCCAGAA CATCAGCGACTACCTGCACTGGTATCAGCAGAAGCCCGGCCAGG CCCCCAGGCTGCTGATCTACTACGCCAGCCAGTCCATCTCCGGCA TCCCCGCCAGGTTCAGCGGCAGCGGCTCCGGCACCGACTTCACC CTGACCATCAGCTCTCTGGAACCCGAGGACTTCGCCGTGTATTAT TGCCAGAACGGCCACAGCTTCCCCCTGACCTTTGGCGGCGGAAC AAAGGTGGAGATCAAG SEC NO ID 95 ATGGGATGGAGCTGCATCATCCTCTTCCTGGTGGCCACGGC TACCGGCGTGCATAGCCAGGTGCAGCTCGTCCAGTCTGGGGCCG AGGTGAAGAAGCCCGGAGCTTCTGTGAAGGTGTCCTGCAAGGCC AGCGGCTATACCTTCATCGACTACGAGATCCATTGGGTGAGGCAG GCTCCCGGGCAGGGCCTGGAGTGGATGGGCGCCATCGACCCAG AGACCGGAGGCACGGCGTACAACCAGAAGTTCAAGGGACGGGTC ACCATGACAACCGATACCAGCACCTCCACCGCTTACATGGAGCTG CGCAGCCTGAGAAGCGACGACACCGCGGTGTACTACTGTACGCG CATCCTGCTCTACTACTACCCCATGGATTACTGGGGCCAGGGCAC ACTAGTCACAGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTT CCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGG CCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACG GTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCC CCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTC ACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAA GTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGA CAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTC AGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA GTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGA GAAAACCATCTCCAAAGCCAAAGGGCAGCCCCAGAACCACAGG TGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAG GTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAA GACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTA CAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACG TCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACA CGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEC NO ID 96 ATGGGATGGAGCTGCATCATCCTCTTCCTGGTGGCCACGGC TACCGGCGTGCATAGCCAGGTGCAGCTCGTCCAGTCTGGGGCCG ACGTGAAGAAGCCCGGAGCTTCTGTGAAGGTGTCCTGCAAGGCC AGCGGCTATACCTTCATCGACTACGAGATCCATTGGGTGAGGCAG GCTCCCGGGCAGGGCCTGGAGTGGATGGGCGCCATCGACCCAG AGACCGGAGGCACGGCGTACAACCAGAAGTTCAAGGGACGGGTC ACCATGACAACCGATACCAGCACCTCCACCGCTTACATGGAGCTG CGCAGCCTGAGAAGCGACGACACCGCGGTGTACTACTGTACGCG CATCCTGCTCTACTACTACCCCATGGATTACTGGGGCCAGGGCAC ACTAGTCACAGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTT CCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGG CCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACG GTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAA GTTGAGCCCAAATCTTGTGACAAACTACACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCC CCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTC ACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAA GTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGA CAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTC AGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA GTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGA GAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGG TGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAG GTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAA GACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTA CAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACG TCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACA CGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO 97 ATGGGATGGTCTTGTATCATCCTGTTCCTGGTGGCGACCGC CACCGGCGTGCACTCCGAGATCGTGCTGACCCAGAGTCCAGCCA CCCTCAGCCTGAGCCCTGGGGAACGCGCCACCCTGTCCTGCCGG GCGAGTCAGAACATCTCCGACTACCTGCATTGGTACCAGCAGAAG CCCGGCCAGGCCCCTCGCCTGCTGATCTACTACGCCTCCCAGAG CATCAGCGGAATCCCCGCCCGGTTCTCCGGAAGTGGGTCCGGAA CCGACTTTACCCTGACCATCAGCTCTCTCGAGCCAGAGGACTTCG CGGTGTACTACTGCCAGAACGGGCATAGTTTCCCACTGACCTTCG GAGGGGGCACAAAGGTGGAGATCAAGCGTACGGTGGCTGCACCA TCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGG CCAAAGTACAGTGGAAGGTGGACAACGCCCTCCAATCGGGTAACT CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTAC AGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA ACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTC GCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG SEC NO I D 98 LLVH LKKLFREG

Claims (47)

1. An antibody or antigen-binding fragment thereof that specifically binds to hIL-13 and comprises CDRH3 as defined in SEQ ID NO 3 or variants thereof in which one or two amino acid residues in CDRH3 differ from those amino acid residues in the corresponding position in SEQ ID NO 3.

2. An antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment neutralizes human L-13. .

3. An antibody or antigen-binding fragment thereof according to claim 1 or 2, wherein the antibody or antigen-binding fragment thereof modulates the binding of human L-13 to its receptor.

4. An antibody or antigen-binding fragment thereof according to any of claims 1 to 3, wherein the CDRH3 comprises the sequence of SEQ ID NO. 3.

