EA042576B1 - ANTI-IL-5 ANTIBODIES - Google Patents

Description

Cross-reference to related applications

This patent application claims priority to U.S. Provisional Application No. 62/438,502, filed December 23, 2016, the disclosure of which is incorporated herein by reference in its entirety.

Sequence listing

The invention includes a sequence listing which has been provided electronically in ASCII format and is hereby incorporated by reference in its entirety. The specified ASCII copy, created on November 30, 2017, is named 102085.000906_sl.txt and has a size of 93529 bytes.

The field of technology to which the invention belongs

The present document discloses novel antibody molecules that immunospecifically bind IL-5 and uses of the disclosed antibodies.

Prior Art

Interleukin-5 (IL-5) is a T helper 2 (Th2) cytokine that induces the proliferation and differentiation of both B cells and eosinophils. In B cells, IL-5 also increases the secretion of immunoglobulins. IL-5 is a key modulator of eosinophils, where it also regulates maturation, tissue migration, survival, and apoptosis prevention.

Through two separate motifs, IL5 binds to its specific receptor (IL5Ra) and signaling receptor, the common β-chain (sun) for interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GMCSF). The affinity of IL-5 for IL5Ra has been reported to be in the mid-low nM range (0.2-100 nM); it shifts to the range of medium pM (~100 pM) in the presence of Sun. IL5-R binds specifically to IL-5, which then recruits everything to IL-5R.

The therapeutic potential for targeting interleukin-5 (IL-5) has been demonstrated through extensive validation of the literature and recent positive phase III clinical trial data for reslizumab and mepolizumab.

The essence of the invention

Disclosed herein are human antibody molecules that immunospecifically bind to human IL-5 with an equilibrium affinity constant (KD) of at least about 40 pM as determined by surface plasmon resonance.

Also provided are antibody molecules comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 8, a light chain CDR1, comprising the amino acid sequence of SEQ ID NO: 5, 21, 24, 27, 30, 33, 36, 39, or 66, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, 42, or 45, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15,48, 51, 54, 57, 60 or 63.

The disclosed antibody molecules may include a heavy chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 16 and a light chain variable region comprising the amino acid sequence which is at least 90, 95, 96, 97, 98, 99 or 100% identical to the amino acid sequence of SEQ ID NO: 17, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52 , 55, 58, 61, 64, or 67, where the variability (ie, at least 90, 95, 96, 97, 98, 99, or 100% identity) occurs outside of the CDR sequence.

Described antibody molecules may include a heavy chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18 or 20 and a light chain comprising an amino acid sequence which is at least 90, 95, 96, 97, 98, 99 or 100% identical to the amino acid sequence of SEQ ID NO: 19, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56, 59, 62, 65, or 68, where the variability (i.e., at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity) occurs outside of the CDR sequence.

Also provided are nucleic acid molecules encoding the disclosed antibody molecules, vectors containing nucleic acid molecules, and cells transformed to express the disclosed antibody molecules.

Also disclosed are pharmaceutical compositions containing any of the antibody molecules disclosed herein.

The present invention also relates to methods of treating a subject having eosinophilic asthma, hypereosinophilia syndrome, nasal polyps with eosinophilic involvement, eosinophilic granulomatosis with polyangiitis, atopic dermatitis, or eosinophilic esophagitis, comprising administering to the subject a therapeutically effective amount of any of the antibody molecules described herein or containing them pharmaceutical compositions for the treatment of eosinophilic asthma, hypereosinophilic syndrome, eosinophilic nasal polyposis, eosinophilic granulomatosis with polyangiitis, atopic dermatitis or eosinophilic esophagitis.

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Also provided is the use of an effective amount of any of the antibody molecules described herein, or pharmaceutical compositions containing them, in the treatment of eosinophilic asthma, hypereosinophilic syndrome, nasal polyposis with eosinophilic involvement, eosinophilic granulomatosis with polyangiitis, atopic dermatitis, or eosinophilic esophagitis.

Further provided is the use of any of the antibody molecules described herein, or pharmaceutical compositions containing them, in the manufacture of a medicament for the treatment of eosinophilic asthma, hypereosinophilic syndrome, nasal polyposis with eosinophilic involvement, eosinophilic granulomatosis with polyangiitis, atopic dermatitis, or eosinophilic esophagitis.

Brief description of the drawings

The brief description as well as the following detailed description are hereinafter understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the disclosed antibody molecules, methods and uses, the drawings show exemplary embodiments of antibody molecules, methods and uses; however, the molecules, methods, and uses of the antibodies are not limited to the specific embodiments disclosed.

Fig. 1 illustrates a TF-1.6G4 assay showing that the 3A5.001 variant (in IgG4 format) retains equivalent potency to the parent 3A5 antibody (in IgG1 format).

Fig. 2 illustrates analysis of TF-1.6G4 showing that the 3A5.040 variant retains equivalent potency to the parent 3A5.001.

Fig. 3 is a graphical matrix showing the position and identity of the various single amino acid substitutions that were generated in the 3A5.040 VH CDR when aligned with the original 3A5.040 VH sequence (upper sequence). The frames contain residues that have been designated as CDR residues according to AbM nomenclature. In addition to the CDR residues, variants were made with Kabat residue numbers 93 and 94 (next to HC CDR3) as described in Example Functional Testing and Antibody Characterization. The various sequences shown in this figure are shown in SEQ ID NO: 73.

Fig. 4 is a graphical matrix showing the position and identity of the various single amino acid substitutions that were generated for the 3A5.040 VL CDRs aligned with the original 3A5.040 VL sequence (upper sequence). The frames contain residues that have been designated as CDR residues according to AbM nomenclature. The various sequences shown in this figure are shown in SEQ ID NO: 74.

Fig. 5 illustrates exemplary light chain CDR consensus sequences aligned with the 3A5.040 VL sequence (upper sequence). 3A5.040 VL CDR variants with a single amino acid substitution that showed potential improvements according to the inclusion criteria described in the examples (variant kd ratio to 3A5.040 >1.5 kd) and (variant expression level to 3A5.040 expression level ratio) >0.5) were included in the consensus sequences. The definitions and numbering of the CDRs correspond to the AbM and Kabat nomenclature, respectively. The frames indicate the provisions of the CDR. The various sequences shown in this figure are shown in SEQ ID NO: 75.

Fig. 6 illustrates a multi-concentration Biacore kinetic assay of binding of antibody 3A5.046 to recombinant human IL-5 at 2.5, 1.25, 0.625, 0.313, and 0.156 μg/mL. The sensorgrams show a decrease in the concentration of IL-5 from about 2.5 μg/ml IL-5 in the upper curve to 0.156 μg/ml IL-5 in the lower curve.

Fig. 7A and FIG. 7B illustrates the proliferation of TF-1.6G4 cells in response to IL-5 and the efficacy of inhibition of IL-5 driven proliferation by 3A5.046. 3A5.046 was a stronger inhibitor of human IL-5 (FIG. 7A) and cynomolgus monkey IL-5 (FIG. 7B) than mepolizumab.

Fig. 8A and FIG. 8B shows an example of an ELISA designed using the 3A5 antibody and a control capture antibody (R&D Systems). ELISA was able to detect recombinant IL-5 (FIG. 8A) and IL-5 derived from CD3/CD28/IL-33 activated primary human T cells from 3 donors (FIG. 8B). Fig. 8B top panel: donor 1, FIG. 8B middle panel: donor 3; fig. 8B bottom panel: donor 4.

Fig. 9 illustrates the results of an experiment in which cord blood CD34+ cells were differentiated into phenotypically mature eosinophils using IL-5 and other cytokines as described in the examples. Antibody 3A5.046 was more potent than mepolizumab in inhibiting IL-5 induced eosinophil differentiation.

Fig. 10A, FIG. 10B, FIG. 10C, fig. 10D and FIG. 10E illustrates the results of a Biacore cross-reactivity assay of antibody 3A5.046 binding to human IL-5 (Fig. 10A), cynomolgus monkey IL-5 (Fig. 10B), mouse IL-5 (Fig. 10C), rat IL-5 ( Fig. 10D) and guinea pig IL-5 (Fig. 10E). Double referenced sensorgrams are shown for cytokine binding at 1 µg/mL or 10 µg/mL.

Fig. 11A, FIG. 11B, FIG. 11C and FIG. 11D illustrate the specificity results of the Biacore assay.

- 2 042576 for antibody 3A5.046. Double referenced sensorgrams are shown for cytokine binding at 10 μg/mL (FIG. 11A and FIG. 11B) or 1 μg/mL (FIG. 11C and FIG. 11D).

Fig. 12 illustrates the results of the Ascaris suum challenge (A. suum in the cynomolgus monkey model of airway eosinophilia. On day 2, there was a significant difference in lung eosinophil count (BALF) when comparing animals treated with 3A5.046 and animals treated with vehicle (placebo) (p<0.01; Mann-Whitney test).

Fig. 13A and FIG. 13B illustrates the response of blood eosinophils 10 days after an A. suum challenge in cynomolgus monkeys that were pretreated with 3A5.046 or a comparable isotype control antibody (placebo) one week before the A. suum challenge (FIG. 13A). Fig. 13B illustrates additional details of blood eosinophil counts in animals treated with antibody 3A5.046 up to 45 days post-challenge (52 days post-dose). The eosinophil count remained below baseline for at least 45 days after the challenge following a single dose of 3A5.046 one week before the challenge.

In FIG. 14 shows BALF eosinophil levels in a knock-in (KI) rat model with human IL-5 in response to an Alternaria alternata challenge. This model can be used to test the effectiveness of an anti-IL-5 antibody to modulate BALF eosinophil count following an Alternaria challenge.

Detailed description of illustrative embodiments

The described antibody molecules, methods, and uses may be more readily understood by reference to the following detailed description in conjunction with the accompanying drawings, which form part of this description. It should be understood that the disclosed antibody molecules, methods and uses are not limited to the specific antibody molecules, methods and uses described and/or shown herein, and that the terminology used herein is intended to describe specific embodiments by way of example only and is not is intended to limit the claimed antibody molecules, methods and uses.

Unless specifically stated otherwise, any description regarding a possible mechanism or mode of action or reason for an improvement is for illustration only, and the disclosed antibody molecules, methods, and uses should not be limited by the correctness or incorrectness of any such proposed mechanism or mode of action or reason for improvement.

Throughout the text, descriptions refer to antibody molecules and methods of using said antibody molecules. Where the disclosure describes or claims a feature or embodiment associated with an antibody molecule, such feature or embodiment is equally applicable to methods of using said antibody molecule. Similarly, where a feature or embodiment is described or claimed in connection with a method of using an antibody molecule, that feature or embodiment is equally applicable to the antibody molecule.

If a range of numerical values is given or stated herein, then that range includes its endpoints and all individual integers and fractions within the range, and also includes each of the narrower ranges formed by all possible combinations of those endpoints and internal integers, and fractions to form subgroups of a larger group of values within a specified range to the same extent as if each of those narrower ranges were explicitly specified. When a range of numerical values is specified herein as being greater than the claimed value, the range is nonetheless finite and limited at its upper end to a value that is valid within the context of the invention as described herein. If a range of numeric values is specified herein as less than the specified value, the range is nevertheless limited at its lower end to a non-zero value. It is not intended that the scope of the invention be limited to the specific values specified in the definition of the range. All ranges are included and combined.

Reference to a specific numerical value includes at least that specific value, unless the context clearly dictates otherwise.

When values are expressed as approximations using the preceding about, it will be understood that a particular value forms a different embodiment. The term about, when used with respect to numerical ranges, limit values, or specific values, is used to indicate that the values given may differ by up to 10% from the stated value. Thus, the term about is used to cover deviations of ±10% or less, deviations of ±5% or less, deviations of ±1% or less, deviations of ±0.5% or less, or deviations of ±0.1% or less of a specified value.

It should be noted that certain features of the disclosed antibody molecules, methods and uses, which, for clarity, are described herein in the context of separate embodiments, may also be presented in combination in one embodiment. Conversely, various features of the disclosed antibody molecules, methods, and uses, which are described for brevity in the context of a single embodiment, may also be provided separately or in any subcombination.

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When used in this document, the terms in the singular, they also include the plural.

Various terms relating to aspects of the description are used in the description and claims. Such terms shall have their usual meaning in the art, unless otherwise indicated. Other specifically defined terms should be interpreted in accordance with the definitions provided in this document.

The term including is intended to include, but is not necessarily limited to, examples covering the terms consisting essentially of and consisting of; similarly, the term consisting essentially of is intended to include, but without necessarily being limited to, the examples covered by the term consisting of.

The term antibody molecule has a broad meaning and includes full-length immunoglobulin molecules and antigen-binding fragments.

Immunoglobulins can be classified into five main classes, namely: IgA, IgD, IgE, IgG, IgM, depending on the amino acid sequence of the heavy chain constant domain. IgA and IgG are further subdivided into IgA1, IgA2, IgG1, IgG2, IgG3 and IgG4 isotypes. The light chains of antibodies from any vertebrate species can be assigned to one of two distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains.

An antigen-binding fragment refers to a portion of an immunoglobulin molecule that retains the antigen-binding properties of the parent full-length antibody (i.e., its antigen-binding fragment). Typical antigen-binding fragments may have: heavy chain complementarity determining regions (HCDR) 1, 2 and/or 3; light chain complementarity determining regions (LCDR) 1, 2 and/or 3; heavy chain variable region (VH); light chain variable region (VL); and their combinations. Antigen binding fragments include: Fab fragment, a monovalent fragment consisting of VL, VH domains, light chain constant domain (CL) and heavy chain constant domain 1 (CH1); F(ab) ₂ fragment, a bivalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region; Fd fragment consisting of VH and CH1 domains; an Fv fragment consisting of the VL and VH domains of one antibody arm; and a domain antibody fragment (dAb) (Ward et al., Nature 341: 544-546, 1989) which consists of a VH domain or a VL domain. The VH and VL domains can be engineered and linked together via a synthetic linker to form various types of single chain antibody constructs where the VH/VL domains are paired intramolecularly or intermolecularly in cases where the VH and VL domains are expressed by a single single chain antibody of the construct to form a monovalent antigen binding site such as a single chain Fv (scFv) or a diabody as described, for example, in International Patent Publication No. WO1998/44001, WO1988/01649, WO1994/13804 and WO1992/01047. These antibody fragments are prepared using methods well known to those skilled in the art and the fragments are screened for suitability in the same manner as full length antibodies.

The expression immunospecifically binds refers to the ability of disclosed antibody molecules to preferentially bind to its target (IL-5, in the case of anti-III-5 antibody molecules) without preferentially binding other molecules in a sample containing a mixed population of molecules. Antibody molecules that immunospecifically bind IL-5 are substantially free of other antibodies having different antigenic specificities (eg, an anti-IL-5 antibody is substantially free of antibodies that specifically bind antigens other than IL-5). However, antibody molecules that immunospecifically bind IL-5 may be cross-reactive with other antigens, such as human IL-5 orthologues, including Macaca flavicularis (cynomolgus monkey) IL-5. The antibody molecules disclosed herein are capable of immunospecifically binding both naturally produced human IL-5 and IL-5 that is produced recombinantly in mammalian or prokaryotic cells.

The variable regions of an antibody consist of four framework regions interrupted by three antigen-binding sites. Antigen binding sites are defined using different definitions: (i) Complementarity Detection Regions (CDRs), three in VH (HCDR1, HCDR2, HCDR3) and three in VL (LCDR1, LCDR2, LCDR3), based on sequence variability (Wu and Kabat J Exp Med 132: 211-50, 1970 Kabat et al Sequences of Proteins of Immunological Interest, 5th Ed Public Health Service, National Institutes of Health, Bethesda, Md., 1991); and (ii) Hypervariable regions (HVR or HV), three in VH (H1, H2, H3) and three in VL (L1, L2, L3), which refers to those antibody variable domain regions that are hypervariable in structure, as defined Chothia and Lesk (Chothia and Lesk Mol Biol 196: 901-17, 1987). The AbM CDR definition is also widely used; it is a compromise between the Kabat and Chothia numbering schemes and is so named because it was used by the Oxford Molecular software for modeling AbM antibodies (Rees, AR, Searle, SMJ, Henry, AHand Pedersen, JT (1996) In Sternberg M.J.E. (ed.), Protein Structure Prediction Oxford University Press, Oxford, 141-172). Other definitions include IMGT-CDR (Lefranc et al., Dev Comparat Immunol 27: 55-77, 2003) and the use of specificity determining residues (SDRUs) (Almagro Mol Recognit 17: 132-43, 2004). ImMunoGeneTics International Database (IMGT) (http://www_imgt_org) provides

- 4 042576 standardized numbering and definition of antigen-binding sites. The correspondence between CDR, HV and IMGT boundaries is described in Lefranc et al., Dev Comparat Immunol. 27:55-77, 2003.

The framework or framework sequences are other variable region sequences other than those defined as antigen binding sites. Since antigen binding sites can be defined in various terms as described above, the exact amino acid sequence of the framework depends on how the antigen binding site has been defined. Human antibody, fully human antibody, and like terms refer to an antibody having heavy and light chain variable regions in which both the backbone and antigen binding sites are derived from sequences of human origin. If the antibody contains a constant region, the constant region is also derived from sequences of human origin. A human antibody contains heavy and/or light chain variable regions that are derived from sequences of human origin if the antibody variable regions are derived from a system that uses human germline immunoglobulin genes or rearranged immunoglobulins. Such systems include human immunoglobulin gene libraries presented on phage and non-human transgenic animals such as mice carrying human immunoglobulin loci as described herein. A human antibody may contain amino acid differences compared to human germline or rearranged immunoglobulin sequences, for example, due to natural somatic mutations or deliberate substitutions in the variable domain (scaffold and antigen binding sites) or constant domain. Typically, a human antibody is at least about 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 identical , 99 or 100% amino acid sequence with the amino acid sequence encoded by the human germline immunoglobulin gene or rearranged immunoglobulin gene. In some cases, the human antibody may contain consensus framework sequences derived from analysis of human framework sequences, for example, as described in Knappik et al., J Mol Biol 296: 57-86, 2000, or synthetic HCDR3 included in human immunoglobulin gene libraries, presented on phage, as described, for example, in Shi et al., J Mol Biol 397: 385-96, 2010 and int. Pat. publ. No. WO2009/085462. Antibodies in which the antigen binding sites are from a non-human species are not included in the definition of a human antibody.

Human antibodies derived from human immunoglobulin sequences may be generated using systems such as phage display including synthetic CDRs and/or synthetic scaffolds, or may be subjected to in vitro mutagenesis to improve antibody properties in variable regions or constant regions or in both, resulting in antibodies that do not naturally exist in the in vivo human germline antibody repertoire.

A recombinant antibody includes all antibodies that are made, expressed, generated, or isolated by recombinant methods, such as: antibodies isolated from an animal (eg, mouse) that is transgenic or transchromosomal human immunoglobulin genes or hybridomas prepared from them (described below); antibodies isolated from a host cell transformed to express the antibody; antibodies isolated from a library of recombinant combinatorial antibodies; and antibodies made, expressed, made or isolated by any other means that involve splicing human immunoglobulin gene sequences with other DNA sequences, or antibodies that are generated in vitro using Fab arm exchange.

A monoclonal antibody refers to a population of antibody molecules of the same molecular composition. A monoclonal antibody composition exhibits a single binding specificity and affinity for a particular epitope or, in the case of a bispecific monoclonal antibody, a double binding specificity for two separate epitopes. Thus, a monoclonal antibody refers to a population of antibodies with a single amino acid composition in each heavy and each light chain, except for possible well-known changes such as removal of the C-terminal lysine from the heavy chain of the antibody. Monoclonal antibodies may have heterogeneous glycosylation within an antibody population. The monoclonal antibody may be monospecific or polyspecific, or monovalent, bivalent or multivalent. A bispecific antibody is included in the term monoclonal antibody.

An epitope refers to the portion of an antigen to which an antibody specifically binds. Epitopes typically consist of reactive (such as polar, nonpolar, or hydrophobic) surface groupings of groups, such as amino acid or polysaccharide side chains, and may have specific three-dimensional structural characteristics as well as specific charge characteristics. An epitope may be composed of contiguous and/or contiguous amino acids that form a conformational spatial unit. For a continuous epitope, amino acids from different parts of the linear antigen sequence are in close proximity in 3-dimensional space through the folding of the protein molecule.

Variant refers to a polypeptide or polynucleotide that differs from the reference poly

- 5 042576 peptide or reference polynucleotide with one or more modifications, such as substitution, insertion or deletion. As used herein, the term mutation is intended to refer to one or more deliberate substitutions that are made in a polypeptide or polynucleotide.

As used herein, 90% identical includes at least 90% identical, 91% identical, 92% identical, 93% identical, 94% identical, 95% identical, 96% identical, 97% identical, 98% identical, 99 % identical or 100% identical to a reference element (eg, biological sequence). In the current description, the term % identical is used to describe a number of sequences. It should be understood that the term % identical means that when comparing two sequences in a specified region, two sequences have a specified number of identical residues at the same position. The identity level can be determined using CLUSTAL W with default options.

The terms treat, treatment, and the like refer to both therapeutic treatment and prophylactic or preventive measures, and include reducing the severity and/or frequency of symptoms, eliminating symptoms and/or the underlying cause of symptoms, reducing the frequency or likelihood of symptoms, and/or their underlying causes, improvement or elimination of damage caused, directly or indirectly, by eosinophilic asthma, hypereosinophilic syndrome, nasal polyposis with eosinophilic involvement, eosinophilic granulomatosis with polyangiitis, atopic dermatitis or eosinophilic esophagitis. The treatment also includes prolonging survival compared to the expected survival of an untreated subject. Subjects to be treated include those who have the condition or disorder, as well as those who are prone to have the condition or disorder, or those in whom the condition or disorder needs to be prevented.

As used herein, the term administration to a subject and similar terms refer to the procedure by which the disclosed antibody molecules, or compositions containing them, are injected into the body of a patient such that target cells, tissues, or body segments of the subject bind to the disclosed antibody molecules.

The expression "therapeutically effective amount" refers to the amount of antibody molecules, as described herein, effective to achieve a particular biological or therapeutic result, such as, without limitation, the biological or therapeutic results disclosed, described, or exemplified in this description. A therapeutically effective amount may vary depending on such factors as disease state, age, sex and weight of the individual and the ability of the composition to elicit the desired response in the subject. Typical indicators of the amount of a therapeutic effect include, for example, improvement in the well-being of the patient, reduction in the symptoms of the disease, stopping or slowing the progression of the symptoms of the disease, and/or the absence of symptoms of the disease.

The following abbreviations are used in this document: Alternaria alternata (Alternaria), Ascaris suum (A. suum); complementarity determining region (CDR); heavy chain (HC); light chain (LC); heavy chain variable region (VH); light chain variable region (VL); surface plasmon resonance (SPR).

Antibody molecules.

Disclosed herein are human antibody molecules that immunospecifically bind to human IL-5. Human antibody molecules can immunospecifically bind to human IL-5 with an equilibrium affinity constant (KD) of at least about 40 pM as determined by surface plasmon resonance (SPR). As used herein, the term at least about 40 pM means that the disclosed antibodies immunospecifically bind human IL-5 with a KD less than or equal to about 40 pM. For example, the disclosed antibodies can immunospecifically bind human IL-5 with a KD of about 40, about 30, about 20, about 10, or less than 10 pM.

Described human antibody molecules may include a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 8, a light chain consensus CDR1, comprising the amino acid sequence of SEQ ID NO: 1, a light chain consensus CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a light chain consensus CDR3 comprising the amino acid sequence of SEQ ID NO: 3.

The light chain consensus CDR1 comprises the amino acid sequence GX1X2X3X4X5X6KX7X8Y (SEQ ID NO: 1) wherein:

X ₁ is G or K;

X ₂ represents N or D;

X ₃ represents N or H;

X ₄ is I or A;

X ₅ is G or D;

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X ₆ is S or K;

X ₇ is N or H; And

X ₈ is V or A.

In some embodiments, the light chain CDR1 amino acid sequence may include GGNNIGSKNVY (SEQ ID NO: 5). In some embodiments, the light chain CDR1 amino acid sequence may include GKNNIGSKNVY (SEQ ID NO: 21). In some embodiments, the light chain CDR1 amino acid sequence may include GGDNIGSKNVY (SEQ ID NO: 24). In some embodiments, the light chain CDR1 amino acid sequence may include GGNHIGSKNVY (SEQ ID NO: 27). In some embodiments, the light chain CDR1 amino acid sequence may include GGNNAGSKNVY (SEQ ID NO: 30). In some embodiments, the light chain CDR1 amino acid sequence may include GGNNIDSKNVY (SEQ ID NO: 66). In some embodiments, the light chain CDR1 amino acid sequence may include GGNNIGKKNVY (SEQ ID NO: 33). In some embodiments, the light chain CDR1 amino acid sequence may include GGNNIGSKHVY (SEQ ID NO: 36). In some embodiments, the light chain CDR1 amino acid sequence may include GGNNIGSKNAY (SEQ ID NO: 39).

The light chain CDR2 amino acid sequence includes DDX8X9RPS (SEQ ID NO: 2) wherein:

X ₈ is S or L; And

X ₉ is D or S.

In some embodiments, the light chain CDR2 amino acid sequence may include DDSDRPS (SEQ ID NO: 7). In some embodiments, the light chain CDR2 amino acid sequence may include DDLDRPS (SEQ ID NO: 42). In some embodiments, the light chain CDR2 amino acid sequence may include DDSSRPS (SEQ ID NO: 45).

The light chain CDR3 amino acid sequence contains QVWX ₁₀ SSSDX11VX ₁₂ (SEQ ID NO: 3) wherein:

X ₁₀ is D or L;

X _p represents H, S, Y or D; And

X ₁₂ is V, A or W.

In some embodiments, the light chain CDR3 amino acid sequence may include QVWDSSSDHVV (SEQ ID NO: 15). In some embodiments, the light chain CDR3 amino acid sequence may include QVWLSSSDHVV (SEQ ID NO: 48). In some embodiments, the light chain CDR3 amino acid sequence may include QVWDSSSDSVV (SEQ ID NO: 51). In some embodiments, the light chain CDR3 amino acid sequence may include QVWDSSSDYVV (SEQ ID NO: 54). In some embodiments, the light chain CDR3 amino acid sequence may include QVWDSSSDDVV (SEQ ID NO: 57). In some embodiments, the light chain CDR3 amino acid sequence may include QVWDSSSSDHVA (SEQ ID NO: 60). In some embodiments, the light chain CDR3 amino acid sequence may include QVWDSSSDHVW (SEQ ID NO: 63).

The described human antibody molecules may include a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 8, a light chain CDR1 comprising amino acid sequence of SEQ ID NO: 5, 21, 24, 27, 30, 33, 36, 39 or 66, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, 42 or 45 and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15, 48, 51, 54, 57, 60, or 63. Exemplary antibody molecules comprise a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a heavy chain CDR3, comprising the amino acid sequence of SEQ ID NO: 8 and

a) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

b) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

c) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 24, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

d) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 27, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

e) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 30, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3,

- 7 042576 comprising the amino acid sequence of SEQ ID NO: 15;

f) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 33, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

g) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 36, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

h) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 39, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

i) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 66, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

j) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

k) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 45, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

l) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 48;

m) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 51;

n) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 54;

o) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 57;

p) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 60; or

q) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 63;

where the position of the amino acid residues of the CDR is determined in accordance with AbM.

Described antibody molecules may include a heavy chain variable region comprising an amino acid sequence that is at least 90, 95, 96, 97, 98, 99, or 100% identical to the amino acid sequence of SEQ ID NO: 16 and a light chain variable region comprising an amino acid sequence that is at least 90, 95, 96, 97, 98, 99, or 100% identical to the amino acid sequence of SEQ ID NOs: 17, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49 , 52, 55, 58, 61, 64, or 67, where the variability (ie, at least 90, 95, 96, 97, 98, 99, or 100% identity) occurs outside of the CDR sequence. Typical antibody molecules are presented in table. 1 and table. 15.

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Table 1

Summary of antibody chain/domain composition

Antibody ID Protein VH / (SEQ ID) Protein VL / (SEQ ID) Protein HC / (SEQ ID) Protein LC / (SEQ ID) FOR5 ZA5 VH (SEQ ID NO: 10) 3A5 VL (SEQ ID NO: 11) 3A5HC (SEQ ID NO: 12) 3A5LC (SEQ ID NO: 13) FOR5.001 3A5 VH (SEQ ID NO: 10) 3A5 VL (SEQ ID NO: 11) 3A5.001HC (SEQ ID NO: 14) 3A5LC (SEQ ID NO: 13) ZA5.040 3A5.040 VH (SEQ ID NO: 16) 3A5.040 VL (SEQ ID NO: 17) 3A5.040HC (SEQ ID NO: 18) 3A5.040LC (SEQ ID NO: 19) ZA5.046 3A5.040 VH (SEQ ID NO: 16) 3A5.040 VL (SEQ ID NO: 17) 3A5.046HC (SEQ ID NO: 20) 3A5.040LC (SEQ ID NO: 19) 3A5.063 3A5.040 VH (SEQ ID NO: 16) 3A5.040 VL + G25K (SEQ ID NO: 22) 3A5.040HC (SEQ ID NO: 18) 3A5.040 LC + G25K (SEQ ID NO: 23) FOR5.070 3A5.040 VH (SEQ ID NO: 16) 3A5.040 VL + N26D (SEQ ID NO: 25) 3A5.040HC (SEQ ID NO: 18) 3A5.040 LC + N26D (SEQ ID NO: 26) ZA5.082 3A5.040 VH (SEQ ID NO: 16) 3A5.040 VL + N27H (SEQ ID NO: 28) 3A5.040HC (SEQ ID NO: 18) 3A5.040 LC + N27H (SEQ ID NO: 29) ZA5.084 3A5.040 VH (SEQ ID NO: 16) 3A5.040 VL + I28A (SEQ ID NO: 31) 3A5.040HC (SEQ ID NO: 18) 3A5.040 LC + I28A (SEQ ID NO: 32) ZA5.097 3A5.040 VH (SEQ ID NO: 16) 3A5.040 VL + G29D (SEQ ID NO: 67) 3A5.040HC (SEQ ID NO: 18) 3A5.040LC + G29D (SEQ ID NO: 68) FA5.107 3A5.040 VH (SEQ ID NO: 16) 3A5.040 VL + S30K (SEQ ID NO: 34) 3A5.040HC (SEQ ID NO: 18) 3A5.040LC+S30K (SEQ ID NO: 35)

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FOR5.125 ZA5.040 VH (SEQ ID NO: 16) 3A5.040 VL + N32H (SEQ ID NO: 37) 3A5.040HC (SEQ ID NO: 18) 3A5.040LC+N32H (SEQ ID NO: 38) FOR5.127 3A5.040VH (SEQ ID NO: 16) 3A5.040 VL + V33A (SEQ ID NO: 40) 3A5.040HC (SEQ ID NO: 18) 3A5.040LC+V33A (SEQ ID NO: 41) FOR5.161 3A5.040VH (SEQ ID NO: 16) 3A5.040 VL + S52L (SEQ ID NO: 43) 3A5.040HC (SEQ ID NO: 18) 3A5.040LC+S52L (SEQ ID NO: 44) FOR5.169 3A5.040 VH (SEQ ID NO: 16) 3A5.040 VL + D53S (SEQ ID NO: 46) 3A5.040HC (SEQ ID NO: 18) 3A5.040LC+D53S (SEQ ID NO: 47) 3A5.232 3A5.040VH (SEQ ID NO: 16) 3A5.040 VL + D92L (SEQ ID NO: 49) 3A5.040HC (SEQ ID NO: 18) 3A5.040LC+D92L (SEQ ID NO: 50) ZA5.276* 3A5.040 VH (SEQ ID NO: 16) 3A5.040 VL + H95bS (SEQ ID NO: 52) 3A5.040HC (SEQ ID NO: 18) 3A5.040 LC + H95bS (SEQ ID NO: 53) ZA5.278* 3A5.040 VH (SEQ ID NO: 16) 3A5.040 VL + H95bY (SEQ ID NO: 55) 3A5.040HC (SEQ ID NO: 18) 3A5.040LC + H95bY (SEQ ID NO: 56) ZA5.279* 3A5.040 VH (SEQ ID NO: 16) 3A5.040 VL + H95bD (SEQ ID NO: 58) 3A5.040HC (SEQ ID NO: 18) 3A5.040LC + H95bD (SEQ ID NO: 59) FOR5.294 3A5.040 VH (SEQ ID NO: 16) 3A5.040 VL + V97A (SEQ ID NO: 61) 3A5.040HC (SEQ ID NO: 18) 3A5.040LC+V97A (SEQ ID NO: 62) 3A5.302 3A5.040 VH (SEQ ID NO: 16) 3A5.040VL + V97W (SEQ ID NO: 64) 3A5.040HC (SEQ ID NO: 18) 3A5.040LC+V97W (SEQ ID NO: 65)

* The lowercase b in each of these sequences refers to the Kabat numbering for the CDR position. Kabat numbering allows variable size CDRs, using alphanumeric numbering to indicate amino acid insertions at certain positions. Additional amino acids were present in these CDR sequences, which were numbered positions 95a and 95b (corresponding to Kabat positions 95A and 95B, respectively). For example, for the 3A5.276 antibody, H95bS indicates a histidine (H) mutation in the (S) series at position 95B in accordance with the Kabat number relative to the VL 3A5.040 chain. Therefore, lower case notation is used herein to distinguish the Kabat number, separate from the mutation at the specified Kabat position.

In some embodiments, disclosed antibody molecules may include a heavy chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 16 and

a) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17;

b) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 22;

c) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 25;

d) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 28;

e) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 31;

f) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ

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ID NO: 34;

g) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 37;

h) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 40;

i) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 43;

j) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 46;

k) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 49;

l) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 52;

m) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 55;

n) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 58;

o) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 61;

p) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 64; or

q) a light chain variable region comprising an amino acid sequence that is at least 90, 95, 96, 97, 98, 99, or 100% identical to the amino acid sequence of SEQ ID NO: 67, where the variability (i.e., identity is at least at least 90, 95, 96, 97, 98, 99, or 100%) occurs out of the CDR sequence.

Described antibody molecules may include one or more mutations, deletions or insertions in the framework and/or constant regions. In some embodiments, the IgG4 antibody molecule may contain the S228P mutation. S228 is located in the hinge region of the IgG4 antibody molecule. The serine (S) to proline (P) mutation serves to stabilize the IgG4 hinge and prevent Fab-arm exchange in vitro and in vivo. In some embodiments, the antibody molecules may include one or more modifications that increase the in vivo half-life of the antibody molecules. For example, in some embodiments, an antibody may contain an M252Y mutation, an S254T mutation, and a T256E mutation (collectively referred to as a YTE mutation). M252, S254 and T256 are located in the CH2 domain of the heavy chain. Mutation of these residues to tyrosine (Y), threonine (T), and glutamate (E), respectively, protects antibody molecules from lysosomal degradation, thereby increasing the serum half-life of antibody molecules. Based on the example of other antibodies, it is contemplated that the introduction of a YTE mutation in an anti-IL-5 antibody can provide sufficient prolongation of the serum half-life to allow for dosing schedules of 3 months or more between doses. In some embodiments, the antibody molecules may include a deletion of the C-terminal heavy chain lysine residue. Removal of the C-terminal heavy chain lysine residue reduces the heterogeneity of antibody molecules when produced by mammalian cells. In some embodiments, the antibody molecules may include a combination of mutations, deletions, or insertions. For example, in some aspects, disclosed antibody molecules may include an S228P mutation and a deletion of a C-terminal heavy chain lysine residue. The disclosed antibodies containing the heavy chain sequence of SEQ ID NO: 18, for example, contain the S228P mutation and a deletion of the C-terminal heavy chain lysine residue. In some aspects, a disclosed antibody molecule may contain an S228P mutation, an M252Y mutation, an S254T mutation, a T256E mutation, and a deletion of a C-terminal heavy chain lysine residue. For example, antibody 3A5.046, which contains the heavy chain of SEQ ID NO: 20, contains an S228P mutation, an M252Y mutation, an S254T mutation, a T256E mutation, and a deletion of the C-terminal heavy chain lysine residue.

An antibody molecule may comprise an IgG1 or IgG4 heavy chain constant region and a lambda light chain constant region. In some embodiments, the antibody molecule comprises an IgG1 heavy chain constant region and a lambda light chain constant region (e.g., an antibody

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3A5). In some embodiments, the antibody molecule includes an IgG4 heavy chain constant region and a lambda light chain constant region.

Described antibody molecules may include a heavy chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18 or 20 and a light chain comprising an amino acid sequence which is at least 90, 95, 96, 97, 98, 99 or 100% identical to the amino acid sequence of SEQ ID NO: 19, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56, 59, 62, 65, or 68, where the variability (ie, at least 90% identity) occurs outside of the CDR sequence. Typical antibody molecules are presented in table. 1 and table. 15. In some embodiments, antibody molecules may include a heavy chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18 and

a) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19;

b) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 23;

c) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26;

d) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 29;

e) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 32;

f) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 35;

g) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 38;

h) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 41;

i) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 44;

j) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 47;

k) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 50;

l) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 53;

m) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 56;

n) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 59;

o) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 62;

p) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 65; or

q) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 68, where the variability (i.e., identity is at least at 90, 95, 96, 97, 98, 99, or 100%) occurs out of the CDR sequence.

Described antibody molecules may include a heavy chain comprising an amino acid sequence that is at least 90, 95, 96, 97, 98, 99, or 100% identical to the amino acid sequence of SEQ ID NO: 20 and a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19 or 100%) occurs outside of the CDR sequence.

In some embodiments, the antibody molecules are full length antibodies (with or without removal of the C-terminal heavy chain lysine residue). In other embodiments, the antibody molecules are antigen-binding fragments. Suitable antibody binding fragments include, but are not limited to, a Fab fragment, a Fab2 fragment, or a single chain antibody.

Antibody molecules may have one or more of the following properties:

a) bind to human IL-5 with an equilibrium affinity constant (KD) of at least about 40 pM as determined by surface plasmon resonance;

b) reduce the binding of IL-5 to the IL-5 receptor;

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c) have a serum half-life of at least about 20 days; or

d) bind human and cynomolgus monkey IL-5 but not mouse, rat or guinea pig IL-5.

Also provided are pharmaceutical compositions containing any of the disclosed antibody molecules.

Also provided are nucleic acid molecules encoding any of the disclosed antibody molecules and vectors containing the disclosed nucleic acid molecules.

Also provided are cells transformed to express any of the disclosed antibody molecules.

Methods and uses

The described antibody molecules or pharmaceutical compositions containing them can be used to treat eosinophilic asthma, hypereosinophilic syndrome, nasal polyposis with eosinophilic lesions, eosinophilic granulomatosis with polyangiitis, atopic dermatitis and eosinophilic esophagitis. Any characteristics of an antibody molecule disclosed herein apply equally to the antibodies used in the disclosed methods and uses.

Disclosed herein are methods of treating a subject having eosinophilic asthma, hypereosinophilia syndrome, nasal polyposis with eosinophilic involvement, eosinophilic granulomatosis with polyangiitis, atopic dermatitis, or eosinophilic esophagitis, comprising administering to the subject a therapeutically effective amount of any of the antibody molecules described or pharmaceutical compositions, containing it, for the treatment of eosinophilic asthma, hypereosinophilic syndrome, nasal polyposis with eosinophilic lesions, eosinophilic granulomatosis with polyangiitis, atopic dermatitis or eosinophilic esophagitis.

Also provided is the use of an effective amount of any of the described antibody molecules, or pharmaceutical compositions containing them, in the treatment of eosinophilic asthma, hypereosinophilic syndrome, nasal polyposis with eosinophilic involvement, eosinophilic granulomatosis with polyangiitis, atopic dermatitis, or eosinophilic esophagitis.

In addition, the use of any of the described antibody molecules, or pharmaceutical compositions containing them, is proposed in the manufacture of a medicament intended for the treatment of eosinophilic asthma, hypereosinophilic syndrome, nasal polyposis with eosinophilic involvement, eosinophilic granulomatosis with polyangiitis, atopic dermatitis or eosinophilic esophagitis.

Examples

The following examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to be illustrative and not limiting of the disclosed embodiments.

Obtaining antibodies against human IL-5.

Antibodies against human IL-5 were obtained from transgenic rats (HMTs) with human V genes cloned into their genomes, which produce antibodies with human V domains and rat Fc domains. Briefly, transgenic rats were genetically immunized with DNA encoding IL-5 four times over 21 days (days 0, 7, 14, 21) and challenged with recombinant human IL-5 on day 28 of the immunization protocol. Serum antibody titers were determined on days 0 and 38 of the immunization protocol by an ELISA assay using recombinant human IL-5. Briefly, sera from each animal were diluted in PBS 1% BSA and tested using ELISA plates coated with 1 μg/ml human IL-5 or BSA as controls. Goat anti-rat IgG R-phycoerythrin conjugate (SouthernBiotech, no. 3030-09) was used as secondary antibody at a concentration of 10 μg/ml. Specific animals were selected for hybridoma fusion based on these serum titers.

To obtain hybridomas that produce anti-human IL-5 monoclonal antibodies, splenocytes and/or lymph node cells from immunized animals were isolated and combined with P3X63Ag8.653 non-secreting murine myeloma (ATCC, CRL-1580) cells. Cells were seeded at about 1 x 105 cells/ml in flat bottom microtiter plates followed by a two week incubation in selective media that included 10% fetal clonal serum and 1 x HAT (Sigma). The hybridomas were propagated by passage through four medium changes in 96-well plates (96-well steps 1-4), then in T25 flasks, and finally in T75 flasks.

Supernatants from the hybridoma clones were analyzed during the hybridoma propagation process, initially in whole cell ELISA using cells transfected with GPI-anchored human IL-5, and then ELISA using the recombinant human IL-5 ELISA assay (the latter as described above). Hybridomas that survived the scaling process to the T75 stage and that gave binding signals above a given threshold in both of these assays were frozen as cell pellets for cloning and sequencing of Ig v domains. After these screening steps, approximately 20 chimeric IgG producing hybridomas were selected for cloning.

Human v-domains from candidate chimeric IgGs were isolated by obtaining cDNA from hybridoma cell pellets, PCR amplification of the v-regions, subcloning and DNA sequencing. IN

- 13 042576 sequencing of these hybridomas resulted in about 35 combinations of heavy and light chains. All antibodies were cloned into a mammalian expression vector and transiently transfected into HEK-293 cells. Antibodies were purified using standard protein A purification protocols.

Functional testing and characterization of antibodies.

Individual antibodies in human IgG1 format were first analyzed for specificity in an ELISA with human IL-5. Briefly, antibodies were diluted in PBS 0.1% BSA and tested using ELISA plates coated with 1 μg/ml human IL-5 or an irrelevant control protein. An anti-IgG antibody conjugated to horseradish peroxidase was used as a secondary antibody.

Antibodies that showed immunospecific binding to human IL-5 were ranked for activity in a human IL-5-dependent T cell proliferation assay using human TF-1.6G4 cells (derived from the human erythroleukemia cell line TF-1). The TF1.6G4 cell line was subcloned and selected for enhanced surface expression of IL-5R and consistent proliferative response to human IL-5. The TF-1.6G4 cell line was maintained in culture according to the standard conditions used for the human erythroleukemic cell line TF-1 (ATCC: CRL-2003). Briefly, dilutions of each antibody were incubated in the presence of 45 pM human IL-5 and 5×10 ⁴ TF-1.6G4 cells per well for 48 hours and cell proliferation was determined using CellTiter-Glo® Luminescent Cell Viability. Assay (Promega, Wisconsin). All proliferation and inhibition curves were built using a three- or four-parameter dose-response model in GraphPad Prism 6 software (version 6.04). Tab. 2 summarizes these results.

table 2

Summary of screening and characterization data from the initial test panel in IgG1 format

Test antibody IC50 (pM) in TF1,6G4 Equilibrium affinity (Kd) inhibits binding to IL-5Ra Specificity confirmed by ELISA FOR5 35.07 36 pM Yes Yes 1AZ 55.5 18 pM Yes Yes 2B4 56.75 42 pM Yes Yes 6G10 72.34 61 pM Yes Yes 1E8 72.45 28 pM Yes Yes 3G4 80.92 41 pM Yes Yes 6S9 81.89 41 pM Yes Yes 5H1 86.42 36 pM Yes Yes 1H10 93.26 18 pM Yes Yes 5H11 109.3 36 pM No Yes 5G9 184.4 52 pM Yes Yes 1B2 214.4 45 pM Yes Yes

In table. 2, the test results are ranked in order of the effectiveness of the analysis for TF1.6G4. The initial test panel was selected based on activity, affinity, IL-5R inhibition, and sequences (immunogenicity and expressiveness).

Biacore assays were used to determine the affinity of test antibodies for recombinant human IL-5 and their activity in inhibiting IL-5Ra binding to human IL-5. Tab. 2 summarizes these results. The binding affinity of test antibodies to human IL-5 (KD; Fig. 6) was determined using a Biacore T200 system (GE Healthcare) by coating a Biacore Series S Sensor Chip Protein A (GE Healthcare) sensor chip with a selected purified IgG antibody with a capture level of 75 RU , then recombinant human IL-5 was injected at 60 μl/min over a 7-step 2-fold serial dilution range starting at 1 μg/ml. All experiments were performed using HBS-EP+ buffer (GE Healthcare). The obtained sensograms had a double control (the values of the tested flow cell were subtracted from the values of the flow cell of the control (surface with protein A without antibody), as well as empty buffer). Binding constants were determined by fitting a 1:1 Langmuir binding model to dual control sensorograms.

To determine if each antibody tested inhibits IL-5 binding to IL5Ra, either the Biacore T200 system or the Biacore 3000 system (GE Healthcare) was used. The Biacore CM5 sensor chip was first derivatized with a Fab capture kit (GE Healthcare) according to the manufacturer's instructions on two adjacent (test and control) flow cells. This surface was used to capture each purified IgG test antibody on one

- 14 042576 flow cell to be tested. Then, recombinant human IL-5 at a concentration of 5 μg/ml or empty buffer was injected through the test and control flow cells to saturate the surface of the test flow cell and control for non-specific association of IL-5, respectively. A second injection of purified IgG test antibody at 10 μg/mL or blank buffer was performed on the test flow cell to block free IL-5 binding sites and control dissociation of IgG test antibody from the Fab capture antibody, respectively.