5. An antibody or antigen-binding fragment thereof. according to any one of claims 1 to 4, wherein the antibody or antigen-binding fragment thereof further comprises one or more of the following CDRH2 sequences: SEC NO ID 2, CDRH1: SEC NO ID 1, CDRL1: SEC NO ID 4, CDRL2: SEC NO ID 5 and CDRL3: SEC NO ID 6 or a variant thereof in which one or two residues of amino acids in the CDR differ from the amino acid residues in the corresponding position in SEC NO ID.

6. An antibody or antigen-binding fragment thereof according to any preceding claim, wherein the The antibody or antigen-binding fragment thereof comprises the following CDRs: CDRH1: SEC NO ID 1 CDRH2: SEC NO ID 2 CDRH3: SEC NO ID 3"? Or CDRL1: SEC NO ID 4 CDRL2: SEC NO ID 5 CDRL3: SEC NO ID 6

7. An antibody or antigen-binding fragment thereof that binds to the peptides indicated in SEQ ID NO. 90, 15 99, 102, 103, 105, 106, 107, 108, 109, 110, 111, 112 and 114, but does not bind to the peptides indicated in SEQ ID NOs 100, 101, 104 and 113.

8. An antibody or antigen-binding fragment thereof according to any preceding claim, which binds Specifically to the epitope set forth in SEQ ID NO 91.

9. An antibody or antigen-binding fragment thereof according to any of the preceding claims, wherein the antibody is an intact antibody.

10. An antibody or antigen-binding fragment of the same as in claim 9, wherein the antibody is a rat, mouse, primate (for example, Cynomolgus, catirrino monkey or great ape) or human.

11. An antibody of any of claims 1 to 9, wherein the antibody is a humanized or chimeric antibody.

12. The antibody of any of claims 9 to 11, wherein the antibody comprises a human constant region.

The antibody of claim 9 to 12, wherein the antibody comprises a constant region of IgG isotype.

14. The antibody of claim 13, wherein the antibody is IgG1, IgG2 or IgG4.

15. The antibody of claim 6, comprising a VH domain of SEQ ID NO: 7 and a VL domain of SEQ ID NO: 8.

16. A humanized antibody of claim 6, comprising a VH domain of SEQ ID NO: 12 and a VL domain of SEQ ID NO: 15.

17. A humanized antibody of claim 6, comprising a VH domain of SEQ ID NO: 13 and a VL domain of SEQ ID NO: 15.

18. A humanized antibody of claim 16 or 17 , which additionally comprises a human constant region of an IgG isotype (e.g., IgG1 or IgG4).

19. A humanized antibody comprising a heavy chain of SEQ ID NO: 19 and a light chain of SEQ ID NO: 22.

20. A humanized antibody comprising a heavy chain of SEQ ID NO: 20 and a light chain of SEQ ID NO: 22.

21. An antigen-binding fragment of any of claims 1-8, wherein the fragment is a Fab, Fab ', 5 F (ab ') 2, Fv, diabody, triabody, tetrabody, miniantibody, minibody, Isolated VH, isolated VL.

22. An antigen-binding fragment according to claim 21, wherein the fragment comprises or consists of a ScFv. • or 23.

An antibody according to any of claims 1 to 20, comprising a mutated Fe region such that the antibody has reduced ADCC and / or complement activation.

A recombinant transformed or transfected host cell comprising a first and a second vector, the first vector comprising a polynucleotide encoding a heavy chain of an antibody according to any preceding claim, and the second vector comprising a polynucleotide encoding a light chain of any preceding claim.

25. The host cell of claim 24, wherein the first vector comprises a polynucleotide selected from the group consisting of SEQ ID NO: 34, 35, 36, 37, 95 and 96, and a second vector comprising a selected polynucleotide. of the group constituted by SEC NO ID 38, 39, 40 and 97.

26. The host cell of claim 24 or 25, wherein the cell is eukaryotic.

27. The host cell of claim 26, wherein the cell is a mammalian cell

28. The host cell of claim 27, wherein the cell is a CHO cell or an NSO cell.

29. A process for the production of an antibody of any of claims 1 to 20, the method comprising the step of culturing a host cell of any of claims 25 to 28 in a serum-free culture medium.

The method of claim 29, wherein the antibody is secreted by the host cell into the culture medium

31. The method of claim 30, wherein the antibody is further purified to at least 95% or more (for example, 98% or more) with respect to the culture medium containing antibody.

32. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof of any of claims 1 to 23 and a pharmaceutically acceptable carrier.

33. A kit of parts comprising the composition of claim 32 together with instructions for use

34. A method of treating a human patient afflicted with asthma, the method comprising the step of administering a therapeutically effective amount of an antibody of 1 to 20.

The method of claim 34, wherein the patient is afflicted with selected asthma. of allergic asthma, severe asthma, difficult asthma, labile asthma, nocturnal asthma, premenstrual asthma, asthma resistant to steroids, asthma dependent on steroids, asthma induced by aspirin, asthma of adult onset, pediatric asthma.

36. A method of treating a human patient afflicted with an asthmatic condition that is refractory to treatment with corticosteroids, the method comprising the step of administering to the patient a therapeutically effective amount of the antibody or antigen-binding fragment of any of claims 1 to 23.