Subsequent injections of IL-5Ra-Fc (R&D Systems) at 5 or 20 µg/mL or empty buffer through both flow cells were used to determine if the test antibody blocked IgG, the interaction between IL-5 and IL-5Ra, or to control dissociation. IgG antibodies from the Fab capture antibody during this step. Antibodies that inhibited IL-5 binding to IL-5R showed a markedly reduced signal upon injection of IL-5R (Table 2). The triple subtraction control method was used for data analysis as described above. All data were exported from Biacore evaluation software and subtracted in Excel software (Microsoft). All experiments were performed using HBS-EP+ buffer (GE Healthcare).

Based on these results, a smaller panel of test antibodies was selected (3A5, 2B4 and 5H11 in Table 2). The antibodies were reformatted to human IgG4 and tested in the same assays. The IgG4-Bepcra antibody 3A5 (originally IgG1) was designated 3A5.001. This fully human antibody was shown to have equivalent potency to the original 3A5 IgGl assay (FIG. 1).

The 3A5.001 antibody variant (designated 3A5.040) was generated with specific amino acid substitutions (VH: S[68]T, N[82A]S; VL: S[2]Y, I[3]V, Y[92]D where residues in square brackets represent Kabat positions) introduced in the V domain region to remove predicted T-cell epitopes. In the TF-1.6G4 assay, antibody 3A5.040 was shown to have equivalent activity to its parent antibody 3A5.001 (FIG. 2).

CDR scan of antibody 3A5.040.

Generation of 3A5.040 Variants - Single mutation variants of the 3A5.040 antibody were made by substituting one of a group of nine representative amino acids -A, S, L, Y, D, Q, K, H, W- at each amino acid position in Light chain CDR1 (CDR-L1), light chain CDR2 (CDR-L2), heavy chain CDR1 (CDR-H1), and heavy chain CDR2 (CDR-H2) (defined by AbM nomenclature). Antibody variants have also been generated by substituting one of a group of ten representative amino acids - A, S, L, Y, D, Q, K, H, W, P - at each amino acid position of the CDR in the light chain CDR3 (CDR-L3), heavy chain CDR3 (CDR-H3) and at Kabat positions 93 and 94 in the heavy chain variable region. A complete listing of all generated variants of a single mutant antibody is shown in FIG. 3 (variable heavy chain) and FIG. 4 (variable light chain), respectively.

Construction of antibody expression vectors - Variable variants. the regions were generated by reverse translation of amino acid sequences into DNA sequences, which were subsequently synthesized de novo by assembling synthetic oligonucleotides. Variable heavy chain (VH) variants were subcloned into a mammalian expression vector containing a human constant region to generate full-length human heavy chains (human IgG4 heavy chain CH1, hinge, CH2 and CH3 domains). Similarly, variable light chain (VL) variants were subcloned into a mammalian expression vector containing a human lambda light chain constant region to generate full-length antibody lambda chains.

Expression of Antibody Variants - Antibodies were generated by co-transfection of separate expression vectors encoding antibody heavy chains and light chains into EXPI293® cells (Life Technologies, Carlsbad, CA). Each strand with one mutation was paired with the parent strand for protein expression in the EXPI293® system. For every 20 ml of transfection, 3.6x107 cells were required in 20 ml of EXPI293® expression medium. The day before transfection, cells were seeded at a density of 0.9x106 viable cells/ml and incubated overnight at 37° C. in a humidified atmosphere with 8% CO ₂ in air on an orbital shaker rotating at 200 rpm. On the day of transfection, the number of cells and their viability was determined using an automatic cell counter. Only cultures with >98% viable cells were used. For each 20 ml of transfection, lipid-DNA complexes were prepared by diluting 10 µg of heavy chain DNA and 10 µg of light chain DNA in OPTI-MEM® I Serum Reduced Medium (Life Technologies, Carlsbad, CA) (cat. no. 31985-062 ) to a total volume of 1.0 ml. 54 µl of EXPIFECTAMINE® 293 reagent (Life Technologies, Carlsbad, CA) was diluted in OPTI-MEM® I medium to a total volume of 1.0 ml. Both vials were gently mixed and incubated for 5 min at room temperature. After incubation, diluted DNA was mixed with diluted EXPIFECTAMINE® 293 Reagent and EXPIFECTAMINE® 293 DNA Reagent and incubated for an additional 20 min at room temperature to form EXPIFECTAMINE® 293 DNA Reagent complexes. After incubation, 2 ml of EXPIFECTAMINE® 293 DNA Reagent complex was added each 50 ml bioreactor tube (TPP Techno Plastic

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Products AG). 2 ml of OPTI-MEM® I medium (Life Technologies, Carlsbad, CA) was added to the negative control tube in place of EXPIFECTAMINE® 293 DNA-reagent complex. Cells were incubated in a 37°C humidified incubator with 8% CO ₂ in air for orbital shaker rotating at 200 rpm. Approximately 16-18 hours after transfection, 100 μl of EXPIFECTAMINE® 293 Transfection Enhancer 1 and 1.0 ml of EXPIFECTAMINE® 293 Transfection Enhancer 2 were added to each bioreactor. Supernatants were collected about 48 hours after transfection.

Purification of Antibody Variants - Each antibody variant was expressed in EXPI293® cells in either 20 or 100 ml of cell culture. The cultures were centrifuged in 50 ml Falcon type tubes at 3000 g for 20 min and the supernatants were filtered using a 0.22 µm filter. Supernatants were purified using a Gilson ASPEC GX274 robot. Briefly, SPE cartridges (Agilent, 12131014) filled with 1.2 ml MABSELECT SURE® Protein A Resin (GE Healthcare) were pre-equilibrated with 3 column volumes of 1X PBS. The supernatant was passed through the columns followed by washing with 4 ml 1X PBS. Each column was washed with 9 ml of 1 M citric acid, pH 2.9. Antibodies were eluted with 2 ml of 0.1 M citric acid, pH 2.9. Antibodies were desalted in SOrensens PBS (5 mM KH ₂ PO ₄ , 3 mM Na ₂ HPO42H ₂ O, 145.4 mM NaCl (pH ~5.8)) using PD-10 columns (GE Healthcare).

Determination of the 3A5.040 variant antibody titer in the supernatant using Biacore Supernatant containing antibodies from expression in EXPI293® cells were analyzed using the Protein A series S chip on the Biacore T200 in order to determine their titer and rank them relative to the parent antibody 3A5.040. Each supernatant sample was diluted with running buffer (1xHBS-EP+, 350 mM NaCl) and injected at 60 µl/min into flow cell (FC) 2. The resulting uptake in response units (RU) was measured on FC 2-1 by subtracting reporting points 5 s after the start of the cycle from the reporting point 5 s after injection. The surface was regenerated by injecting 50 mM NaOH for 12 s at a flow rate of 60 μl/min on FC 1 and 2 every 4 cycles. After each regeneration, the surface and the sensorgram were stabilized for 120 s by introducing the working buffer. Due to the large number of antibodies that have been screened in this manner, many batch runs have been carried out.

The capture levels (in Biacore RU response units) obtained for each supernatant sample were adjusted by multiplying the value obtained for each 30 sec injection by the supernatant dilution factor, which allows comparison of the capture levels between supernatants diluted to varying degrees among different experimental runs. . The relative level of antibody expression (titer) of each mutant was compared with the supernatant fluid specific for batch 3A5.040 (Table 3) using the following formula:

(corrected RU of reference 3A5.040 for 30 sec injection/corrected RU of variant antibody for 30 sec injection) x100 = Proportional titer of parent antibody (% titer of 3A5.040)

Formula 1

Variant antibodies with a higher titer than the parent antibody 3A5.040 had a % titer 3A5.040 value of >100%, and antibodies with a lower titer had a value of <100%. This allowed the identification of variant antibodies that could have improved expression compared to the parent antibody 3A5.040. Some variants were not titered by Biacore analysis of supernatant samples but were expressed and purified as above and their purified yields were determined by spectrophotometric analysis (A ₂₈₀ ) and then compared to the parent antibody 3A5.040 (Table 5).

Determination of IL-5 binding kinetics of variant antibody 3A5.040 using Biacore - supernatant containing antibodies from expression in EXPI293® cells or purified antibodies were analyzed using the Protein A series S chip in the Biacore T200 system (GE Healthcare), their affinity was determined binding to recombinant human IL-5 and ranked them in relation to the parental antibody 3A5.040.

Each antibody was diluted in running buffer (1xHBS-EP+, 350 mM NaCl) and captured at 60 µl/min to about 50 RU per FC 2. The surface and sensorogram were then stabilized for 120 s by injecting running buffer. Recombinant human IL-5 at a concentration of 5 μg/ml or running buffer was injected into FC 1 and 2 at a flow rate of 60 μl/min for 70 seconds. IL-5 was allowed to dissociate in running buffer for 300 s. The surface was regenerated by injecting 50 mM NaOH for 12 s at a flow rate of 60 μl/min in FC 1 and 2. Buffer was injected to further drift in purification for 60 s at a flow rate of 60 μl/min in FC 1 and 2. The surface was stabilized for 300 seconds with running buffer over FC 1 and 2. The supernatant containing the parental 3A5.040 antibody that was transfected with each batch was run approximately every 25 cycles during each run. Purified sample 3A5.040 and lambda isotype control IgG4 were run with each batch to measure inter-assay variability in results.

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Due to the large number of antibodies that have been screened in this manner, many batch runs have been carried out.

Data were double controlled (flow cell 2 subtracted from flow cell 1 and empty buffer) and sensorgrams were fitted to a 1:1 Langmuir binding model using Biacore Evaluation software. The kd value (rate of dissociation) was calculated for each sample of 3A5.040 supernatant throughout the run, and they were averaged to give the reference kd, except for run 2.1, which had only one sample of 3A5.040 supernatant (Table 3 and 6-11). The calculated kd value for each supernatant antibody was compared to the average reference kd 3A5.040 using the following formula:

(reference kd 3A5.040/kd variant antibody) x100 = proportional kd of parent antibody (% 3A5.040 kd)

Formula 2

Variant antibodies with a lower kd (slower dissociation rate) than the parent antibody 3A5.040 had a % 3A5.040 kd value >100%, and antibodies with a higher kd (faster dissociation rate) had a value <100%. This allowed the identification of variant antibodies that could improve IL-5 binding kinetics and therefore improve function compared to the parent antibody, 3A5.040. For variants in which only purified protein was obtained (Table 6), the Biacore kinetic assay was performed in triplicate as above using these purified antibodies, and the averages from each triplicate assay were used to perform the proportional kd calculation. as above (Tables 4 and 8-11).

Table 3

Determination of the titer of the antibody variant 3A5.040 in the supernatant and the kinetics of binding to IL-5 using Biacore

No. run Antibody ID Parallel analysis number Amino acid replacement Capture level ka (1/ms) kd (1/s) K _D (M) Rmax (RU) % FOR5,040 kd % titra ZA5.040 1.1 ZA5.040 1 wild type 51.6 7.20E+05 1D5E-04 1.60E-10 16.3 1.1 ZA5.040 2 wild type 51.6 7.27E+05 8.96E-05 1.23E-10 16.6 1.1 ZA5.040 3 wild type 51.8 7D8E+05 9.21Е-05 1.28E-10 16.7 1.1 ZA5.040 4 wild type 52 6.96E+05 9.95Е-05 1.43Е-10 16.8 1.1 ZA5.040 Average wild type 51.75 7.15E+05 9.91Е-05 1.39E-10 16.6 100 100 1.1 IgG4 isotype 54.4 N/A N/A N/A 0.7 N/A N/A 1.1 ZA5.040 (Cleaned) wild type 56.4 7D7E+05 1.06E-04 1.48Е-10 17.8 93.0 1.1 3A5.304 VHG26A 54.6 7.41E+05 7.73Е-05 1.04Е-10 17.1 128 49 1.1 3A5.305 VHG26S 53.1 7.36E+05 1.09Е-04 1.48Е-10 16.7 91 59 1.1 3A5.306 VHG26L 49.1 7.49E+05 8.74Е-05 1D7E-10 15.6 FROM 15 1.1 3A5.308 VHG26D 52.5 6.75E+05 8.57Е-05 1.27E-10 16.4 116 61 1.1 3A5.309 VHG26Q 55.1 7.47E+05 9.23Е-05 1.24Е-10 17.4 107 86 1.1 3A5.310 VHG26K 51.8 7.36E+05 1.01E-04 1.37E-10 16.4 98 100 1.1 3A5.311 VHG26H 50.9 7.60E+05 1D1E-04 1.46Е-10 16.3 89 85 1.1 3A5.312 VHG26W 56.1 8.54E+05 1.21E-04 1.41Е-10 18 82 107 1.1 3A5.313 VHG27A 54.5 6.97E+05 1D7E-04 1.68E-10 17.3 85 99 1.1 3A5.314 VHG27S 50.9 7D6E+05 9.81Е-05 1.37E-10 16.2 101 95 1.1 3A5.315 VHG27L 54.3 7.01E+05 1.31Е-04 1.87E-10 17.1 76 118 1.1 3A5.316 VHG27Y 56 6.66E+05 8.56Е-04 1.29Е-09 16.9 12 80 1.1 3A5.317 VHG27D 57.4 6.56E+05 1D6E-04 1.76E-10 17.8 85 73 1.1 3A5.318 VHG27Q 55.2 7.31E+05 1.49Е-04 2.04Е-10 17.4 67 82 1.1 3A5.319 VHG27K 54.8 7.70E+05 2.04Е-04 2.65E-10 17.5 49 95 1.1 3A5.320 VHG27H 54.4 7D2E+05 2.43Е-04 3.42E-10 16.9 41 71

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1.1 3A5.322 VHS28A 58 7.49E+05 l,05E-04 l,41E-10 18 94 62 1.1 3A5.323 VHS28L 53.8 7.18E+05 9.30E-05 l,30E-10 17 107 70 1.1 3A5.324 VHS28Y 54.8 8.13E+05 8.60E-05 l,06E-10 17 115 51 1.1 3A5.325 VHS28D 54.9 6.03E+05 9.16E-05 l,52E-10 17 108 68 1.1 3A5.326 VHS28Q 56.9 6.78E+05 9.97E-05 l,47E-10 17.7 99 77 1.1 3A5.327 VHS28K 53.7 7.22E+05 l,15E-04 l,59E-10 16.9 86 84 1.1 3A5.328 VHS28H 54 7.82E+05 l,23E-04 l,57E-10 16.9 81 71 1.1 3A5.329 VHS28W 55 8.33E+05 l,36E-04 l,63E-10 17 73 41 1.1 3A5.330 VHI29A 56.3 6.54E+05 l,69E-04 2.58E-10 16.8 59 thirty 1.1 3A5.331 VHI29S 53.3 5.87E+05 2.04E-04 3.48E-10 15.7 49 28 1.1 3A5.332 VHI29L 55.3 8.26E+05 l,16E-04 l,41E-10 17.5 85 75 1.1 3A5.333 VHI29Y 55.4 5.44E+05 9.31E-04 l,71E-09 15.7 eleven 24 1.1 3A5.334 VHI29D 52.8 3.53E+06 5.37E-03 l,52E-09 H.9 2 21 1.1 3A5.336 VHI29K 53.7 6.17E+05 6.75E-04 l,10E-09 14.8 15 29 1.1 3A5.338 VHI29W 56.6 l,31E+06 2.34E-03 l,78E-09 14.9 4 38 1.1 3A5.340 VHS30L 48.7 6.51E+05 l,47E-04 2.25E-10 15.6 67 153 1.1 3A5.341 VHS30Y 54.3 7.54E+05 l,37E-04 l,82E-10 17.3 72 103 1.1 3A5.342 VHS30D 54.9 6.17E+05 l,23E-04 2,OOE-10 17.4 81 103 1.1 3A5.347 VHN31A 53.8 7.53E+05 6.75E-04 8.97E-10 17.3 15 118 1.1 3A5.348 VHN31S 54.6 7.82E+05 5.03E-04 6.44E-10 17.7 20 107 1.1 3A5.350 VHN31Y 56.2 9.01E+05 8.80E-04 9.76E-10 17.6 eleven NE 1.1 3A5.351 VHN31D 59.8 6.40E+05 2.03E-04 3.17E-10 19.2 49 75 1.1 3A5.352 VHN31Q 54.8 6.93E+05 4.21E-04 6.07E-10 17.7 24 156 1.1 3A5.353 VHN31K 55.5 6.85E+05 7.54E-04 l,10E-09 17.7 13 170 1.1 3A5.354 VHN31H 53.7 7.63E+05 l,32E-04 l,73E-10 17.5 75 143 1.1 3A5.356 VHG32A 52.3 5.25E+05 3.02E-04 5.76E-10 16.4 33 179 1.1 3A5.357 VHG32S 49.2 6.02E+05 l,23E-03 2.04E-09 15.3 8 153 1.1 3A5.495 VHS94K 55 6.76E+05 2.91E-04 4.31E-10 17.6 34 127 1.1 3A5.497 VHS94W 56.8 l,67E+06 2.92E-03 l,75E-09 12.5 3 38 1.1 3A5.498 VHS94P 55.5 4.45E+05 l,17E-04 2.63E-10 16 85 17 1.1 3A5.500 VHL95S 2.7 NE NE 1.1 3A5.504 VHL95K 51.7 l,53E+06 3.12E-03 2.03E-09 11.3 67 1.1 3A5.505 VHL95H 52.9 5.59E+05 6.66E-04 l,19E-09 16.3 15 88 1.1 3A5.507 VHL95P 54.7 NB 40 1.1 3A5.509 VHG96S 54.4 5.94E+05 l,92E-04 3.23E-10 17 52 88 1.1 3A5.510 VHG96L 54 4.11E+O6 7.90E-03 l,92E-09 8.5 1 63 1.1 3A5.513 VHG96Q 54.8 4.45E+05 5.13E-04 l,15E-09 16.5 19 64 1.1 3A5.514 VHG96K 54.9 5.14E+06 6.84E-03 1.33E-O9 H.4 1 147 1.1 3A5.515 VHG96H 53.2 4.37E+05 l,20E-03 2.74E-09 15.3 8 117 1.1 3A5.516 VHG96W 53 l,31E+06 l,40E-02 l,07E-08 6.7 1 55 1.1 3A5.517 VHG96P 47.8 l,35E+05 5.04E-04 3.73E-09 H.7 20 15 1.1 3A5.518 VHN97A 52 5.35E+05 l,72E-04 3.21E-10 16.3 58 95 1.1 3A5.520 VHN97L 54.5 4.73E+05 1.11E-O4 2.35E-10 16 89 96 1.1 3A5.521 VHN97Y 54.7 5.05E+05 3.34E-04 6.62E-10 16.1 thirty 75 1.1 3A5.523 VHN97Q 53.7 5.06E+05 9.79E-05 l,94E-10 16.6 101 127 1.1 3A5.524 VHN97K 52.5 2.89E+05 l,37E-04 4.75E-10 15.1 72 167 1.1 3A5.525 VHN97H 53.1 4D1E+05 2.14E-04 5.20E-10 15 46 113 1.1 3A5.526 VHN97W 53.7 5.28E+05 5.26E-04 9.95E-10 15.5 19 56 1.1 3A5.527 VHN97P 55.1 4.21E+05 4.38E-04 l,04E-09 15.5 23 68 1.1 3A5.528 VHW98A 57.6 7.26E+05 l,87E-04 2.57E-10 18.4 53 114 1.1 3A5.529 VHW98S 53.9 6.23E+05 2.36E-04 3.78E-10 16.8 42 83 1.1 3A5.530 VHW98L 54.3 3.38E+05 l,72E-04 5.08E-10 14.9 58 38

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1.1 3A5.531 VHW98Y 56.3 7D5E+05 1D2E-04 1.56E-10 18.1 88 143 1.1 3A5.532 VHW98D 56.4 2D7E+05 8.87Е-05 4.09Е-10 14.6 112 42 1.1 3A5.533 VHW98Q 53.8 5D1E+05 1.54Е-04 3.08E-10 15.8 64 51 1.1 3A5.534 VHW98K 53.4 3.46E+05 8.25Е-04 2.38Е-09 I,5 12 73 1.1 3A5.535 VHW98H 53.8 6DZE+05 1.45Е-04 2.37E-10 17 68 81 1.1 3A5.536 VHW98P 56.1 9.97E+04 8D7E-04 8.20E-09 14.2 12 31 1.1 3A5.537 VH-F99A 54.2 1.54E+05 4.90E-04 ZD8E-09 13.7 20 37 1.1 3A5.538 VH F99S 53.3 1D8E+05 1.02E-03 8.67Е-09 9.9 10 40 1.1 3A5.539 VH F99L 54.2 7D5E+05 1D5E-04 1.63Е-10 16.7 86 55 1.1 3A5.540 VHF99Y 55.6 5.27E+05 9DZE-05 1.73Е-10 14.9 109 41 1.1 3A5.541 VH F99D 53.9 1.46E+05 1D1E-02 7.56Е-08 4.4 1 32 1.1 3A5.542 VHF99Q 53.8 9.93E+04 1.00Е-03 1.01Е-08 13 10 35 1.1 3A5.543 VH F99K 54.6 NB 38 1.1 3A5.544 VHF99H 54.8 2D5E+05 9.50Е-05 4.64Е-10 14.5 104 41 1.1 3A5.545 VH F99W 54.5 5.35E+04 4.09Е-04 7.66Е-09 6 24 29 1.1 3A5.546 VHF99P 53.1 NB 43 1.1 3A5.547 VH-D101A 55.6 1.68E+05 1.40E-04 8.37E-10 14.7 71 69 1.1 3A5.548 VHD101S 55.2 2.38E+05 1D1E-04 4.67E-10 15.3 89 78 1.1 3A5.549 VH-D101L 53.6 5.94E+05 4.76E-04 8.01Е-10 16.3 21 43 1.1 3A5.551 VHD101Q 54.5 5.93E+05 2D9E-04 3.69E-10 17.1 45 78 1.2 3A5.040 1 wild type 50.3 7.40E+05 1,ZZE-04 1.80E-10 16.3 1.2 3A5.040 2 wild type 50.3 7D4E+05 8.22E-05 1D5E-10 16.1 1.2 3A5.040 wild type 50 7.28E+05 1.01E-04 1.39E-10 16.1 1.2 3A5.040 4 wild type 50.2 7.32E+05 1D0E-04 1.50E-10 16.2 1.2 3A5.040 5 wild type 50.1 7.27E+05 9.36Е-05 1.29E-10 16.1 1.2 3A5.040 Average wild type 50.2 7.28E+05 1.04Е-04 1.43Е-10 16.2 100 100 1.2 IgG4 isotype 50.8 N/A N/A N/A 0 N/A 1.2 ZA5.040 (Cleaned) wild type 52.6 7.35E+05 1D1E-04 1.51Е-10 16.6 94 1.2 3A5.553 VHD101H 51.9 4.41E+05 1.63E-04 3.69E-10 15.5 64 66 1.2 ZA5.555 VHD101P 51.3 7.54E+03 8.00Е-04 1.06E-07 23.6 13 39 1.2 ZA5.556 VH_Y102A 50.6 6.60E+05 8.94Е-05 1.35E-10 16.4 116 106 1.2 ZA5.557 VH_Y102S 53.5 6.85E+05 1D1E-04 1.61E-10 17.2 94 135 1.2 ZA5.558 VH_Y102L 53.2 7.40E+05 1D4E-04 1.54Е-10 16.8 91 51 1.2 ZA5.559 VHY102D 52.8 7.03E+05 1.41Е-04 2.01E-10 16.7 74 51 1.2 ZA5.560 VHY102Q 52.6 7D4E+05 1.08E-04 1.51Е-10 16.9 96 87 1.2 ZA5.561 VHY102K 55.9 7.23E+05 8.01Е-05 1D1E-10 17.7 130 90 1.2 ZA5.562 VHY102H 50.4 7.22E+05 1.00Е-04 1.39E-10 16.4 104 132 1.2 3A5.563 VHY102W 50.9 7.51E+05 1D6E-04 1.54Е-10 16.8 90 117 1.2 ZA5.564 VH_Y102P 53 6.44E+05 1.29Е-04 2.01E-10 15 81 32 2.1 ZA5.040 1 wild type 68.5 7DZE+05 1D6E-04 1.63Е-10 22.6 2.1 ZA5.040 Average wild type 68.5 7DZE+05 1.16E-04 1.63Е-10 22.6 100 100 2.1 IgG4 isotype 60.7 N/A N/A N/A 1.6 N/A 2.1 ZA5.040 (Cleaned) wild type 75.6 7.37E+05 1.05Е-04 1.42Е-10 24.3 110 2.1 ZA5.048 VLG24A 69 7D6E+05 9D8E-05 1.28E-10 22.7 126 104 2.1 ZA5.049 VLG24S 72.5 6.98E+05 1.03Е-04 1.47Е-10 23.7 FROM 104 2.1 FOR5.050 VLG24L 73.8 6.79E+05 8DZE-05 1.20E-10 23.9 143 103 2.1 ZA5.051 VLG24Y 61.7 6.40E+05 1D2E-04 1.75E-10 20.3 104 91 2.1 ZA5.052 VLG24D 66.7 7D6E+05 9.71Е-05 1.36E-10 21.9 119 104