37. A method of preventing acute asthmatic attacks in a human patient, the method comprising the step of administering to the patient a therapeutically effective amount of an antibody of claims 1 to 23.

38. A method of reducing the frequency and / or mitigating the effects of acute asthmatic attacks in a human patient, the method comprising the step of administering to the patient a therapeutically effective amount of an antibody of any of claims 1 to 23.

39. A method of treating a human patient afflicted with a disease or disorder selected from the group consisting of atopic dermatitis, allergic rhinitis, Crohn's disease, COPD, fibrotic diseases or disorders such as idiopathic pulmonary fibrosis, progressive systemic sclerosis, liver fibrosis, hepatic granulomas , schistosomiasis, leishmaniasis, cell cycle regulation diseases such as Hodgkins disease, chronic B-cell lymphocytic leukemia, the method comprising administering to a human patient a therapeutically effective amount of an antibody of any of claims 1 to 23.

40 Use of an antibody or antigen-binding fragment thereof of any of claims 1 to 23 in the manufacture of a medicament for the treatment of a disease or disorder selected from the group consisting of allergic asthma, severe asthma, difficult asthma, asthma labile, nocturnal asthma, asthma premenstrual, steroid-resistant asthma, steroid-dependent asthma, aspirin-induced asthma, adult-onset asthma, pediatric asthma, atopic dermatitis, allergic rhinitis, Crohn's disease, COPD, fibrotic diseases or disorders such as idiopathic pulmonary fibrosis, progressive systemic sclerosis , liver fibrosis, hepatic granulomas, schistosomiasis, leishmaniasis, diseases of cell cycle regulation such as Hodgkins disease, leukemia B-cell lymphocytic disease

41. A method of treating a human patient afflicted with a disease or disorder selected from the group consisting of: allergic asthma, severe asthma, difficult asthma, labile asthma, nocturnal asthma, premenstrual asthma, steroid-resistant asthma , steroid-dependent asthma, aspirin-induced asthma, adult onset asthma, pediatric asthma, atopic dermatitis, allergic rhinitis, Crohn's disease, COPD, fibrotic diseases or disorders such as idiopathic pulmonary fibrosis, progressive systemic sclerosis, liver fibrosis, hepatic granulomas , schistosomiasis, leishmaniasis, diseases of cell cycle regulation such as Hodgkins disease, chronic B-cell lymphocytic leukemia; the method comprising administering a therapeutically effective amount of an antibody of any of claims 1 to 25 and a therapeutically effective amount of an anti-IL-4 monoclonal antibody.

42. The method of claim 41, wherein the anti-IL-4 monoclonal antibody is administered simultaneously, sequentially or separately to the antibody of any of claims 1 to 25.

43. The method of claim 41 or 42, in that the anti-L-4 antibody is pascolizumab.

44. Use of an antibody of any one of claims 1 to 25 and an anti-IL-4 monoclonal antibody such as pascolizumab in the manufacture of a medicament for the treatment of a disease or disorder selected from the group consisting of allergic asthma, severe asthma, difficult asthma, labile asthma, nocturnal asthma, premenstrual asthma, steroid-resistant asthma, asthma dependent asthma, asthma induced by aspirin, adult onset asthma, pediatric asthma, atopic dermatitis, allergic rhinitis, Crohn's disease, COPD, fibrotic diseases or disorders such as idiopathic pulmonary fibrosis, progressive systemic sclerosis, hepatic fibrosis, hepatic granulomas, schistosomiasis, leishmaniasis, cell cycle regulation such as Hodgkins disease, chronic B-cell lymphocytic leukemia.

45. Use of an antibody of any of claims 1 to 25 and an anti-IL-4 monoclonal antibody such as pascolizumab in the manufacture of a kit of parts for the treatment of a disease or disorder selected from the group consti due to allergic asthma, severe asthma, difficult asthma, labile asthma, nocturnal asthma, premenstrual asthma, steroid-resistant asthma, steroid-dependent asthma, aspirin-induced asthma, adult onset asthma, pediatric asthma, atopic dermatitis, allergic rhinitis, of Crohn, COPD, fibrotic diseases or disorders such as idiopathic pulmonary fibrosis, progressive systemic sclerosis, hepatic fibrosis, hepatic granulomas, schistosomiasis, leishmaniasis, diseases of cell cycle regulation such as Hodgkins disease, B-cell chronic lymphocytic leukemia.

46. A kit of parts comprising a first pharmaceutical composition comprising an antibody of any of claims 1 to 25 and a pharmaceutically acceptable carrier, and a second pharmaceutical composition comprising an anti-IL-4 monoclonal antibody such as pascolizumab and a pharmaceutically acceptable carrier, optionally together with instructions for use.

47. A pharmaceutical composition comprising a first antibody of any of claims 1 to 25 and a second antibody, wherein the second antibody is an anti-IL-4 antibody such as pascolizumab, and a pharmaceutically acceptable carrier.