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2.1 3A5.053 VLG24Q 72.6 6.99E+05 9.84Е-05 1.41Е-10 23.6 118 95 2.1 3A5.054 VLG24K 74.2 7D2E+05 9.59Е-05 1.35E-10 24.1 121 98 2.1 3A5.055 VLG24H 60.9 6.90E+05 9D7E-05 1,ZZE-10 20.2 126 99 2.1 3A5.056 VLG24W 64.4 6.41E+05 8.06Е-05 1.26E-10 21D 144 111 2.1 3A5.057 VLG25A 69.9 7.04E+05 8.75Е-05 1.24Е-10 22.9 133 109 2.1 3A5.059 VLG25L 63.1 7D6E+05 1.04Е-04 1.45E-10 21 112 83 2.1 3A5.060 VLG25Y 67.7 7D5E+05 8.55Е-05 1.21E-10 22.2 136 96 2.1 3A5.061 VLG25D 71.9 7.26E+05 1D1E-04 1.53Е-10 23.4 105 94 2.1 3A5.062 VLG25Q 73.2 6.52E+05 9.24Е-05 1.42Е-10 23.5 126 94 2.1 3A5.064 VLG25H 60.4 6.90E+05 9.21Е-05 1,ZZE-10 20.1 126 108 2.1 3A5.065 VLG25W 70.8 7.37E+05 8.97Е-05 1.22E-10 23.1 129 81 2.1 3A5.066 VL_N26A 76.8 7.27E+05 8.75Е-05 1.20E-10 24.7 133 77 2.1 3A5.069 VLN26Y 71.2 6.79E+05 8.73Е-05 1.28E-10 22.9 133 100 2.1 3A5.070 VLN26D 62.7 7.22E+05 7.87Е-05 1.09Е-10 20.7 147 95 2.1 3A5.071 VLN26Q 67.4 7D5E+05 1.08E-04 1.53Е-10 22 107 95 2.1 3A5.072 VLN26K 69.7 7.04E+05 1D7E-04 1.66E-10 22.7 99 99 2.1 3A5.073 VLN26H 74.8 7D5E+05 1D1E-04 1.55Е-10 24 105 95 2.1 3A5.074 VLN26W 62.6 6.41E+05 9.82Е-05 1.53Е-10 20.3 118 87 2.1 3A5.075 VL_N27A 62.7 6.55E+05 9.29E-05 1.42Е-10 20.7 125 120 2.1 3A5.076 VL_N27S 71.7 7.04E+05 1.09Е-04 1.55Е-10 23.2 106 93 2.1 3A5.077 VL_N27L 71.7 6.73E+05 8.98E-05 1,ZZE-10 23.4 129 102 2.1 3A5.078 VL_N27Y 61.5 6D6E+05 1.02E-04 1.65E-10 20.3 114 103 2.1 3A5.080 VLN27Q 68.3 6.52E+05 1.07Е-04 1.64Е-10 22.1 108 91 2.1 3A5.081 VL_N27K 71.5 6.89E+05 8.84Е-05 1.28E-10 23.2 131 96 2.1 3A5.082 VLN27H 74.7 7.06E+05 7.85Е-05 1.11E-10 24.1 148 90 2.1 3A5.084 VLI28A 62.1 6.71E+05 6.20E-05 9.24Е-11 20.3 187 91 2.1 3A5.085 VLI28S 91.9 6.37E+05 1D6E-04 1.82Е-10 31.3 100 47 2.1 3A5.086 VLI28L 81.5 6.02E+05 1.04Е-04 1.73Е-10 27.2 112 62 2.1 3A5.087 VLI28Y 73.1 7D7E+05 8.52Е-05 1.20E-10 23.8 136 93 2.1 3A5.088 VLI28D 80.3 5.56E+05 9.83Е-05 1.77E-10 27.9 118 40 2.1 3A5.089 VLI28Q 79.8 5.80E+05 1.03Е-04 1.77E-10 27.8 FROM 54 2.1 3A5.093 VLG29A 68.4 5.42E+05 1D0E-04 2.04Е-10 22.6 105 59 2.1 3A5.094 VL_G29S 67.6 6.98E+05 9.31Е-05 1,ZZE-10 21.9 119 93 2.2 3A5.040 1 wild type 52.4 7.77E+05 1.05Е-04 1.35E-10 17.9 2.2 3A5.040 2 wild type 52.7 7.89E+05 1.09Е-04 1.38E-10 17.9 2.2 3A5.040 3 wild type 52.7 7.72E+05 1.37Е-04 1.77E-10 18.1 2.2 3A5.040 Average wild type 52.6 7.79E+05 1D7E-04 1.50E-10 17.9 100 100 2.2 IgG4 isotype 56.6 N/A N/A N/A 0.5 N/A 2.2 ZA5.040 (Cleaned) wild type 54.9 7.93E+05 1.06E-04 1,ZZE-10 18.7 110 2.2 ZA5.095 VL_G29L 55.4 7D7E+05 9.08Е-05 1.27E-10 18.7 122 75 2.2 ZA5.096 VLG29Y 56.7 6.92E+05 1,ZZE-04 1.92E-10 19.2 83 58 2.2 ZA5.097 VLG29D 56.2 7.31E+05 7D9E-05 9.84Е-11 18.7 154 85 2.2 FOR5.099 VLG29K 49.9 7D8E+05 9.08Е-05 1.26E-10 17.2 122 71 2.2 FOR5.100 VLG29H 52 7.38E+05 8.65Е-05 1D7E-10 17.7 128 100 2.2 FOR5.101 VLG29W 55.8 7.59E+05 9.40E-05 1.24Е-10 18.7 118 114 2.2 FA5.102 VL_S30A 56.3 6.85E+05 1.09Е-04 1.58E-10 18.7 102 84 2.2 ZA5.1oz VLS30L 49.5 7.87E+05 9.94Е-05 1.26E-10 16.9 112 126 2.2 FA5.104 VL_S30Y 54.7 8D7E+05 1.08E-04 1,ZZE-10 18.5 103 93 2.2 FOR5.105 VLS30D 56.4 8.20E+05 8.91Е-05 1.09Е-10 18.8 125 119 2.2 FA5.106 VL_S30Q 58.3 7.22E+05 9D0E-05 1.26E-10 19.7 122 78

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2.2 3A5.107 VLS30K 50.6 7.85E+05 7.34Е-05 9.34Е-11 17.3 151 102 2.2 3A5.113 VLK31Y 53.8 8.35E+05 8.73Е-05 1.05E-10 18.4 127 99 2.2 3A5.114 VLK31D 54.5 4.89E+05 4.73Е-04 9.65E-10 17.9 23 105 2.2 3A5.115 VLK31Q 57.9 4.65E+05 4.60E-04 9.91Е-10 19 24 85 2.2 3A5.116 VLK31H 49.5 5.52E+05 2.46Е-04 4.46E-10 16.7 45 104 2.2 3A5.117 VLK31W 52.7 5.34E+05 1,ZZE-04 2.49Е-10 17.7 83 125 2.2 3A5.118 VL_N32A 55.8 5.07E+05 6.39Е-04 1.26E-09 18.3 17 67 2.2 3A5.121 VL_N32Y 56.1 9.57E+05 9.68Е-05 1.01E-10 19.1 115 91 2.2 3A5.122 VLN32D 49.8 5.68E+05 1.25E-04 2.20E-10 15.8 89 115 2.2 3A5.123 VL-N32Q 53.9 8.85E+05 1.25E-04 1.41Е-10 18.6 89 102 2.2 3A5.125 VLN32H 56.4 9.01E+05 7.73Е-05 8.58E-11 19.2 144 90 2.2 3A5.126 VL_N32W 56.6 6.35E+05 9.26Е-05 1.46Е-10 18.8 120 79 2.2 3A5.127 VLV33A 49.1 7D5E+05 8.05Е-05 1.13E-10 16.6 138 74 2.2 3A5.128 VLV33S 51.5 2.85E+05 9.65Е-05 3.38E-10 13.7 115 126 2.2 3A5.130 VLV33Y 56.1 7.41E+05 9.16Е-05 1.24Е-10 19 121 68 2.2 3A5.131 VLV33D 52.4 7.40E+05 9.67Е-05 1.31E-10 19.3 115 40 2.2 3A5.132 VLV33Q 48.7 6.61E+05 1.38E-04 2.09Е-10 16.7 80 50 2.2 3A5.135 VLV33W 48.4 5.26E+05 1.04Е-04 1.99E-10 18.8 107 24 2.2 3A5.137 VL_Y34S 48.3 6.96E+05 9.88Е-05 1.42Е-10 19 112 32 2.2 3A5.138 VLY34L 49.4 5.94E+05 2.16E-04 3.64Е-10 16.6 51 56 2.2 3A5.139 VLY34D 52.8 4.63E+05 4.90E-04 1.06E-09 13.1 23 68 2.2 3A5.140 VLY34Q 54.4 7.01E+05 5.40E-04 7.71E-10 18.2 21 55 2.2 3A5.141 VLY34K 56 8D6E+05 3.72E-04 4.56E-10 18.8 thirty 64 2.2 3A5.142 VLY34H 48.8 6.71E+05 5.00Е-04 7.46E-10 16.3 22 82 2.2 3A5.143 VLY34W 53.5 6.98E+05 2D9E-03 ZDZE-09 9.7 5 58 2.2 3A5.165 VLS52K 52.6 5.32E+05 9, ZOE-04 1.75Е-09 16.6 12 167 2.2 3A5.168 VLD53A 57.2 1.20E+06 2.04Е-03 1.71Е-09 17.1 5 51 2.2 3A5.172 VLD53Q 50.3 7DZE+05 1.08E-04 1.51Е-10 17.1 103 97 2.2 3A5.174 VLD53H 53 7.45E+05 1.23E-04 1.65E-10 17.7 90 120 2.2 3A5.186 VLP55S 55.8 7.97E+05 1.08E-04 1.35E-10 18.6 103 108 2.2 3A5.199 VLS56K 57.3 7.71E+05 1.18E-04 1.54Е-10 18.8 94 104 2.2 3A5.201 VLS56W 49.6 7.41E+05 1.24Е-04 1.67E-10 17.1 90 92 2.2 3A5.210 VLQ89P 53.5 3.80E+05 4.78E-04 1.26E-09 18 25 72 2.2 3A5.211 VL_V90A 55.7 7.65E+05 1.06E-04 1.39E-10 18.8 105 78 3.1 3A5.040 1 wild type 53.3 7.72E+05 1.32E-04 1.71Е-10 18.2 3.1 3A5.040 2 wild type 53.4 7.76E+05 1D5E-04 1.48Е-10 18.1 3.1 3A5.040 3 wild type 53.3 7.73E+05 1.03Е-04 1.34Е-10 18.1 3.1 3A5.040 4 wild type 54 7.69E+05 1.14Е-04 1.49Е-10 18.5 3.1 3A5.040 5 wild type 53.8 7.84E+05 1.20E-04 1.53Е-10 18.4 3.1 3A5.040 Average wild type 53.6 7.75E+05 1.17E-04 1.51Е-10 18.2 100 100 3.1 IgG4 isotype 56 N/A N/A N/A 0.7 N/A 3.1 ZA5.040 (Cleaned) wild type 52.5 8.07E+05 1.40E-04 1.74Е-10 17.9 83 3.1 3A5.213 VLV90L 53.7 7.49E+05 1.55Е-04 2.06Е-10 18.2 75 58 3.1 FOR5.214 VL_V90Y 54 6.50E+05 2.92E-04 4.49Е-10 18 40 85 3.1 FOR5.215 VLV90D 52.9 5.54E+05 4D9E-04 7.56E-10 19.9 28 27 3.1 FOR5.216 VLV90Q 48.6 5.93E+05 1.88Е-04 3.18E-10 16.3 62 74 3.1 FOR5.217 VLV90K 44.3 6.34E+05 8, ZOE-05 1.31E-10 17 141 48 3.1 FOR5.218 VLV90H 47.5 5.90E+05 2.99E-04 5.07Е-10 17.6 39 60 3.1 FOR5.219 VL_V90W 53.4 5.69E+05 6.64Е-04 1.17E-09 17.9 18 77 3.1 FOR5.220 VLV90P 47.7 2.72E+05 7.61E-03 2.79Е-08 1.7 2 76

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3.1 3A5.221 VLW91A 51.8 3.05E+05 7.08E-03 2.32E-08 2.4 2 79 3.1 3A5.223 VLW91L 53.6 2.59E+06 2.55E-02 9.83E-09 7.7 0 98 3.1 3A5.224 VL_W91Y 45.1 8.82E+05 9.03E-04 l,02E-09 15.8 13 64 3.1 3A5.226 VLW91Q 51.1 5.38E+06 3.79E-02 7.05E-09 6.8 0 75 3.1 3A5.227 VLW91K 51.8 NB 71 3.1 3A5.228 VLW91H 50.9 l,53E+06 7.24E-03 4.74E-09 9 2 62 3.1 3A5.229 VLW91P 39.4 4.02E+05 7.40E-03 l,84E-08 1.4 2 36 3.1 3A5.23O VLD92A 51.2 5.63E+05 9.94E-05 l,77E-10 16.5 118 113 3.1 3A5.231 VLD92S 53.2 7.67E+05 9.46E-05 l,23E-10 17.5 124 113 3.1 3A5.232 VLD92L 54.3 9.17E+05 7.59E-05 8.27E-11 18 154 130 3.1 3A5.233 VLD92Y 47.7 1.11E+O6 Ι,ΙΟΕ-04 9.92E-11 16.4 106 72 3.1 3A5.234 VL_D92Q 50.9 5.25E+05 l,39E-04 2.64E-10 15.7 84 194 3.1 3A5.235 VLD92K 54.7 7.63E+05 8.84E-05 l,16E-10 18 132 92 3.1 3A5.236 VLD92H 54.3 7.93E+05 l,09E-04 l,37E-10 17.6 107 122 3.1 3A5.237 VLD92W 0.5 NE NE 3.1 3A5.238 VL_D92P 46.8 5.21E+05 l,43E-04 2.75E-10 16.1 82 63 3.1 3A5.239 VL_S93A 52.2 ZD2E+06 3.65E-03 1D7E-09 15.9 3 112 3.1 3A5.240 VLS93L 54.8 2.39E+07 2.45E-01 l,03E-08 6.5 0 124 3.1 3A5.241 VLS93Y 50.1 6.20E+05 7.48E-03 l,21E-08 2 2 118 3.1 3A5.242 VLS93D 51.6 5.18E+05 l,68E-02 3.25E-08 2.9 1 73 3.1 3A5.243 VLS93Q 54.4 l,90E+06 l,51E-02 7.95E-09 8.2 1 111 3.1 3A5.244 VL_S93K 55.5 NB 162 3.1 3A5.245 VLS93H 49.7 2.92E+06 2.23E-02 7.64E-09 7.3 1 133 3.1 3A5.246 VLS93W 52.8 3.27E+05 4.33E-03 l,33E-08 0.8 3 115 3.1 3A5.247 VLS93P 53.8 6.94E+05 5.33E-02 7.68E-08 1.7 0 112 3.1 3A5.248 VL_S94A 56.1 8.15E+05 l,22E-04 l,50E-10 19.1 96 101 _____________ 3.1 3A5.249 VLS94L 49.7 7.81E+05 5.00E-04 6.41E-10 17.1 23 90 3.1 3A5.253 VL_S94K 53 6.74E+05 l,48E-04 2.20E-10 17.9 79 109 3.1 3A5.254 VLS94H 53.7 6.24E+05 l,51E-04 2.42E-10 18.1 77 104 3.1 3A5.256 VLS94P 49.7 6.97E+05 l,27E-04 l,82E-10 16.7 92 139 3.1 3A5.257 VL_S95A 52.1 7.34E+05 1D9E-04 l,62E-10 17.7 98 99 3.1 3A5.258 VLS95L 54 7.73E+05 1DZE-04 l,47E-10 18.3 104 99 3.1 3A5.259 VLS95Y 55.7 8.35E+05 l,07E-04 l,28E-10 18.7 109 83 3.1 3A5.260 VLS95D 49.2 6.07E+05 l,25E-04 2.07E-10 16.5 94 109 3.1 3A5.261 VL_S95Q 48.6 7.87E+05 9D9E-05 1D7E-10 17.8 127 62 3.1 3A5.262 VLS95K 53.1 7.99E+05 l,01E-04 l,26E-10 18.2 116 118 3.1 3A5.263 VLS95H 55.4 7.83E+05 1.00E-04 l,28E-10 18.7 117 101 3.1 3A5.264 VLS95W 49 7.95E+05 l,27E-04 l,60E-10 16.5 92 87 3.1 3A5.265 VL_S95P 52.7 6.45E+05 5.55E-03 8.61E-09 7.1 2 147 3.1 3A5.266 VL_D95aA 53.7 5.78E+06 8.07E-03 l,40E-09 10.4 1 109 3.1 3A5.267 VL_D95aS 55.3 4.53E+05 l,21E-03 2.68E-09 16.7 10 101 3.1 3A5.268 VL_D95aL 48.5 9.19E+06 l,35E-02 l,47E-09 8.7 1 71 3.1 3A5.269 VL_D95aY 51.8 l,77E+06 6.74E-03 3.80E-09 8 2 95 3.1 3A5.270 VL_D95aQ 53.6 5.26E+06 7D1E-03 l,35E-09 H.4 2 110 3.1 3A5.271 VL_D95aK 53.8 3.92E+05 3.83E-02 9.77E-08 2 0 70 3.1 3A5.272 VL_D95aH 49.7 2.56E+06 4.90E-03 l,92E-09 10.1 2 188 3.1 3A5.273 VL_D95aW 53.1 l,27E+06 l,47E-02 1D5E-08 7.1 1 94 3.1 3A5.274 VL_D95aP 54.6 1D7E+06 3.05E-03 2.61E-09 9.8 4 150 3.1 3A5.276 VL_H95bS 52.1 8.47E+05 7.33E-05 8.66E-11 19.6 160 61 3.1 3A5.281 VL_H95bK 45.5 7.08E+05 9.58E-05 l,35E-10 16.3 122 64 3.1 3A5.307 VHG26Y 48.1 8.73E+05 l,02E-04 1D7E-10 18.3 115 60 3.1 3A5.321 VHG27W 55 7.64E+05 5.59E-04 7.31E-10 18.4 21 97

- 22 042576

3.1 3A5.335 VHI29Q 37.9 5.64E+05 3.90E-04 6.92E-10 14.9 thirty 37 3.1 3A5.343 VHS30Q 51.9 7.55E+05 l,06E-04 l,40E-10 17.7 110 121 3.1 3A5.344 VHS30K 53.9 7.41E+05 l,39E-04 l,88E-10 18 84 156 3.1 3A5.345 VHS30H 54.8 7.34E+05 l,46E-04 l,99E-10 18.7 80 77 3.1 3A5.349 VHN31L 47.1 7.69E+05 7DZE-04 9.27E-10 16.3 16 69 3.1 3A5.355 VHN31W 45.3 8.52E+05 4.80E-04 5.63E-10 17.3 24 59 3.1 3A5.359 VH_G32Y 53.7 3.28E+06 4.30E-03 l,31E-09 15.5 3 90 3.1 3A5.360 VHG32D 54.2 l,05E+06 6.78E-03 6.44E-09 8D 2 105 3.1 3A5.361 VHG32Q 49.5 3.98E+06 6.22E-03 l,56E-09 H.8 2 133 3.1 3A5.362 VHG32K 52.6 6.07E+05 2.20E-03 3.62E-09 7.6 5 171 3.1 3A5.363 VHG32H 55.4 l,81E+06 3.01E-03 l,66E-09 15.3 4 114 3.1 3A5.364 VH_G32W 52.3 l,46E+07 l,27E-02 8.65E-10 13.5 1 66 3.1 3A5.365 VHG33A 48.7 6.97E+05 9.24E-05 l,33E-10 16.6 127 116 3.1 3A5.366 VHG33S 53 8.56E+05 2.68E-03 ZD4E-09 8.3 4 117 3.1 3A5.367 VHG33L 54.2 8.03E+05 3.05E-04 3.79E-10 17.9 38 82 3.1 3A5.368 VHG33Y 55.4 3.97E+06 4.08E-03 l,03E-09 13.4 3 107 3.2 3A5.040 1 wild type 54.7 6.75E+05 9.46E-05 l,40E-10 19 3.2 3A5.040 2 wild type 55.2 6.82E+05 7.26E-05 l,07E-10 19 3.2 3A5.040 3 wild type 55.7 7D7E+05 9.30E-05 l,30E-10 19.3 3.2 3A5.040 4 wild type 55.3 7.08E+05 8.82E-05 l,25E-10 19.1 3.2 3A5.040 5 wild type 55.2 6.95E+05 l,05E-04 l,51E-10 19.2 3.2 3A5.040 Average wild type 55.2 6.95E+05 9.07E-05 l,31E-10 19.1 100 100 3.2 IgG4 isotype 55.8 N/A N/A N/A 0 N/A 3.2 ZA5.040 (Cleaned) wild type 54.5 7D2E+05 8.25E-05 1D6E-10 l,85E+01 110 3.2 3A5.369 VHG33D 52.4 9.85E+05 2.46E-03 2.50E-09 9.4 4 277 3.2 3A5.370 VHG33Q 54.5 5.33E+05 l,07E-03 2.00E-09 17.2 8 279 3.2 3A5.371 VHG33K 58.5 2.08E+06 2.02E-03 9.72E-10 14.1 4 350 3.2 3A5.372 VHG33H 51.5 l,45E+06 2.67E-03 l,83E-09 14.4 273 3.2 3A5.373 VHG33W 52.4 6.71E+05 l,32E-03 l,96E-09 15.9 7 172 3.2 3A5.374 VHY34A 56.4 5.91E+05 l,27E-04 2D6E-10 19.2 71 162 3.2 3A5.375 VHY34S 56.4 6.23E+05 l,24E-04 2,OOE-10 19.1 73 159 3.2 3A5.376 VHY34L 50 5.79E+05 l,60E-04 2.77E-10 17.2 57 160 3.2 3A5.377 VHY34D 54.7 5.40E+05 6.04E-04 1D2E-09 18.1 15 103 3.2 3A5.378 VHY34Q 54.4 5.98E+05 l,51E-04 2.53E-10 18.5 60 165 3.2 3A5.379 VHY34K 56.6 6D7E+05 4.91E-04 7.96E-10 19.1 18 407 3.2 3A5.38O VHY34H 49.8 6.40E+05 7.06E-04 1D0E-09 16.7 13 223 3.2 3A5.382 VHY35A 52.8 2.48E+05 2.46E-03 9.91E-09 0.9 4 289 3.2 3A5.383 VHY35S 55.8 3.34E+05 8.50E-03 2.54E-08 1.9 1 129 3.2 3A5.384 VHY35L 57 5.98E+05 l,42E-03 2.37E-09 17.5 6 190 3.2 3A5.385 VHY35D 48.5 2.75E+06 6DZE-OZ 2.23E-09 8.1 1 87 3.2 3A5.386 VHY35Q 51.8 1D8E+07 2.72E-01 2.31E-08 5.4 0 127 3.2 3A5.387 VHY35K 56.2 NB 382 3.2 3A5.388 VHY35H 58 3.40E+05 9.25E-03 2.72E-08 3.3 1 195 3.2 3A5.389 VHY35W 50 3.65E+06 5.41E-03 l,48E-09 8.8 2 225 3.2 3A5.390 VH_W35aA 47 6.84E+05 l,74E-03 2.55E-09 15.4 5 37 3.2 3A5.392 VH_W35aL 55 4.59E+05 1D4E-03 2.49E-09 17.1 8 100 3.2 3A5.393 VH_W35aY 49.1 6.34E+05 l,87E-04 2.94E-10 16.7 49 104 3.2 3A5.394 VH_W35aD 0.7 NE NE 3.2 3A5.395 VH_W35aQ 50.4 5.46E+05 8.47E-04 l,55E-09 18.8 eleven 34 3.2 3A5.397 VH_W35aH 39.6 5D7E+05 2.44E-04 4.82E-10 15.8 37 53

- 23 042576

3.2 3A5.399 VH_S35bL 46 1.08E+05 2.86E-04 2.64E-09 14D 32 39 3.2 3A5.400 VH_S35bY 51.7 4.43E+05 7.06E-03 l,59E-08 1.8 1 88 3.2 3A5.402 VH_S35bQ 38.8 l,84E+05 5D5E-04 2.80E-09 13.6 18 45 3.2 3A5.404 VH_S35bH 48.8 6D8E+05 l,88E-03 3.05E-09 13.3 5 75 3.2 3A5.405 VH_S35bW 49.6 2.93E+05 7D9E-03 2.45E-08 0.7 1 50 3.2 3A5.406 VHY50A 50.6 4.79E+05 5.88E-04 l,23E-09 16D 15 268 3.2 3A5.407 VHY50S 56.1 4.95E+05 3.64E-04 7.34E-10 17.5 25 327 3.2 3A5.408 VHY50L 57 4.31E+05 3.22E-04 7.46E-10 17.3 28 122 3.2 3A5.409 VHY50D 56.9 7.63E+05 l,45E-03 l,90E-09 16 6 169 3.2 3A5.410 VHY50Q 50.9 5.95E+05 3.69E-04 6.20E-10 17D 25 241 3.2 3A5.411 VHY5OK 53.5 5.51E+05 4.47E-04 8D1E-10 17.5 20 135 3.2 3A5.412 VHY50H 55.5 6.72E+05 7.88E-04 1D7E-09 18.2 12 300 3.2 3A5.413 VHY50W 57.2 6.67E+05 l,61E-03 2.41E-09 16.9 6 131 3.2 3A5.414 VHI51A 51.9 7.29E+05 1DZE-04 l,56E-10 17.7 80 244 3.2 3A5.415 VHI51S 54.2 7.38E+05 1D5E-04 l,56E-10 18.6 79 130 3.2 3A5.416 VHI51L 54.6 6.62E+05 l,39E-04 2D0E-10 19 65 87 3.2 3A5.417 VHI51Y 57.2 5.42E+05 7.77E-03 l,43E-08 7.9 1 106 3.2 3A5.418 VHI51D 40.4 5D5E+05 6.36E-04 l,23E-09 15.8 14 48 3.2 3A5.419 VHI51Q 51.6 6.26E+05 5.02E-04 8.01E-10 17.7 18 95 3.2 3A5.420 VHI51K 53.3 7.42E+05 1D6E-03 l,57E-09 17.3 8 124 3.2 3A5.421 VHI51H 54.1 7.46E+06 8.34E-03 1D2E-09 13.4 1 93 3.2 3A5.422 VHI51W 49.7 ZD8E+05 3.31E-03 l,04E-08 0.9 3 139 3.2 3A5.423 VHY52A 54.9 l,49E+07 l,08E-02 7.23E-10 H.8 1 304 3.2 3A5.424 VHY52S 57.3 6.79E+05 l,29E-03 l,89E-09 H.7 7 325 3.2 3A5.425 VHY52L 59.4 l,90E+06 8.83E-03 4.66E-09 YUD 1 209 3.2 3A5.426 VHY52D 51.7 NB 333 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3A5.427 3A5.428 3A5.429 3A5.430 3A5.431 3A5.432 3A5.433 3A5.434 3A5.435 3A5.436 3A5.437 3A5.438 3A5.439 3A5.440 3A5.441 3A5.442 3A5.443 3A5.444 3A5.445 3A5.446 3A5.447 VHY52Q VHY52K VHY52H VHY52W VHY53A VHY53S VHY53L VHY53D VHY53Q VHY53K VHY53H VHY53W VHS54A VHS54L VHS54Y VHS54D VHS54Q VHS54K VHS54H VHS54W VHG55A 55.5 58.4 61.5 48.6 53 55 57.3 50.8 53.4 56.7 57 49.2 53.1 53.4 55 51.4 54 55.6 57.5 46.7 45.7 l,86E+06 5.62E+05 6.79E+05 6.79E+05 6.94E+05 6.02E+05 4.80E+05 6.27E+05 6D7E+05 6.71E+05 6.91E+05 6.98E+05 9D7E+06 l.57E+06 8.06E+05 6.04E+05 2.65E+06 7D0E+05 7.24E+05 6.76E+05 8.86E-03 2.91E-04 l.26E-03 5.21E-04 l.57E-04 4.43E-04 5.94E-04 4.41E-04 9.61E-04 l,91E-04 2.35E-04 l.54E-04 8.95E-03 2D7E-03 2.02E-03 l.07E-03 3.55E-03 4.59E-04 8.68E-04 l.05E-04 4.76E-09 5D7E-10 l.86E-09 7.67E-10 2.26E-10 7.36E-10 l.24E-09 7.03E-10 l.56E-09 2.85E-10 3.40E-10 2, 20E-10 9.76E-10 l.38E-09 2.50E-09 l,77E-09 l,34E-09 6.46E-10l,20E-09 l,55E-10 9.2 20.6 15.9 17.9 18.8 19D 16.6 17.9 18D 19D 16.8 18D 13.6 16.5 14.4 17.6 15.5 19.3 14.8 17D 1NB 31 7 17 58 20 15 21 9 47 39 59 1 4 4 8 20 10 86 264 348 286 102 249 226 102 182 206 232 206 152 112 158 92 200 150 201 97 112 68 3.2 3A5.448 VHG55S 48.4 7.30E+05 l,24E-04 l,70E-10 18 73 72 3.2 3A5.449 VHG55L 47.7 6D4E+05 6.30E-04 l,03E-09 17.7 14 66 3.2 3A5.450 VHG55Y 38.6 6.88E+05 7.06E-04 l,03E-09 14.2 13 49 4.1 3A5.040 1 wild type 82.7 l,00E+06 1D6E-04 1D6E-10 24.9

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4.1 3A5.040 2 wild type 82.7 1.02E+06 1.07Е-04 1.04Е-10 25.1 4.1 3A5.040 3 wild type 85.2 1.03E+06 1D2E-04 1.09Е-10 25.1 4.1 3A5.040 4 wild type 85.1 1.01E+06 1.06E-04 1.05E-10 25.3 4.1 3A5.040 5 wild type 83.5 9.91E+05 9.29E-05 9.37E-11 25.3 4.1 3A5.040 Average wild type 83.84 1.01E+06 1.07Е-04 1.06Е-10 25.14 100 100 4.1 IgG4 isotype 61.4 N/A N/A N/A 0 N/A 4.1 ZA5.040 (Cleaned) wild type 84.2 1.06E+06 1.09Е-04 1, OZE-10 23.8 98 4.1 3A5.133 VLV33K 52.7 7.83E+05 1.34Е-04 1.71Е-10 15.9 80 15 4.1 FOR5.222 VL_W91S 62.8 1.38E+06 2.85Е-03 2.06Е-09 12.5 4 14 4.1 3A5.391 VH_W35aS 68.4 6.35E+05 1D9E-03 1.87Е-09 15.6 9 22 4.1 3A5.396 VH_W35aK 65.9 7.21E+05 2.08E-03 2.88Е-09 9.4 5 26 4.1 ZA5.401 VH_S35bD 53.1 5.96E+05 1D9E-04 2.01E-10 14.5 90 16 4.1 FOR5.4oz VH_S35bK 53.1 1.83E+05 1.23E-02 6.68Е-08 2.8 1 12 4.1 FOR5.275 VL_H95bA 69.7 5.47E+05 1.62E-04 2.95E-10 18 66 24 4.1 FOR5.282 VL_H95bW 77.5 7D8E+05 1.07Е-04 1.49Е-10 21.1 100 152 4.1 3A5.283 VL_H95bP 63.4 5.90E+05 4.22E-02 7D5E-08 3.6 0 154 4.1 FOR5.285 VL_V96S 74.4 9.02E+05 2.01Е-04 2.23Е-10 19.9 53 21 4.1 FOR5.287 VLV96Y 92.4 7,33E+06 1.50E-03 2.05Е-10 17.6 7 62 4.1 FOR5.288 VLV96D 68.8 7.32E+05 1, ZOE-OZ 1.78Е-09 16.8 8 9.5 4.1 FOR5.289 VLV96Q 77.1 1.62E+06 6.54Е-04 4, OZE-10 20.4 16 25 4.1 FOR5.290 VLV96K 64.6 8.08E+05 2.32E-03 2.87Е-09 13.1 5 15 4.1 FOR5.291 VLV96H 5.2 NB 45 4.1 FOR5.292 VLV96W 66.4 3.83E+07 2.01Е-02 5.26E-10 10.6 1 19 4.1 3A5.293 VLV96P 81.5 8.54E+05 5.22E-04 6D1E-10 23.4 20 106 4.1 FOR5.110 VLK31A 74 7.01E+05 1.86Е-04 2.65E-10 21.1 58 122 4.1 FOR5.111 VLK31S 79.2 7D0E+05 1.36E-04 1.92E-10 23.6 79 109 4.1 FA5.112 VLK31L 79.9 6.30E+05 3.91E-04 6.21E-10 22.3 27 125 4.1 3A5.134 VLV33H 5.8 NB 52 4.1 3A5.136 VLY34A 59.9 1.05E+06 3.45Е-04 3.28E-10 17.2 31 170 4.1 ZA5.206 VLQ89D 71.6 5.68E+05 8.76Е-05 1.54Е-10 18.6 122 12 4.1 FOR5.225 VLW91D 114.2 6.31E+05 1.05Е-02 1.66Е-08 3.7 1 74 4.1 FOR5.250 VL_S94Y 74.6 8D4E+05 3.48E-04 4.27E-10 20.3 31 147 4.1 ZA5.252 VLS94Q 63.4 8.25E+05 1.65Е-04 2.00E-10 18 65 136 4.2 ZA5.040 1 wild type 50.4 6.96E+05 1.03Е-04 1.48Е-10 16.2 4.2 ZA5.040 2 wild type 50.5 7D0E+05 1.06E-04 1.49Е-10 16 4.2 ZA5.040 Average wild type 50.4 7.03E+05 1.05Е-04 1.49Е-10 16.1 100 100 4.2 IgG4 isotype 52.5 N/A N/A N/A N/A 4.2 ZA5.040 (Purified) wild type 48.7 7.21E+05 6.63Е-05 9.20E-11 16.5 150 4.2 ZA5.451 VHG55D 33.1 4.54E+05 2.50E-04 5.50E-10 9.9 42 39 4.2 ZA5.452 VHG55Q 37.2 6.09E+05 1.94Е-04 ZD8E-10 I,7 54 42 4.2 3A5.453 VHG55K 43.8 5.49E+05 2.07Е-04 3.76E-10 12.4 50 51 4.2 ZA5.454 VHG55H 38.2 5.92E+05 1.81E-04 3.05Е-10 I,7 58 41 4.2 ZA5.455 VHG55W 31.2 6J7E+05 6.65Е-04 1.08E-09 10 16 33 4.2 ZA5.456 VHS56A 49.7 6.44E+05 1D8E-04 1.84Е-10 15.5 89 104 4.2 ZA5.457 VHS56L 51.1 5.49E+05 8.63Е-05 1.57E-10 15.6 121 101 4.2 ZA5.458 VHS56Y 47.6 5.44E+05 1.92E-04 3.53E-10 14.2 54 85 4.2 ZA5.459 VHS56D 49 5.05E+05 4.57Е-04 9.06Е-10 15 23 84 4.2 ZA5.460 VHS56Q 50.2 5.90E+05 9.69Е-05 1.64Е-10 15.8 108 106 4.2 ZA5.461 VHS56K 52.9 6D1E+05 7.84Е-05 1.28E-10 16.6 133 119

- 25 042576

4.2 3A5.463 VHS56W 47.7 4.72E+05 2.85E-04 6.03E-10 13.9 37 98 4.2 3A5.464 VHT57A 50 7.50E+05 l,26E-04 l,67E-10 16.1 83 104 4.2 3A5.465 VHT57S 48.5 7.29E+05 l,26E-04 l,73E-10 15.6 83 69 4.2 3A5.467 VHT57Y 44 7.66E+05 9.50E-05 l,24E-10 13.8 110 49 4.2 3A5.468 VHT57D 42.5 7.02E+05 9.89E-05 l,41E-10 14 106 46 4.2 3A5.469 VHT57Q 45.1 7.24E+05 l,07E-04 l,48E-10 14.2 98 58 4.2 3A5.470 VHT57K 46.5 7.28E+05 l,21E-04 l,66E-10 14.6 86 61 4.2 3A5.471 VHT57H 43.8 7.34E+05 l,09E-04 l,49E-10 13.9 96 50 4.2 3A5.472 VHT57W 39.2 7.57E+05 l,34E-04 l,77E-10 13.3 78 40 4.2 3A5.473 VHY58A 48.1 l,56E+06 2.86E-03 l,83E-09 13 4 95 4.2 3A5.474 VHY58S 50.7 2.76E+06 3.84E-03 l,39E-09 13.7 3 101 4.2 3A5.475 VHY58L 48.6 5.58E+06 5.88E-03 l,05E-09 8.3 2 70 4.2 3A5.476 VHY58D 42.4 l,89E+07 l,68E-02 8.88E-10 7.3 1 47 4.2 3A5.477 VHY58Q 46.6 6.62E+05 1.33E-O3 2.02E-09 13.9 8 75 4.2 3A5.478 VHY58K 49.2 5.75E+05 1.31E-O3 2.28E-09 14.6 8 102 4.2 3A5.479 VHY58H 50.6 6.68E+05 5.75E-04 8.62E-10 15.8 18 91 4.2 3A5.480 VHY58W 48.1 6.58E+05 5.53E-04 8.41E-10 14.7 19 79 4.2 3A5.481 VHA93S 45.3 7D8E+05 9.31E-05 1.3OE-1O 13.9 112 58 4.2 3A5.482 VHA93L 13 2.55E+05 2.02E-04 7.90E-10 5.2 52 17 4.2 3A5.484 VHA93D 0.5 NE NE 4.2 3A5.485 VHA93Q 40.4 6.48E+05 1.00E-04 l,54E-10 12.7 105 44 4.2 3A5.486 VHA93K 17 NE NE 4.2 3A5.487 VHA93H 28.8 NE NE 4.2 3A5.489 VHA93P 6.5 NE NE 4.2 3A5.491 VHS94L 37.4 5.33E+05 8.11E-O4 l,52E-09 12.5 13 40 4.2 3A5.492 VH_S94Y 30.3 3.27E+05 Ι,ΙΟΕ-OZ 3.37E-09 9.7 10 thirty 4.2 3A5.493 VHS94D 4.6 NE NE 4.2 3A5.494 VHS94Q 42 6.74E+05 6.37E-04 9.45E-10 13.6 16 49 4.2 3A5.496 VHS94H 47.1 2.19E+06 4.62E-03 2.11E-O9 6.5 2 72 4.2 3A5.501 VHL95Y 49 4.17E+06 5.88E-03 l,41E-09 12.4 2 96 4.2 3A5.502 VHL95D 21.2 NB 22 4.2 3A5.506 VHL95W 46.4 6.20E+06 7.36E-03 l,19E-09 8.4 1 68 4.2 3A5.511 VHG96Y 45.5 NB 59 4.2 3A5.519 VH_N97S 48 5.61E+05 2.27E-04 4.04E-10 14.9 46 80 4.2 3A5.552 VHD101K 47.1 6.10E+05 3.63E-04 5.95E-10 14.6 29 67 4.2 3A5.358 VH_G32L 48.4 2.01E+06 3.83E-O3 l,91E-09 12.3 3 75 4.2 3A5.381 VHY34W 42.4 7.09E+05 2.18E-04 3.07E-10 14 48 47 4.2 3A5.398 VH_S35bA 47 6.82E+05 l,02E-04 1.5OE-1O 14.7 102 88 4.2 3A5.488 VHA93W 14.2 NB 17 4.2 3A5.490 VHS94A 49.6 6.78E+05 8.70E-05 l,28E-10 15.1 120 104 4.2 3A5.499 VHL95A 43.4 3.09E+06 7.48E-03 2.42E-09 10.4 1 51 4.2 3A5.508 VH_G96A 47.1 5.77E+05 l,25E-04 2D7E-10 14.8 84 75 4.2 3A5.522 VH_N97D 49 l,00E+06 l,92E-04 l,91E-10 15.5 54 91 4.2 3A5.554 VHD101W 32.7 1.38E+O5 6.18E-04 4.47E-09 8.3 17 33 4.2 3A5.144 VLD50A 47.1 5.29E+05 l,67E-04 ZD5E-10 14.5 63 77 4.2 3A5.145 VLD50S 48.2 5.74E+05 l,05E-04 1.83E-1O 15.1 100 90 4.2 3A5.146 VLD50L 48 5.92E+05 2.59E-04 4.38E-10 15 40 86 4.2 3A5.147 VLD50Y 48 5.36E+05 l,95E-04 3.63E-10 15 54 78 4.2 3A5.148 VLD50Q 47 5.99E+05 l,93E-04 3.22E-10 15 54 70 4.2 3A5.149 VLD50K 45.8 6.00E+05 l,61E-04 2.68E-10 13.2 65 74 4.2 3A5.150 VLD50H 48.2 4.07E+05 l,68E-04 4D4E-10 14.3 62 95 4.2 3A5.151 VLD50W 48 5.36E+05 2.35E-04 4.38E-10 15 44 74

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4.2 3A5.152 VLD51A 47 6.34E+05 1.34Е-04 2D1E-10 14.6 78 88 4.2 3A5.153 VLD51S 46.1 8.53E+05 1.60E-04 1.87E-10 14.1 65 72 4.2 3A5.154 VLD51L 47.8 6.22E+05 1.63E-04 2.63Е-10 14.3 64 83 4.2 3A5.155 VLD51Y 48.1 6D4E+05 1.78Е-04 2.90E-10 13.7 59 75 4.2 3A5.156 VLD51Q 47.8 6.48E+05 1D5E-04 1.77E-10 15 91 85 4.2 3A5.157 VLD51K 45.2 5.85E+05 1.20E-04 2.05Е-10 13.2 87 68 4.2 3A5.158 VL_D51H 48.3 6D5E+05 1.82E-04 2.95E-10 14.7 57 86 4.2 3A5.159 VLD51W 45.7 4.93E+05 1.96E-04 3.98E-10 14.1 53 57 4.2 3A5.160 VLS52A 47.7 6.61E+05 1D1E-04 1.68E-10 15.2 94 80 4.2 3A5.161 VLS52L 47.8 6.87E+05 5.74Е-05 8.36E-P 15 182 106 4.2 3A5.162 VLS52Y 49 7.26E+05 9.91Е-05 1.36E-10 15.8 105 114 5.1 3A5.040 1 wild type 49.9 6.56E+05 1.22E-04 1.86Е-10 14.5 5.1 3A5.040 2 wild type 48.5 6.43E+05 1D2E-04 1.75E-10 14.4 5.1 3A5.040 wild type 48.1 6.67E+05 1.25E-04 1.87E-10 13.7 5.1 3A5.040 4 wild type 50.4 6.63E+05 1D7E-04 1.77E-10 14.4 5.1 3A5.040 Average wild type 49.2 6.57E+05 1.19E-04 1.81Е-10 14.3 100 100 5.1 IgG4 isotype 51.2 N/A N/A N/A 0.1 N/A 5.1 ZA5.040 (Cleaned) wild type 48.9 7D7E+05 1.08E-04 1.53Е-10 15.6 BY 5.1 3A5.337 VHI29H 48.1 4.79E+05 1D2E-03 2.34Е-09 13.7 And 24 5.1 3A5.339 VHS30A 50.7 6.79E+05 1D2E-04 1.65E-10 16.3 106 6 5.1 3A5.346 VHS30W 53.4 6.42E+05 1.32E-04 2.06Е-10 16.7 90 69 5.1 ZA5.058 VLG25S 47.6 6.93E+05 1.08E-04 1.56E-10 15.7 BY 43 5.1 ZA5.090 VLI28K 49.1 5.73E+05 1.04Е-04 1.81Е-10 16.2 114 51 5.1 ZA5.092 VLI28W 47 6DZE+05 1, ZOE-04 2D2E-10 15.5 92 35 5.1 FOR5.212 VL_V90S 46.1 5.71E+05 ZD1E-04 5.45E-10 14.6 38 4.8 5.1 ZA5.251 VLS94D 52.9 2.77E+05 4.98E-04 1.79Е-09 15.5 24 7 5.1 FOR5.255 VL_S94W 48.5 5.54E+05 2.86Е-04 5D6E-10 14.7 42 19 5.1 FOR5.299 VLV97Q 48.5 5.86E+05 9.90E-05 1.69Е-10 15.5 120 71 5.1 ZA5.462 VHS56H 50 6.35E+05 1D6E-04 1.83Е-10 15.9 103 41 5.1 ZA5.466 VHT57L 44.9 6.39E+05 1.02E-04 1.59Е-10 14.2 117 14 5.1 3A5.483 VHA93Y 38.2 NB 8 5.1 FOR5.5oz VHL95Q 48.5 4D4E+05 6D8E-04 1.53Е-09 14.4 19 18 5.1 3A5.163 VLS52D 49.3 6.65E+05 1.01E-04 1.52E-10 16.4 118 177 5.1 FOR5.164 VLS52Q 49.6 6.57E+05 1D7E-04 1.78E-10 15.8 102 9.8 5.1 FOR5.166 VLS52H 51.6 6.71E+05 Ι,ΠΕ-04 1.66E-10 16.9 107 167 5.1 FOR5.167 VLS52W 52.3 7D9E+05 Ι,ΠΕ-04 1.55Е-10 17.2 107 166 5.1 FOR5.169 VLD53S 50.6 6.38E+05 6.35Е-05 9.97E-11 16.5 187 151 5.1 FOR5.170 VLD53L 48.8 6.87E+05 9.50Е-05 1.38E-10 15.8 125 143 5.1 FOR5.171 VLD53Y 51 6.79E+05 1.09Е-04 1.60E-10 16.1 109 208 5.1 3A5.173 VLD53K 52.6 6.35E+05 1.09Е-04 1.71Е-10 16.7 109 175 5.1 FOR5.175 VLD53W 50 5.88E+05 9.74Е-05 1.66E-10 15.7 122 178 5.1 FOR5.176 VLR54A 50.4 6.51E+05 9.75Е-05 1.50E-10 16.8 122 138 5.1 FOR5.177 VLR54S 50.1 6.45E+05 Ι,ΠΕ-04 1.72E-10 16.8 107 131 5.1 FOR5.178 VLR54L 51.5 6.60E+05 1.01E-04 1.53Е-10 17 118 135 5.1 FOR5.179 VLR54Y 49.2 6.66E+05 1.24Е-04 1.86Е-10 16.4 96 138 5.1 FOR5.180 VLR54D 49.5 6.79E+05 9.89Е-05 1.46Е-10 16.6 120 128 5.1 FOR5.181 VLR54Q 51.3 6.58E+05 9.55Е-05 1.45E-10 17 125 148 5.1 FOR5.182 VLR54K 51.5 6.50E+05 1D7E-04 1.79Е-10 17 102 165 5.1 3A5.183 VLR54H 49.1 6.47E+05 8.44Е-05 1, ZOE-10 16.3 141 137 5.1 FOR5.184 VLR54W 50 6D4E+05 1.22E-04 1.99E-10 15.8 98 7.5

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5.1 FOR5.185 VLP55A 51.9 6.87E+05 l,34E-04 l,95E-10 16.5 89 8.9 5.1 FOR5.187 VLP55L 49.6 7.00E+05 9.58E-05 l,37E-10 16.3 124 153 5.1 FOR5.188 VLP55Y 49.2 6.61E+05 1D9E-04 l,80E-10 16.4 100 127 5.1 FOR5.189 VLP55D 51.1 6.48E+05 9.21E-05 l,42E-10 16.7 129 155 5.1 FOR5.190 VLP55Q 48.8 6.55E+05 l,08E-04 l,64E-10 16.4 110 151 5.1 FOR5.191 VLP55K 49.3 6.38E+05 l,05E-04 l,64E-10 16.3 113 137 5.1 ZA5.192 VLP55H 51.5 6.51E+05 l,16E-04 l,78E-10 16.7 103 176 5.1 3A5.193 VLP55W 51.5 6.41E+05 8.80E-05 l,37E-10 16.8 135 160 5.1 FOR5.194 VLS56A 49.8 6.41E+05 l,06E-04 l,65E-10 16.1 112 143 5.1 ZA5.195 VLS56L 49.6 6.85E+05 l,06E-04 l,54E-10 16.3 112 131 5.1 ZA5.196 VLS56Y 50.2 6.89E+05 1D4E-04 l,66E-10 16.5 104 123 5.1 ZA5.197 VLS56D 50.1 6.87E+05 1D9E-04 l,73E-10 16.5 100 153 5.1 ZA5.198 VLS56Q 49.6 6.86E+05 8.85E-05 l,29E-10 16.4 134 131 5.1 FOR5.200 VLS56H 49.3 6.83E+05 1D5E-04 l,68E-10 16.3 103 138 5.1 ZA5.207 VLQ89K 49.9 6.84E+05 l,27E-04 l,86E-10 16.4 94 136 5.1 ZA5.209 VLQ89W 48.6 5.57E+05 l,27E-04 2.28E-10 15.7 94 72 5.1 FOR5.278 VL_H95bY 49.9 7.65E+05 7.90E-05 l,03E-10 16.3 151 139 5.1 FOR5.279 VL_H95bD 49.6 7.01E+05 7.84E-05 1D2E-10 16.5 152 210 5.1 FOR5.280 VL_H95bQ 50.3 7.47E+05 l,51E-04 2.02E-10 16.6 79 133 5.1 FOR5.284 VL_V96A 48.2 7.24E+05 l,88E-04 2.60E-10 15.9 63 65 5.1 FOR5.286 VLV96L 48.4 6.50E+05 l,94E-04 2.98E-10 15.9 61 79 5.1 FOR5.294 VLV97A 48.6 6.27E+05 7.68E-05 l,23E-10 16 155 133 5.1 FOR5.295 VL_V97S 48.6 6D2E+05 l,07E-04 l,74E-10 15.9 111 110 5.1 FOR5.296 VLV97L 48 6.71E+05 9.60E-05 l,43E-10 15.9 124 95 5.1 FOR5.297 VLV97Y 48.4 6.72E+05 l,07E-04 l,60E-10 16.2 111 90 5.1 FOR5.298 VLV97D 47.7 5.94E+05 l,30E-04 2D8E-10 15.8 92 96 5.1 3A5.300 VLV97K 50.1 5.88E+05 1D8E-04 2.01E-10 15.8 101 4.7 5.1 3A5.301 VLV97H 49.4 6.34E+05 8.79E-05 l,39E-10 16.1 135 168 5.1 3A5.063 VL_G25K 49 6.90E+05 7.21E-05 l,05E-10 16.2 165 90 5.1 ZA5.067 VL_N26S 49 6.52E+05 1D0E-04 l,69E-10 16 108 162 5.1 3A5.083 VL_N27W 49.6 6.03E+05 l,29E-04 2D4E-10 16.4 92 148 5.1 ZA5.091 VLI28H 47.7 5.71E+05 l,30E-04 2.27E-10 15.7 92 75 5.1 ZA5.098 VLG29Q 49.7 6.53E+05 l,05E-04 l,61E-10 16.2 113 139 5.1 FA5.108 VLS30H 49.4 6.95E+05 l,02E-04 l,46E-10 16.2 117 145 5.1 FA5.109 VL_S30W 48 6.77E+05 l,35E-04 2.00E-10 15.5 88 112 5.1 FA5.119 VL_N32S 48.6 8.35E+05 l,08E-04 l,29E-10 16.3 110 98 5.1 FOR5.120 VL_N32L 49.2 8.72E+05 l,03E-04 1D8E-10 16.4 116 119 5.1 FA5.129 VLV33L 48.8 5.80E+05 l,42E-04 2.45E-10 15.8 84 99 5.1 FOR5.277 VL_H95bL 50.4 6.79E+05 l,40E-04 2.06E-10 16.6 85 180 5.1 3A5.302 VLV97W 47.7 7D8E+05 7.59E-05 l,06E-10 15.9 157 73 5.1 3A5.303 VLV97P 48.7 6.99E+05 l,21E-04 l,73E-10 16.2 98 21

This table contains a summary of the calculated kinetic data and titer data for each supernatant antibody tested. Variant antibodies with a lower kd value (slower dissociation rate) than the parent antibody 3A5.040 have a % 3A5.040 kd value >100%, while antibodies with a higher kd value (faster dissociation rate) have a value <100 %. Variant antibodies with a higher titer than the parent antibody 3A5.040 have a %3A5.040>100% value, and lower titer antibodies have a value of <100%. N/A, Not applicable. NB, no binding. NE, no expression.

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Table 4

Determination of IL-5 Binding Kinetics with Purified Antibody Variant 3A5.040 Using Biacore

run number Antibody ID Parallel analyzes Amino acid replacement Capture level ka (1/Mc) kd (1/c) KD(M) Rmax (RU) % 3A5.040 kd 6 ZA5.040 (batch 6) 1 wild type 48.6 l,44E+06 2.32E-04 l,61E-10 16 6 ZA5.040 (batch 6) 2 wild type 49.4 l,44E+06 2D4E-04 l,48E-10 15.7 6 ZA5.040 (batch 6) 3 wild type 49.2 l,36E+06 2.61E-04 l,93E-10 16 6 ZA5.040 (batch 6) 4 wild type 49.2 l,36E+06 2.46E-04 l,80E-10 16 6 ZA5.040 (batch 6) 5 wild type 49.3 l,47E+06 2.52E-04 l,71E-10 16.1 6 ZA5.040 (batch 6) 6 wild type 49.2 l,45E+06 2DZE-04 l,47E-10 16 6 ZA5.040 (batch 6) 7 wild type 49.2 l,41E+06 2.29E-04 l,63E-10 16.1 6 ZA5.040 (batch 6) 8 wild type 50.9 l,40E+06 2.45E-04 l,75E-10 16.8 6 ZA5.040 (batch 6) Average wild type 49.3 l,42E+06 2.37E-04 l,67E-10 16.1 100 6 IgG4 iso 1 48.8 N/A N/A N/A 0 6 IgG4 iso 2 48.9 N/A N/A N/A 0 6 IgG4 iso 3 48.8 N/A N/A N/A 0 6 IgG4 isotype Average 49.8 N/A N/A N/A 0 N/A 6 ZA5.040 (Purified) 1 wild type 49.6 l,43E+06 2.39E-04 l,68E-10 16.1 6 ZA5.040 (Purified) 2 wild type 49.8 l,48E+06 2.85E-04 l,93E-10 16.2 6 ZA5.040 (Purified) 3 wild type 49.7 l,45E+06 2.32E-04 l,60E-10 16.1 6 ZA5.040 (Purified) Average wild type 49.7 l,45E+06 2.52E-04 l,74E-10 16.1 94 6 3A5.237 1 VL_D92W 47.9 l,57E+06 2.67E-04 l,70E-10 15.5 6 3A5.237 2 VLD92W 48.7 l,55E+06 2.58E-04 l,66E-10 15.6 6 3A5.237 3 VLD92W 48.5 l,52E+06 2D2E-04 l,40E-10 15.7 6 3A5.237 Average VLD92W 48.3 l,55E+06 2.46E-04 l,59E-10 15.6 96 6 FOR5.161 1 VLS52L 49.4 l,47E+06 2.62E-04 l,78E-10 16.2 6 FOR5.161 2 VLS52L 49.9 l,43E+06 2.41E-04 l,69E-10 16.2 6 FOR5.161 3 VLS52L 49.9 l,40E+06 2D9E-04 l,57E-10 16.4 6 FOR5.161 Average VLS52L 49.7 l,43E+06 2.41E-04 l,68E-10 16.2 99 6 FOR5.169 1 VL_D53S 48.9 l,23E+06 2.43E-04 l,98E-10 15.6 6 FOR5.169 2 VLD53S 49.5 l,26E+06 2.44E-04 l,93E-10 15.9 6 FOR5.169 3 VLD53S 49.7 l,23E+06 2.46E-04 l,99E-10 16.1 6 FOR5.169 Average VLD53S 49.3 l,24E+06 2.44E-04 l,97E-10 15.8 97 6 3A5.183 1 VLR54H 47.9 l,44E+06 2.32E-04 l,61E-10 15.6 6 3A5.183 2 VLR54H 48.2 l,44E+06 2.50E-04 l,74E-10 15.8 6 3A5.183 3 VLR54H 48.4 l,39E+06 2.04E-04 l,47E-10 15.8 6 ZA5L83 Average VL-R54H 48.1 l,42E+06 2.29E-04 l,61E-10 15.7 104 6 3A5.193 1 VLP55W 48.5 l,32E+06 2.32E-04 l,76E-10 15.7 6 3A5.193 2 VLP55W 48.3 l,34E+06 2.51E-04 l,88E-10 15.3 6 3A5.193 3 VLP55W 48.7 l,29E+06 2.57E-04 l,99E-10 15.6 6 3A5.193 Average VLP55W 48.5 l,32E+06 2.47E-04 l,88E-10 15.5 96 6 ZA5.198 1 VLS56Q 49.1 l,42E+06 2.43E-04 l,71E-10 16 6 ZA5.198 2 VLS56Q 49 l,49E+06 2.90E-04 l,95E-10 15.7 6 ZA5.198 3 VLS56Q 49.3 l,42E+06 2.38E-04 l,68E-10 15.9 6 ZA5.198 Average VLS56Q 49.1 l,44E+06 2.57E-04 l,78E-10 15.8 92 6 FOR5.278 1 VL_H95bY 48.3 l,55E+06 2.53E-04 l,63E-10 15.9 6 FOR5.278 2 VL_H95bY 48.2 l,62E+06 2.43E-04 l,49E-10 15.7 6 FOR5.278 3 VL_H95bY 48.5 l,57E+06 2D4E-04 l,36E-10 15.8 6 FOR5.278 Average VL H95bY 48.3 l,58E+06 2.37E-04 l,49E-10 15.8 100 6 FOR5.279 1 VL_H95bD 50 l,58E+06 2.50E-04 l,58E-10 16.3 6 FOR5.279 2 VL_H95bD 49.7 l,61E+06 2.42E-04 l,50E-10 16.1 6 FOR5.279 3 VL_H95bD 50 l,61E+06 2.43E-04 l,51E-10 16.4

- 29 042576

6 3A5.279 Average VL H95bD 49.9 1.60E+06 2.45E-04 l,53E-10 16.2 97 6 3A5.294 1 VLV97A 49.1 l,31E+06 2.54E-04 l,94E-10 15.9 6 3A5.294 2 VLV97A 48.6 l,31E+06 2.13E-04 l,62E-10 15.7 6 3A5.294 3 VLV97A 48.6 l,37E+06 2.15E-04 l,57E-10 15.6 6 3A5.294 Average VL-V97A 48.7 l,33E+06 2.27E-04 l,71E-10 15.7 104 6 3A5.301 1 VLV97H 48.4 l,51E+06 2.76E-04 l,83E-10 15.8 6 3A5.301 2 VLV97H 48.1 l,58E+06 l,06E-04 6.71E-11 15.6 6 3A5.301 3 VLV97H 47.8 l,60E+06 2.45E-04 l,53E-10 15.4 6 3A5.301 Average VLV97H 48.1 l,56E+06 2.09E-04 l,34E-10 15.6 114 6 3A5.063 1 VLG25K 48 l,37E+06 2.61E-04 l,90E-10 15.7 6 3A5.063 2 VLG25K 48.1 l,36E+06 2.70E-04 l,99E-10 15.5 6 3A5.063 3 VLG25K 47.8 l,42E+06 2.50E-04 l,76E-10 15.3 6 3A5.063 Average VL-G25K 47.9 l,38E+06 2.60E-04 l,88E-10 15.5 91 6 3A5.302 1 VLV97W 48.9 l,65E+06 2.35E-04 l,42E-10 16 6 3A5.302 2 VLV97W 48.9 l,69E+06 2.35E-04 l,39E-10 15.8 6 3A5.302 3 VLV97W 48.5 l,66E+06 2.40E-04 l,45E-10 15.7 6 3A5.302 Average VL V97W 48.7 l,67E+06 2.37E-04 L42E-10 15.8 100 6 3A5.202 1 VLQ89A 48.9 l,09E+06 2.49E-04 2.29E-10 15.8 6 3A5.202 2 VLQ89A 48.7 l,07E+06 l,89E-04 l,77E-10 15.6 6 3A5.202 3 VLQ89A 48.8 l,09E+06 2.44E-04 2.25E-10 15.7 6 3A5.202 Average VLQ89A 48.8 l,08E+06 2.27E-04 2.10E-10 15.7 104 6 3A5.203 1 VLQ89S 49 l,28E+06 2.82E-04 2.20E-10 15.9 6 3A5.203 2 VLQ89S 48.6 l,28E+06 2.26E-04 l,76E-10 15.6 6 3A5.203 3 VLQ89S 48.9 l,27E+06 2.36E-04 l,86E-10 15.7 6 3A5.203 Average VLQ89S 48.8 l,28E+06 2.48E-04 L94E-10 15.7 96 6 3A5.204 1 VLQ89L 49.9 5.01E+05 2.20E-04 4.38E-10 14.4 6 3A5.204 2 VLQ89L 49.9 5.02E+05 l,88E-04 3.74E-10 14.2

- 30 042576

Table 5

Expression yield of purified protein for selected antibody variants 3A5.040

No. run Antibody ID Amino acid replacement % yield of purified antibody relative to parent 3A5.040 6 ZA5.040 Parent Sequence 100 6 3A5.237 VLD92W 89 6 FOR5.161 VLS52L 160 6 FOR5.169 VL-D53S 173 6 3A5.183 VL-R54H 172 6 3A5.193 VLP55W 187 6 ZA5.198 VLS56Q 205 6 FOR5.278 VL H95bY 210 6 FOR5.279 VL H95bD 143 6 FOR5.294 VLV97A 140 6 3A5.301 VLV97H 151 6 3A5.063 VL_G25K 110 6 3A5.302 VL V97W 156 6 ZA5.202 VL_Q89A 64 6 FOR5.2oz VL_Q89S 129 6 ZA5.204 VL_Q89L 61 6 ZA5.205 VL_Q89Y 41 6 ZA5.208 VL-Q89H 54 6 FOR5.550 VHD101Y 88 6 ZA5.512 VH-G96D 72 6 FOR5.124 VLN32K 128 7 ZA5.040 Parent Sequence 100 7 ZA5.068 VLN26L 96 7 ZA5.079 VL_N27D 99

Table 6

Scanning matrix VH CDR1

VH CDR1 26 G 27 G 28 S 29 I thirty S 31 N 32 G 33 G 34 Y 35 Y 35A W 35V S 0.5 1.3 1 0.8 0.6 0.9 0.3 0.6 0.1 1.1 1.2 0.1 1.8 0.3 1.2 1.3 1.6 0.7 2.9 0 0.4 0.1 0.9 1 0.6 0.9 ^eleven 0.3 0.5 1.1 0.2 1.5 0.1 1.2 0 1.6 0.7 1.3 0 0.2 0.1 0.2 1.1 1.2 0.8 0.7 1.1 0.8 0.9 1.5 0.7 0.7 0.2 0.8 0 0.8 0.4 1.6 0.6 1.9 0.1 1 0.1 0.4 0.3 0.6 1.1 0.8 0.1 0.5 1.2 0.2 0.1 1 0.7 0.6 0.1 0.9 0 1.1 0 1 0.5 0.9 0 0.6 1.2 0.7 0.9 0.7 1.1 0.2 0 1 0.8 0.8 0.5 1.1 about 2.8 0 1 0.2 0.9 0 NE NE 0.2 0.9 0.9 1.1 0.8 0.7 0.8 1 0.4 0.3 1.2 1.1 1.6 0.2 1.3 0.1 2.8 0.1 1.7 0.6 1.3 0 0.3 0.1 0.5 0.2 eleven 1 0.5 0.8 0.9 0.3 0.1 1.6 0.8 1.7 0.1 1.7 0 3.5 0 4.1 0.2 3.8NB 0.3 0.1 0.1 0 0.9 0.9 0.7 0.4 0.7 0.8 0.2 0.1 0.8 0.8 1.4 0.8 1.1 about 2.7 0 2.2 0.1 20 0.5 0.4 0.8 0 1.1 0.8 1 0.2 0.4 0.7 0.4 0 0.7 0.9 0.6 0.2 0.7 0 1.7 0.1 0.5 0.5 2.3 0 0.5 0

and kd

VH CDR1 for options

SC A S

D Q K n W P

Summary of differences in titer of antibody variant 3A5.040 (determination

AbM). Amino acid numbering according to Kabat and amino acids of the parent 3A5.040 are shown in the top row. Mutated residues are listed in the left column. The leftmost value in each cell is the proportional titer of each variant compared to the parent 3A5.040 (>1=higher titer, <1=lower titer), while the rightmost value is proportional to kd (>1=lower kd , <1=higher kd) of each variant compared to parent 3A5.040. Unmade options are marked in grey. NB, no binding. NE, no expression (The VH CDR1 sequence is disclosed as residues 26-37 of SEQ ID NO: 73).

Table 7

Scanning matrix VH CDR2

SC VHCDR2 50 Y 51 I 52 Y 53 Y 54 S 55 G 56 S 57 T 58 Y A 2.7 0.2 2.4 0.8 thirty 2.5 0.2 1.1 0.6 0.7 0.9 1 0.9 1 0.8 10 S L 3.3 0.2 1.2 0.3 1.3 0.8 0.9 0.7 3.3 0.1 2.1 0 2.3 0.6 1 0.2 1.6 0 0.7 0.7 0.7 0.1 1 1.2 0.7 0.8 OD 1.2 10 0.7 0 Y D 1.7 0.1 1.1 about 0.5 0.1 3.3 N.B. 1.8 0.2 0.9 0 20 0.5 0.1 0.4 0.4 0.9 0.5 0.8 0.2 0.5 1.1 0.5 1.1 0.5 0 Q 2.4 0.2 1 0.2 2.6 0 2.1 0.2 1.5 0.1 0.4 0.5 1.1 1.1 0.6 1 0.8 0.1 TO 1.4 0.2 1.2 0.1 3.5NB 2.3 0.1 20 0.5 0.5 1.2 1.3 0.6 0.9 1 0.1 n 3 0.1 0.9 0 2.9 0.3 2.1 0.5 1 0.2 0.4 0.6 0.4 1 0.5 1 0.9 0.2 W 1.3 0.1 1.4 0 1 OD 1.5 0.4 1.1 0.1 0.3 0.2 1 0.4 0.4 0.8 0.8 0.2 R

Summary of differences in 3A5.040 variant antibody titer and kd for CDR2 VH variants (AbM detection). Amino acid numbering according to Kabat and the original amino acids 3A5.040 are shown in the top row. Mutated residues are listed in the left column. The leftmost value in each cell is the proportional titer of each variant compared to the parent 3A5.040 (>1=higher titer, <1=lower titer), while the rightmost value is proportional to kd (>1=lower kd , <1=higher kd) of each variant compared to parent 3A5.040. Unmade options are marked in grey. NB, no binding. NE, no expression (VH CDR2 sequence disclosed as residues 52-60 of SEQ ID NO: 73).

Table 8

Scanning matrix VH CDR3

VH CDR3 93 94 95 96 97 98 99 101 102 SC A S L G N W F D Y A 1 1.2 0.5 0 0.8 0.8 1 0.6 1.1 0.5 0.4 0.2 0.7 0.7 1.1 1.2 S 0.6 1.1 NE NE 0.9 0.5 0.8 0.5 0.8 0.4 0.4 0.1 0.8 0.9 1.4 0.9 L 0.2 0.5 0.4 0.1 0.6 0 1 0.9 0.4 0.6 0.6 0.9 0.4 0.2 0.5 0.9 Y 0.1NB 0.3 0.1 10 0.6NB 0.8 0.3 1.4 0.9 0.4 1.1 0.9 0.5 D NE NE NE NE 0.2NB 0.7 0 0.9 0.5 0.4 1.1 0.3 0 0.5 0.7 Q 0.4 1 0.5 0.2 0.2 0.2 0.6 0.2 1.3 1 0.5 0.6 0.4 0.1 0.8 0.5 0.9 1 TO 0.2NB 1.3 0.3 0.7 0 1.5 0 1.7 0.7 0.7 0.1 0.4NB 0.7 0.3 0.9 1.3 n 0.3NB 0.7 0 0.9 0.1 1.2 0.1 1.1 0.5 0.8 0.7 0.4 1 0.7 0.6 1.3 1 W 0.2NB 0.4 0.0 0.7 0 0.6 0 0.6 0.2 0.3 0.2 0.3 0.2 1.2 0.9 R 0.1NB 0.2 0.8 0.4NB 0.2 0.2 0.7 0.2 0.3 0.1 0.4NB 0.4 0.1 0.3 0.8

Summary of differences in 3A5.040 variant antibody titer and kd for CDR3 VH variants (AbM detection) and Kabat amino acid positions 93 and 94. Kabat amino acid numbering and the original 3A5.040 amino acids are shown in the top row. Mutated residues are indicated in the left column. The leftmost value in each cell is the proportional titer of each variant compared to the parent 3A5.040 (>1=higher titer, <1=lower titer), while the rightmost value is proportional to kd (>1=lower kd , <1=higher kd) of each variant compared to parent 3A5.040. Unmade options are marked in grey. NB, no binding. NE, no expression. (The VH CDR3 sequence is disclosed as residues 98-106 of SEQ ID NO: 73).

Table 9

Scanning matrix VL CDR1

VL CDR1 24 25 26 27 28 29 thirty 31 32 33 34 G G N N I G S To N V Y 1 1.3 1.1 1.3 0.8 1.3 1.2 1.2 0.9 1.9 0.6 1.1 0.8 1.1 1.2 0.6 0.7 0.2 0.7 1.5 1.7 0.3 1 1.1 0.4 1.1 1.6 1.1 0.9 1.1 0.5 1 0.9 1.2 1.1 0.8 1 1.1 1.3 1.2 0.3 1.2 1 1.4 0.8 1.1 eleven 1 1.3 0.6 1.1 0.8 1.3 1.3 1.2 1.3 0.3 1.2 1.2 1 0.8 0.6 0.5 0.9 1 1 1.4 1 1.3 1 1.1 0.9 1.4 0.6 0.9 0.9 1.1 1 1.3 0.9 1.2 0.7 1.3 1 1.2 0.9 1 1 1.5 eleven 0.4 1.2 0.9 1.6 1.2 1.3 1.1 0.2 1.2 0.9 0.4 1.2 0.7 0.2 1 1.2 0.9 1.3 1 1.1 0.9 1.1 0.5 1.1 1.4 1.1 0.8 1.3 0.9 0.3 1 0.9 0.5 0.8 0.6 0.2 1 1.2 0.9 1.7 eleven 1 1.3 0.5 1.1 0.7 1.3 1 1.6 1.3 I 0.1 1 0.6 0.3 1 1.3 1.1 1.3 eleven 0.9 1.5 0.8 0.9 1 1.4 1.5 1.2 1 0.5 0.9 1.5 0.5NB 0.8 0.2 1.1 1.4 0.8 1.3 0.9 1.2 1.5 0.9 0.4 0.9 1.1 1.2 1.1 0.9 1.3 0.9 0.8 1.3 0.2 1.1 0.6 0.1

Summary of differences in variant 3A5.040 antibody titer and kd for CDR1 VL variants (AbM detection). Amino acid numbering according to Kabat and the original amino acids 3A5.040 are shown in the top row. Mutated residues are listed in the left column. The leftmost value in each cell is the

- 32 042576 portional titer of each variant compared to the parent 3A5.040 (>1=higher titer, <1=lower titer), while the right value is proportional to kd (>1=lower kd, <1= higher kd) of each variant compared to parent 3A5.040. Unmade options are marked in grey. NB, no binding. NE, no expression. (The VL CDR1 sequence is disclosed as residues 23-33 of SEQ ID NO: 74).

Table 10

Scanning matrix VL CDR2

VLCDR2 50 51 52 53 54 55 56 SC D D S D R R S A 0.8 0.6 0.9 0.8 0.8 0.9 0.5 0.1 1.4 1.2 0.1 0.9 1.4 1.1 S 0.9 1 0.7 0.7 1.5 1.9 1.3 1.1 1.1 1 L 0.9 0.4 0.8 0.6 1.1 1.8 1.4 1.3 1.4 1.2 1.5 1.2 1.3 1.1 Y 0.8 0.5 0.8 0.6 1.1 1.1 2.1 1.1 1.4 1.0 1.3 1 1.2 1 D 1.8 1.2 1.3 1.2 1.6 1.3 1.5 1 Q 0.7 0.5 0.9 0.9 0.1 1 eleven 1.5 1.2 1.5 1.1 1.3 1.3 To 0.7 0.6 0.7 0.9 1.7 0.1 1.8 1.1 1.7 1.0 1.4 1.1 1 0.9 n 1 0.6 0.9 0.6 1.7 1.1 1.2 0.9 1.4 1.4 1.8 1 1.4 1 W 0.7 0.4 0.6 0.5 1.7 1.1 1.8 1.2 ο,ι 1.0 1.6 1.4 0.9 0.9 R

Summary of differences in 3A5.040 variant antibody titer and kd for VL CDR2 variants (AbM determination). Amino acid numbering according to Kabat and the original amino acids 3A5.040 are shown in the top row. Mutated residues are indicated in the left column. The leftmost value in each cell is the proportional titer of each variant compared to the parent 3A5.040 (>1=higher titer, <1=lower titer), while the rightmost value is proportional to kd (>1=lower kd , <1=higher kd) of each variant compared to parent 3A5.040. Unmade options are marked in grey. NB, no binding. NE, no expression (VL CDR2 sequence disclosed as residues 49-55 of SEQ ID NO: 74).

Table 11

Scanning matrix VL CDR3

VL CDR3

SC 89 Q 90 V 91 W 92 D 93 S 94 S 95 S 95A D 95V H 96 V 97 V A 0.6 1 0.8 1 0.8 0 1.1 1.2 1.1 about eleven eleven 1.1 0 0.2 0.7 0.7 0.6 1.3 1.5 S 1.3 1 0 0.4 10 1.1 1.2 1 0.1 0.6 1.6 0.2 0.5 1.1 1.1 L 0.6 1.2 0.6 0.8 10 1.3 1.5 1.2 0 0.9 0.2 ^eleven 0.7 0 1.8 0.9 0.8 0.6 1 1.2 Y 0.4 1 0.9 0.4 0.6 0.1 0.7 1.1 1.2 0 1.5 0.3 0.8 1.1 10 1.4 1.5 0.6 0.1 0.9 1.1 D 0.1 1.2 0.3 0.3 0.7 0 0.7 0 0.1 0.2 1.1 0.9 2.1 1.5 0.1 0.1 1 0.9 Q 0.8 0.6 0.8 0 1.9 0.8 1.1 about 1.4 0.6 0.6 1.3 1.1 0 1.3 0.8 0.3 0.2 0.7 1.2 TO 1.4 0.9 0.5 1.4 0.7NB 0.9 1.3 1.6 N.B. 1.1 0.8 1.2 1.2 0.7 0 0.6 1.2 0.2 0 0 1 H 0.5 0.9 0.6 0.4 0.6 0 1.2 1.1 1.3 0 1 0.8 1 1.2 1.9 0 0.5NB 1.7 1.4 W 0.7 0.9 0.8 0.2 NE NE 1.2 0 0.2 0.4 0.9 0.9 0.9 0 1.5 1 0.2 0 0.7 1.6 R 0.7 0.2 0.8 0 0.4 0 0.6 0.8 1.1 about 1.4 0.9 1.5 0 1.5 0 1.5 0 1.1 0.2 0.2 1

Summary of differences in variant 3A5.040 antibody titer and kd for CDR3 VL variants (AbM determination). Amino acid numbering according to Kabat and the original amino acids 3A5.040 are shown in the top row. Mutated residues are listed in the left column. The leftmost value in each cell is the proportional titer of each variant compared to the parent 3A5.040 (>1=higher titer, <1=lower titer), while the rightmost value is proportional to kd (>1=lower kd , <1=higher kd) of each variant compared to parent 3A5.040. Unmade options are marked in grey. NB, no binding. NE, no expression. (The VL CDR3 sequence is disclosed as residues 88-98 of SEQ ID NO: 74).

Creation of an expression vector.

The nucleotide sequence can influence gene expression and the subsequent level of protein expression. Several different nucleotide sequences were examined for optimal expression of 3A5.046. These sequences are shown in the following table:

Table 12

Nucleotide sequence

Gene name SEQIDNo: ZA5.046 VH SEQID NO 69 ZA5.046 VL SEQID NO 71 constant region ZA5.046 NS SEQID NO 70 constant region ZA5.046 LC SEQID NO: 72

- 33 042576

Measurement of the affinity of the antibody 3A5.046 to recombinant human IL-5 using SPR.

The affinity of antibodies 3A5.046 to recombinant human IL-5 was determined using the Biacore T200 system (GE Healthcare). Briefly, a commercial mouse anti-human IgG antibody (Thermo Scientific) was attached to two adjacent (control and test) flow cells on a Biacore CM5 chip (GE Healthcare) according to the manufacturer's recommendations. Antibody 3A5.046 was captured at low density (about 125 RU) on the surface of the test flow cell, and dilutions of recombinant human IL-5 or blank buffer were injected through the test and control flow cell at a rate of 30 μl/min (Fig. 6, Table . 13).

The obtained sensograms were double controls (test flow cell values subtracted from control flow cell values (surface bound to human anti-IgG without coated antibody) and empty buffer). Subtracted sensograms from human IL-5 injections at 2.5, 1.25, 0.625, 0.313, and 0.156 µg/mL were fitted to a 1:1 Langmuir binding model using Biacore Evaluation software to determine binding constants from duplicate assays ( Table 13).

Table 13

Kinetic constants from a multi-concentration Biacore kinetic assay of binding of antibody 3A5.046 to recombinant human IL-5 at 2.5, 1.25, 0.625, 0.313, and 0.156 µg/mL

Antibody Experiment ka (1/ms) kd (1/s) KD (pM) Chi ² (RU ² ) ZA5.046 Repeat 1 8D6E+05 1.58Е-05 19.4 0.0269 Repeat 2 8.49E+05 1.84Е-05 21.7 0.0296

These results indicate that the 3A5.046 antibody has a high affinity for recombinant human IL-5.

Activity of 3A5.046 compared to mepolizumab in the TF1.6G4 cell line proliferation assay 3A5.046 and mepolizumab were used in the TF-1.6G4 cell line proliferation assay. 3A5.046 and mepolizumab inhibited human IL-5 induced proliferation with mean IC _50s of −13.8 pM and 534 pM, respectively (see Table 14 and Figure 7A). Both antibodies showed inhibition of cynomolgus IL-5 on the TF1.6G4 cell line (FIG. 7B), with a mean IC ₅₀ for 3A5.046 of 43.8 pM and for mepolizumab of 584 pM.

Table 14

Antibody Agonist Number of observations mean (pM) Art. off mepolizumab cynomolgus macaque IL-5 4 584.0982 129.9019 human IL-5 4 534.2803 150.2546 ZA5.046 cynomolgus macaque IL-5 8 43.80916 12.62095 human IL-5 8 13.83667 4.219783

Detection of native IL5 from primary cells by ELISA using anti-IL-5 antibodies of the invention.

The 3A5 antibody was used as the capture reagent in the sandwich ELISA. In combination with a commercially available detection antibody (TRFk5R; R&D systems, #MAB405), levels of recombinant IL-5 in analyte buffer samples can be quantified (FIG. 8). This method was then applied to detect native IL-5 secreted by primary cells. CD4+ T cells from four donors were stimulated to secrete IL-5. IL-5 levels were then determined using a sandwich ELISA with 3A5 antibody as the capture reagent. Three of the four donor T cells responded to T cell stimulation and had detectable levels of IL-5 in the cell culture supernatant (FIG. 8). Similar studies were performed with human IL-5 secreted from primary human donor CD4+ T cells using the 3A5.046 antibody as the capture agent and the results were consistent with those obtained with the 3A5 antibody (data not shown).

Anti-IL-5 inhibition of eosinophil differentiation by antibody.

A survival assay using cord blood CD34+ cells was used to assess the ability of anti-IL-5 antibodies to inhibit IL-5 dependent differentiation of bone marrow progenitor cells into eosinophils and to assess the ability of anti-IL-5 antibodies to inhibit phenotypically mature eosinophil survival. In IL-5 treated control cells, phenotypically mature eosinophils were the predominant population at day 28 (FIG. 9, shaded area in the graph). Antibody 3A5.046 is able to inhibit the differentiation of CD34+ umbilical cells

- 34 042576 wine blood, incubated with IL-5 for 28 days, in eosinophils. Antibody 3A5.046 was a stronger inhibitor of IL-5-mediated eosinophil differentiation than mepolizumab (FIG. 9).

X-ray diffraction analysis.

The molecular structure of the complex between Fab antibody 3A5.046 and recombinant human IL-5 was examined using X-ray crystallography. To prepare for X-ray crystallography experiments, 3A5.046 was digested with papain, which cleaves intact antibody at the hinge region, separating the Fc and Fab domains. Fab 3A5.046 was purified by standard protein A affinity chromatography and complexed with recombinant non-glycosylated human IL-5. The 3A5.046 Fab:human IL-5 complex was purified for crystallization experiments using standard size exclusion chromatography. The complex was used at varying concentrations in commercially available sparse matrix protein crystallization screens for a wide selection of crystallization conditions. Optimization of any hitting conditions provided by the crystals of the complex from sparse matrix protein crystallization screens was performed to improve crystal morphology and crystal diffraction as needed.

Crystals of the 3A5.046 Fab:human IL-5 complex were harvested, flash frozen in liquid nitrogen, and transported to the synchrotron complex for diffraction tests and data collection. Crystalline diffraction testing was performed on a synchrotron that generates high energy x-ray microbeams to obtain high resolution diffraction. Thus, crystal X-ray diffraction data of the 3A5.046 Fab: human IL-5 complex were obtained. The initial structural model of the complex can be generated using standard molecular displacement techniques with published IL-5 and Fab molecular structures as templates. The final structure of the complex of Fab and human IL-5 3 A5.046 can be obtained by iterative refinement of the structure model until the fitting errors are better than 30% (final R _free is 0.3) and the chemical bond parameters ( for example, bond length and angle distributions, stereochemistry, and hydrogen bonds) will not be within acceptable limits.

Characterization of binding of antibody 3A5.046 to IL-5 from non-human model species.

Antibody 3A5.046 was tested by Biacore assay using the T200 system (GE Healthcare) for binding to recombinant human IL-5, rat IL-5, mouse IL-5 and guinea pig IL-5 cytokines. This panel of non-human IL-5s was chosen to represent the main types of animal models used in preclinical development. Isotype control antibody (IgG4) and antibody 3A5.046 were immobilized on flow cells 1 and 2 of the S series CM5 chip (GE Healthcare), respectively, using standard amine coupling methods. Cytokines were diluted to 1 and 10 μg/ml in HBS-EP+ running buffer (GE Healthcare) and injected through flow cells 1 and 2. Injections of buffer only through flow cells 1 and 2 were included for dual control. Data analysis was performed using Biacore T200 evaluation software. The obtained sensograms had a double control (the values of the tested flow cell were subtracted from the values of the control flow cell, as well as the empty buffer).

Antibody 3A5.046 was found to bind to human IL-5 and cynomolgus monkey IL-5, but not to mouse IL-5, rat IL-5, or guinea pig IL-5 (FIGS. 10A and 10E). This indicated that 3A5.046 could be used in preclinical cynomolgus monkey models.

Antibody 3A5.046 does not bind to other human cytokines closely related to IL-5.

Antibody 3A5.046 was tested by Biacore assay using the T200 system (GE Healthcare) for binding to recombinant human cytokines IL-2, IL-3, IL-4, IL-5, granulocyte-macrophage colony stimulating factor (GM-CSF ), macrophage colony stimulating factor (M-CSF) and growth hormone (GH). This representative group of closely related human cytokines was selected based on their structural and functional similarity to human IL-5. Isotype control antibody (IgG4) and antibody 3A5.046 were immobilized on flow cells 1 and 2 of the S series CM5 chip (GE Healthcare), respectively, using standard amine coupling methods. Cytokines were diluted to 1 and 10 μg/ml in HBS-EP+ running buffer (GE Healthcare) and injected through flow cells 1 and 2. Buffer alone injections through flow cells 1 and 2 were included for dual control. Data analysis was performed using Biacore T200 evaluation software. The received sensograms had a double control (the values of the tested flow cell were subtracted from the values of the control flow cell, as well as the empty buffer).

The 3A5.046 antibody was found to bind only to human IL-5, but not to the human cytokines IL-2, IL-3, IL-4, GM-CSF, M-CSF, or GH (FIGS. 11A and 11D) , thus demonstrating the high specificity of 3A5.046 for human IL-5.

Evaluation of 3A5.046 antibodies in a cynomolgus macaque airway eosinophilia model induced by Ascaris suum.

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Antibody 3A5.046 was tested using the Ascaris suum cynomolgus monkey model of acute airway eosinophilia as described in Hart, T., et al., Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys. J Allergy Clin Immunol, 2001. 108(2): p. 250-7.

Sixteen female cynomolgus monkeys that had previously been sensitized to Ascaris suum were assessed for residual susceptibility using an A. suum intradermal challenge challenge. Fourteen of these animals were selected to participate in the study based on the response to the challenge test, skin blisters, and randomized into two groups of n=7 per group. Two weeks after intradermal skin serum testing, baseline blood and bronchoalveolar lavage fluid (BALF) samples were taken (Day 8). Approximately 24 hours after initial sample collection, animals were treated with either placebo (containing aqueous buffer pH 6.3 with 200 mM arginine and 25 mM histidine) or antibody 3A5.046 (10 mg/kg IV, in aqueous buffer pH 6.3 with 200 mM arginine and 25 mM histidine) as a blind study (day 7). One week after placebo or antibody treatment, a second intradermal injection of A. suum was performed and all animals were injected with A. suum by delivering an equal amount of A. suum extract (Greer Laboratories Inc.; 5 mg/mL in sterile water) via a PARI LC nebulizer ( day 0). The diameter of the skin blisters was measured 15 min after the provocative test. Two days after the A. suum inhalation challenge, blood and BALF samples were taken. Additional blood samples for hematological endpoints and PK analysis were collected weekly from day 10 to day 45.

There were no significant differences in skin blister response between the first and second A. suum intradermal challenge tests. All animals showed an increase in eosinophils in BALF as a result of the A. suum challenge, but in animals treated with antibody 3A5.046, this increase was negligible. In BALF, 3A5.046-treated animals had significantly fewer eosinophils than 48 hours after the A. suum challenge in placebo-treated animals (p<0.01; Mann-Whitney test; Fig. 12).

The A. suum challenge also resulted in a significant increase in blood eosinophils from baseline in placebo-treated animals up to day 10 post challenge (FIG. 13A). Treatment with antibody 3A5.046 resulted in a significant decrease in blood eosinophil levels to levels below baseline (FIG. 13A), and this decrease in blood eosinophils was maintained for at least 52 days after the initial dose (FIG. 13B).

Thus, treatment with 3A5.046 significantly reduced A. suum-induced airway eosinophilia 48 hours after challenge, and significantly reduced blood eosinophils, below baseline levels, for at least 52 days after a single intravenous (IV) doses of 10 mg/kg.

Investigation of antibody function in a rat model of airway eosinophilia with humanized IL-5.

Alternaria alternata (Alternaria) is a fungal allergen known to cause asthma in humans and can lead to eosinophilia and asthma-like symptoms in rodents. In the Alternaria challenge, knock-in rats with humanized IL-5 (animals in which rat IL-5 has been replaced with human IL-5) show increased levels of eosinophils in bronchoalveolar lavage fluid (BALF) from the lungs (Fig. 14) .

A single intratracheal instillation of Alternaria suspension was administered to humanized IL-5 rats and blood and BALF samples were taken 2, 3 or 4 days after Alternaria administration. Typically in this model, eosinophils are significantly elevated in BALF samples and may be either increased or unchanged in blood samples.

Test antibodies were administered prior to induction of eosinophilia with Alternaria and evaluated for their ability to reduce eosinophil counts in BALF and blood.

Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the present invention, and that such changes and modifications can be made without departing from the spirit of the present invention. Therefore, the appended claims are intended to cover all such equivalent variations as fall within the true spirit and scope of the invention.

The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference in their entirety.

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Table 15

Sequences

protein chain Subsequence protein chain Subsequence LCDR1 consensus GX1X2X3X4X5X6KX7X8Y SEQ ID NO: 1 LCDR2 consensus DDX ₈ X ₉ RPS SEQ ID NO: 2 LCDR3 consensus QVWX10SSSDX11VX12 SEQ ID NO: 3 Antibody ZA5 ZA5 HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5 LCDR1 GGNNIGSKNVY SEQ ID NO: 5 ZA5 HCDR2 YIYYSGSIY SEQ ID NO: 6 3A5 LCDR2 DDSDRPS SEQ ID NO: 7 ZA5 HCDR3 LGNWFDY SEQ ID NO: 8 3A5 LCDR3 QVWYSSSDHVV SEQ ID NO: 9 ZA5 VH S SEQ ID NO: 10 ZA5 VL SSILTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHDD SDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWYSSSDHWFGG GTKLTVLG SEQ ID NO: 11 ZA5 NS QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVSISVDTSKNQFSLKLNSVTAADTAVYYCASL GNWFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS S VVTVPS S SLGTQIYIC NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT LMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 12 ZA5 LC SSILTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHDD SDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWYSSSDHWFGG GTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWK ADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEG S SEQ ID NO: 13 Antibody ZA5.001 FOR5.001 HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5.001 LCDR1 GGNNIGSKNVY SEQ ID NO: 5 FOR5.001 HCDR2 YIYYSGSIY 3A5.001 LCDR2 DDSDRPS

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SEQ ID NO: 6 SEQ ID NO: 7 3A5.001 HCDR3 LGNWFDY SEQ ID NO: 8 3A5.001 LCDR3 QVWYSSSDHVV SEQ ID NO: 9 3A5.001 VH S SEQ ID NO: 10 3A5.001 VL SSILTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHDD SDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWYSSSDHWFGG GTKLTVLG SEQ ID NO: 11 3A5.001 NS QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSIYYNPSLKSRVSISVDTSKNQFSLKLNSVTAADTAVYYCASL GNWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS SVVTVPS S SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSIYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 14 3A5.001LC SSILTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHDD SDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWYSSSDHWFGG GTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWK ADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEG S SEQ ID NO: 13 Antibody 3A5.040 3A5.040HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5.040 LCDR1 GGNNIGSKNVY SEQ ID NO: 5 3A5.040HCDR2 YIYYSGSIY SEQ ID NO: 6 3A5.040 LCDR2 DDSDRPS SEQ ID NO: 7 3A5.040 HCDR3 LGNWFDY SEQ ID NO: 8 3A5.040 LCDR3 QVWDSSSDHW SEQ ID NO: 15 3A5.040 VH S SEQ ID NO: 16 3A5.040 VL SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVFG GGTKLTVLG SEQ ID NO: 17 3A5.040HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSIYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG

- 38 042576

NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS S VVTVPS S SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 18 3A5.040LC SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSSDHVVFG GGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW KADSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSTVSYSCQVTHECS SEQ ID NO: 19 Antibody 3A5.046 3A5.046 HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5.046 LCDR1 GGNNIGSKNVY SEQ ID NO: 5 3A5.046 HCDR2 YIYYSGTY SEQ ID NO: 6 3A5.046 LCDR2 DDSDRPS SEQ ID NO: 7 3A5.046 HCDR3 LGNWFDY SEQ ID NO: 8 3A5.046 LCDR3 QVWDSSSDHW SEQ ID NO: 15 3A5.046 VH S SEQ ID NO: 16 3A5.046 VL SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVFG GGTKLTVLG SEQ ID NO: 17 3A5.046HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS S VVTVPS S SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLYITR EPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 20 3A5.046LC SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSSDHVVFG GGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW KADSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSTVSYSCQVTHECS SEQ ID NO: 19 Antibody 3A5.063 3A5.063 HCDR1 GGSISNGGYYWS 3A5.063 LCDR1 GKNNIGSKNVY

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SEQ ID NO: 4 SEQ ID NO: 21 3A5.063 HCDR2 YIYYSGTY SEQ ID NO: 6 3A5.063 LCDR2 DDSDRPS SEQ ID NO: 7 3A5.063 HCDR3 LGNWFDY SEQ ID NO: 8 3A5.063 LCDR3 QVWDSSSDHW SEQ ID NO: 15 3A5.063 VH S SEQ ID NO: 16 3A5.063 VL G25K SYVLTQPPSVSVAPGQTARITCGKNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVFG GGTKLTVLG SEQ ID NO: 22 3A5.063 NS QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS S VVTVPS S SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 18 3A5.063LC G25K SYVLTQPPSVSVAPGQTARITCGKNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVFG GGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW KADSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSTVSYSCQVTHECS SEQ ID NO: 23 Antibody 3A5.070 3A5.070HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5.070 LCDR1 GGDNIGSKNVY SEQ ID NO: 24 3A5.070HCDR2 YIYYSGTY SEQ ID NO: 6 3A5.070 LCDR2 DDSDRPS SEQ ID NO: 7 3A5.070 HCDR3 LGNWFDY SEQ ID NO: 8 3A5.070 LCDR3 QVWDSSSDHW SEQ ID NO: 15 3A5.070 VH S SEQ ID NO: 16 3A5.070 VL N26D SYVLTQPPSVSVAPGQTARITCGGDNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSSDHVVFG GGTKLTVLG

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SEQ ID NO: 25 3A5.070 NS QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS S VVTVPS S SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 18 ZA5.070 LC N26D SYVLTQPPSVSVAPGQTARITCGGDNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVFG GGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW KADSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSTVSYSCQVTHECS SEQ ID NO: 26 Antibody ZA5.082 ZA5.082 HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5.082 LCDR1 GGNHIGSKNVY SEQ ID NO: 27 ZA5.082 HCDR2 YIYYSGTY SEQ ID NO: 6 3A5.082 LCDR2 DDSDRPS SEQ ID NO: 7 ZA5.082 HCDR3 LGNWFDY SEQ ID NO: 8 3A5.082 LCDR3 QVWDSSSDHW SEQ ID NO: 15 ZA5.082 VH S SEQ ID NO: 16 3A5.082 VL N27H SYVLTQPPSVSVAPGQTARITCGGNHIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVFG GGTKLTVLG SEQ ID NO: 28 3A5.082 NS QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS S VVTVPS S SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 18 3A5.082LC N27H SYVLTQPPSVSVAPGQTARITCGGNHIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVFG GGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW KADSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSTVSYSCQVTHECS

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SEQ ID NO: 29 Antibody ZA5.084 ZA5.084 HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5.084 LCDR1 GGNNAGSKNVY SEQ ID NO: 30 ZA5.084 HCDR2 YIYYSGTY SEQ ID NO: 6 3A5.084 LCDR2 DDSDRPS SEQ ID NO: 7 ZA5.084 HCDR3 LGNWFDY SEQ ID NO: 8 3A5.084 LCDR3 QVWDSSSDHW SEQ ID NO: 15 ZA5.084 VH S SEQ ID NO: 16 3A5.084 VL I28A SYVLTQPPSVSVAPGQTARITCGGNNAGSKNVYWYQQKPGQAPVLVVH DDSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVF GGGTKLTVLG SEQ ID NO: 31 3A5.084 NS QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 18 3A5.084LC I28A SYVLTQPPSVSVAPGQTARITCGGNNAGSKNVYWYQQKPGQAPVLVVH DDSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVF GGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVA WKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVT HE SEQ ID NO: 32 Antibody 3 A5.107 3A5.107 HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5.107 LCDR1 GGNNGKKNVY SEQ ID NO: 33 3A5.107 HCDR2 YIYYSGTY SEQ ID NO: 6 3A5.107 LCDR2 DDSDRPS SEQ ID NO: 7 3A5.107 HCDR3 LGNWFDY SEQ ID NO: 8 3A5.107 LCDR3 QVWDSSSDHW SEQ ID NO: 15 3A5.107 VH S SEQ ID NO: 16

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3A5.107 VL S30K SYVLTQPPSVSVAPGQTARITCGGNNIGKKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVFG GGTKLTVLG SEQ ID NO: 34 3A5.107 HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS S VVTVPS S SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 18 3A5.107LC S30K SYVLTQPPSVSVAPGQTARITCGGNNIGKKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVFG GGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW KADSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHE SEQ ID NO: 35 Antibody 3A5.125 3A5.125HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5.I25 LCDR1 GGNNIGSKHVY SEQ ID NO: 36 3A5.125HCDR2 YIYYSGTY SEQ ID NO: 6 3A5.125 LCDR2 DDSDRPS SEQ ID NO: 7 3A5.125 HCDR3 LGNWFDY SEQ ID NO: 8 3A5.I25 LCDR3 QVWDSSSDHW SEQ ID NO: 15 3A5.125 VH S SEQ ID NO: 16 3A5.125 VL N32H SYVLTQPPSVSVAPGQTARITCGGNNIGSKHVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVFG GGTKLTVLG SEQ ID NO: 37 3A5.125HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS S VVTVPS S SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 18 3A5.125LC SYVLTQPPSVSVAPGQTARITCGGNNIGSKHVYWYQQKPGQAPVLVVHD

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N32H DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVFG GGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW KADSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHE GSTVEKTVAPTECS SEQ ID NO: 38 Antibody 3A5.127 ZA5.127 HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5.127 LCDR1 GGNNIGSKNAY SEQ ID NO: 39 ZA5.127 HCDR2 YIYYSGSIY SEQ ID NO: 6 3A5.127 LCDR2 DDSDRPS SEQ ID NO: 7 ZA5.127 HCDR3 LGNWFDY SEQ ID NO: 8 3A5.127 LCDR3 QVWDSSSDHW SEQ ID NO: 15 ZA5.127 VH S SEQ ID NO: 16 3A5.127 VL V33A SYVLTQPPSVSVAPGQTARITCGGNNIGSKNAYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVFG GGTKLTVLG SEQ ID NO: 40 3A5.127HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS S VVTVPS S SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 18 3A5.127LC V33A SYVLTQPPSVSVAPGQTARITCGGNNIGSKNAYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVFG GGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW KADSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHECS GS SEQ ID NO: 41 Antibody 3 A5.161 3A5.161 HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5.161 LCDR1 GGNNIGSKNVY SEQ ID NO: 5 3A5.161 HCDR2 YIYYSGSIY SEQ ID NO: 6 3A5.161 LCDR2 DDLDRPS SEQ ID NO: 42 3A5.161 HCDR3 LGNWFDY SEQ ID NO: 8 3A5.161 LCDR3 QVWDSSSDHW SEQ ID NO: 15 3A5.161 VH QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI

-44042576

GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVS S SEQ ID NO: 16 3A5.161 VL S52L SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DLDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVF GGGTKLTVLG SEQ ID NO: 43 3A5.161 HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS SVVTVPS S SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 18 3A5.161LC S52L SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DLDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVF GGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVA WKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVT HE SEQ ID NO: 44 Antibody 3 A5.169 3A5.169 HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5.169 LCDR1 GGNNIGSKNVY SEQ ID NO: 5 3A5.169 HCDR2 YIYYSGTY SEQ ID NO: 6 3A5.169 LCDR2 DDSSRPS SEQ ID NO: 45 3A5.169 HCDR3 LGNWFDY SEQ ID NO: 8 3A5.169 LCDR3 QVWDSSSDHW SEQ ID NO: 15 3A5.169 VH S SEQ ID NO: 16 3A5.169L D53S SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSSRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVFG GGTKLTVLG SEQ ID NO: 46 3A5.169HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS SVVTVPS S SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS

-45042576

FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQID NO: 18 3A5.169LC D53S SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSSRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSSDHVVFG GGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW KADSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSTVSYSCQVTHECS SEQ ID NO: 47 Antibody 3A5.232 3A5.232HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5.232 LCDR1 GGNNIGSKNVY SEQ ID NO: 5 3A5.232HCDR2 YIYYSGTY SEQ ID NO: 6 3A5.232 LCDR2 DDSDRPS SEQ ID NO: 7 3A5.232HCDR3 LGNWFDY SEQ ID NO: 8 3A5.232 LCDR3 QVWLSSSDHVV SEQ ID NO: 48 3A5.232 VH S SEQID NO: 16 3A5.232 VL D92L SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWLSSSDHWFG GGTKLTVLG SEQ ID NO: 49 3A5.232HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS S VVTVPS S SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQID NO: 18 3A5.232LC D92L SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWLSSSDHWFG GGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW KADSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSTVSYSCQVTHECS GS SEQ ID NO: 50 Antibody 3A5.276 3A5.276HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5.276 LCDR1 GGNNIGSKNVY SEQ ID NO: 5 3A5.276HCDR2 YIYYSGTY SEQ ID NO: 6 3A5.276 LCDR2 DDSDRPS SEQ ID NO: 7

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3A5.276 HCDR3 LGNWFDY SEQ ID NO: 8 3A5.276 LCDR3 QVWDSSSDSW SEQ ID NO: 51 3A5.276 VH S SEQ ID NO: 16 3A5.276VL H95bS SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDSWFG GGTKLTVLG SEQ ID NO: 52 3A5.276HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS S VVTVPS S SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 18 3A5.276LC H95bS SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDSWFG GGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW KADSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSTVSYSCQVTHECS SEQ ID NO: 53 Antibody 3A5.278 3A5.278HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5.278 LCDR1 GGNNIGSKNVY SEQ ID NO: 5 3A5.278HCDR2 YIYYSGTY SEQ ID NO: 6 3A5.278 LCDR2 DDSDRPS SEQ ID NO: 7 3A5.278HCDR3 LGNWFDY SEQ ID NO: 8 3A5.278 LCDR3 QVWDSSSDYVV SEQ ID NO: 54 3A5.278 VH S SEQ ID NO: 16 3A5.278L H95bY SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDYVVFG GGTKLTVLG SEQ ID NO: 55 3A5.278HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS S VVTVTYPS S SLGTKTYPS

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VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 18 3A5.278LC H95bY SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDYVVFG GGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW KADSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSTVSYSCQVTHECS SEQ ID NO: 56 Antibody 3A5.279 3A5.279HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5.279 LCDR1 GGNNIGSKNVY SEQ ID NO: 5 3A5.279HCDR2 YIYYSGTY SEQ ID NO: 6 3A5.279 LCDR2 DDSDRPS SEQ ID NO: 7 3A5.279HCDR3 LGNWFDY SEQ ID NO: 8 3A5.279 LCDR3 QVWDSSDDW SEQ ID NO: 57 3A5.279 VH S SEQ ID NO: 16 3A5.279L H95bD SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDDVVFG GGTKLTVLG SEQ ID NO: 58 3A5.279HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS S VVTVPS S SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 18 3A5.279LC H95bD SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDDVVFG GGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW KADSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSTVSYSCQVTHECS SEQ ID NO: 59 Antibody 3A5.294 3A5.294HCDR1 GGSISNGGYYWS 3A5.294 LCDR1 GGNNIGSKNVY

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SEQ ID NO: 4 SEQ ID NO: 5 3A5.294HCDR2 YIYYSGTY SEQ ID NO: 6 3A5.294 LCDR2 DDSDRPS SEQ ID NO: 7 3A5.294 HCDR3 LGNWFDY SEQ ID NO: 8 3A5.294 LCDR3 QVWDSSSSDHVA SEQ ID NO: 60 3A5.294 VH S SEQ ID NO: 16 3A5.294L V97A SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVAFG GGTKLTVLG SEQ ID NO: 61 3A5.294HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS S VVTVPS S SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 18 3A5.294LC V97A SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVAFG GGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW KADSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHECS SEQ ID NO: 62 Antibody 3 A5.3 02 3A5.302HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5.302 LCDR1 GGNNIGSKNVY SEQ ID NO: 5 3A5.302 HCDR2 YIYYSGTY SEQ ID NO: 6 3A5.302 LCDR2 DDSDRPS SEQ ID NO: 7 3A5.302 HCDR3 LGNWFDY SEQ ID NO: 8 3A5.302 LCDR3 QVWDSSSDHVW SEQ ID NO: 63 3A5.302 VH S SEQ ID NO: 16 3A5.302 VL V97W SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVWF GGGTKLTVLG SEQ ID NO: 64

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3A5.302 NS QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQS SGLYSLS SVVTVPS S SLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 18 3A5.302LC V97W SYVLTQPPSVSVAPGQTARITCGGNNIGSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVWF GGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVA WKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVT HE SEQ ID NO: 65 ZA5.097 ZA5.097 HCDR1 GGSISNGGYYWS SEQ ID NO: 4 3A5.097 LCDR1 GGNNIDSKNVY SEQ ID NO: 66 3A5.097 HCDR2 YIYYSGTY SEQ ID NO: 6 3A5.097 LCDR2 DDSDRPS SEQ ID NO: 7 3A5.097 HCDR3 LGNWFDY SEQ ID NO: 8 3A5.097 LCDR3 QVWDSSSDHW SEQ ID NO: 15 3A5.097 VH S SEQ ID NO: 16 3A5.097 VL G29D SYVLTQPPSVSVAPGQTARITCGGNNIDSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVFG GGTKLTVLG SEQ ID NO: 67 3A5.097HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISNGGYYWSWIRQHPGKGLEWI GYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASLG NWFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 18 3A5.097LC G29D SYVLTQPPSVSVAPGQTARITCGGNNIDSKNVYWYQQKPGQAPVLVVHD DSDRPSGIPERFSGSNSGNTATLTISRVEVGDEADYSCQVWDSSSDHVVFG GGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW KADSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSTVSYSCQVTHECS

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SEQ ID NO: 68 ZA5.046 VH nucleotide Sequence b (synthetic) CAGGTGCAGCTGCAGGAATCTGGCCCTGGCCTGGTCAAGCCCAGCCA GACCCTGAGCCTGACCTGTACCGTGTCCGGCGGCAGCATCAGCAACGG CGGCTACTACTGGTCCTGGATCAGACAGCACCCCGGCAAGGGCCTGG AATGGATCGGCTACATCTACTACAGCGGCAGCACCTACTACAACCCCA GCCTGAAGTCCAGAGTGACCATCAGCGTGGACACCAGCAAGAACCAG TTCAGCCTGAAGCTGAGCAGCGTGACAGCCGCCGACACCGCCGTGTAC TACTGCGCCAGCCTGGGCAATTGGTTCGACTACTGGGGCCAGGGCACC CTCGTGACAGTGTCCTCA SEQ ID NO: 69 Nucleotide sequence of human HC constant region ZA5.046 (synthetic) GCTAGCACCAAGGGCCCCAGCGTGTTCCCCCTGGCCCCTTGTAGCAGA AGCACCAGCGAGAGCACAGCCGCCCTGGGCTGCCTGGTGAAAGACTA CTTCCCCGAGCCCGTCACCGTGTCCTGGAACAGCGGAGCCCTGACCAG CGGCGTGCACACCTTTCCAGCCGTGCTGCAGAGCAGCGGCCTGTACAG CCTGAGCAGCGTGGTGACAGTGCCCTCCAGCAGCCTGGGCACCAAGA CCTACACCTGTAACGTGGACCACAAGCCCAGCAACACCAAGGTGGAC AAGCGGGTGGAATCTAAGTACGGCCCACCCTGCCCCCCCTGCCCTGCC CCTGAATTTCTGGGCGGACCCTCCGTGTTCCTGTTCCCCCCAAAGCCCA AGGACACCCTGTATATCACTCGGGAGCCCGAAGTGACCTGCGTGGTGG TGGACGTGTCCCAGGAAGATCCCGAGGTCCAGTTCAATTGGTACGTGG ACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACA GTTCAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCA GGACTGGCTGAACGGCAAAGAGTACAAGTGCAAAGTCTCCAACAAGG GCCTGCCCAGCTCCATCGAGAAAACCATCAGCAAGGCCAAGGGCCAG CCCCGCGAGCCTCAGGTGTACACACTGCCCCCCAGCCAGGAAGAGAT GACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAAGGCTTCTACCC CAGCGATATCGCCGTGGAATGGGAGAGCAACGGCCAGCCCGAGAACA ACTACAAGACCACCCCCCCTGTGCTGGACAGCGACGGCAGCTTCTTCC TGTACTCCCGGCTGACCGTGGACAAGAGCCGGTGGCAGGAAGGCAAC GTCTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACC CAGAAGTCCCTGAGCCTGAGCCTGGGC SEQ ID NO: 70 Nucleotide sequence b3A5.046VL (synthetic) AGCTACGTGCTGACCCAGCCTCCTAGCGTGTCCGTGGCCCCTGGCCAG ACCGCCAGAATCACCTGTGGCGGCAACAACATCGGCAGCAAGAACGT GTACTGGTATCAGCAGAAGCCCGGCCAGGCCCCCGTGCTGGTGGTGCA CGACGACAGCGACAGACCCAGCGGCATCCCCGAGCGGTTCAGCGGCA GCAACAGCGGCAATACCGCCACCCTGACCATCAGCCGGGTGGAAGTG GGCGACGAGGCCGACTACAGCTGCCAGGTCTGGGACAGCAGCAGCGA CCACGTGGTGTTCGGCGGAGGCACCAAGCTGACCGTCCTAGGT SEQ ID NO: 71 Nucleotide sequence of human constant region ZA5.046 LC (synthetic) CAGCCCAAGGCCGCTCCCAGCGTGACCCTGTTCCCCCCAAGCAGCGAG GAACTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCAGCGACTTC TACCCTGGGGCCGTGACCGTGGCCTGGAAGGCCGATAGCAGCCCTGTG AAGGCCGGCGTGGAAACCACCACCCCCTCCAAGCAGAGCAACAACAA ATACGCCGCCAGCAGCTACCTGTCCCTGACCCCCGAGCAGTGGAAGTC CCACCGGTCCTACAGCTGCCAGGTGACACACGAGGGCAGCACCGTGG AAAAGACCGTGGCCCCCACCGAGTGCAGC SEQ ID NO: 72

Incarnations.

The following list of embodiments is intended to supplement, and not to distort or replace, previous descriptions.

Embodiment 1 A human antibody molecule that immunospecifically binds to human IL-5 with an equilibrium affinity constant (KD) of at least about 40 pM as determined by surface plasmon resonance.

Embodiment 2. A human antibody molecule that immunospecifically binds to human IL-5, wherein the antibody molecule comprises: a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a heavy chain CDR3 , comprising the amino acid sequence of SEQ ID NO: 8, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, 21, 24, 27, 30, 33, 36, 39 or 66, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, 42, or 45, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15, 48, 51, 54, 57, 60, or 63.

Embodiment 3. An antibody molecule according to embodiment 1 or 2, wherein the antibody molecule comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 8, and

a) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

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b) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

c) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 24, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

d) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 27, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

e) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 30, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

f) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 33, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

g) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 36, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

h) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 39, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

i) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 66, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

j) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

k) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 45, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

l) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 48;

m) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 51;

n) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 54;

o) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 57;

p) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 60; or

q) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 63;

where the position of the amino acid residues of the CDR is determined in accordance with AbM.

Embodiment 4. An antibody molecule according to embodiment 3, wherein the antibody molecule comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 8, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15.

Embodiment 5 An antibody molecule according to any of the previous embodiments, wherein the antibody molecule comprises a heavy chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 16 and

a) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17;

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b) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 22;

c) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 25;

d) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 28;

e) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 31;

f) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 34;

g) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 37;

h) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 40;

i) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 43;

j) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 46;

k) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 49;

l) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 52;

m) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 55;

n) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 58;

o) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 61;

p) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 64; or

q) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 67.

Embodiment 6 An antibody molecule according to any of the previous embodiments, wherein the antibody molecule comprises a heavy chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 16 and a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17.

Embodiment 7 An antibody molecule according to any of the previous embodiments, wherein the antibody molecule comprises:

a) S228P mutation;

b) M252Y mutation, S254T mutation and T256E mutation;

c) deletion of the C-terminal heavy chain lysine residue; or

d) any combination of a-c.

Embodiment 8 An antibody molecule according to embodiment 7 wherein the antibody molecule comprises an S228P mutation and a deletion of a C-terminal heavy chain lysine residue.

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Embodiment 9 An antibody molecule according to embodiment 7, wherein the antibody molecule comprises an S228P mutation, an M252Y mutation, an S254T mutation, a T256E mutation, and a deletion of a C-terminal heavy chain lysine residue.

Embodiment 10 An antibody molecule according to any of the previous embodiments, wherein the antibody molecule comprises an IgG4 heavy chain constant region and a lambda light chain constant region.

Embodiment 11 An antibody molecule according to any of the previous embodiments, wherein the antibody molecule comprises a heavy chain comprising an amino acid sequence that is at least 90%, 95, 96, 97, 98, 99, or 100% identical to the amino acid sequence of SEQ ID NO: 18 and

a) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19;

b) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 23;

c) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26;

d) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 29;

e) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 32;

f) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 35;

g) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 38;

h) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 41;

i) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 44;

j) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 47;

k) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 50;

l) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 53;

m) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 56;

n) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 59;

o) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 62;

p) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 65; or

q) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 68.

Embodiment 12 An antibody molecule according to any one of embodiments 1-10, wherein the antibody molecule comprises a heavy chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%. identical to the amino acid sequence of SEQ ID NO: 20 and a light chain containing an amino acid sequence that is at least 90, 95, 96, 97, 98, 99 or 100% identical to the amino acid acid sequence of SEQ ID NO: 19.

Embodiment 13 An antibody molecule according to embodiment 2 or embodiment 3, wherein the antibody molecule is a Fab fragment, a Pab2 fragment, or a single chain antibody.

Embodiment 14 An antibody molecule according to any of the previous embodiments, wherein the antibody molecule has one or more of the following properties:

a) reduces the binding of IL-5 to the IL-5 receptor;

b) has a serum half-life of at least about 20 days; or

c) binds human and cynomolgus monkey IL-5, but not mouse, rat or guinea pig IL-5.

Embodiment 15 An antibody molecule according to embodiment 2, wherein the antibody molecule binds to human IL-5 with an equilibrium affinity constant (KD) of at least about 40 pM as determined by surface plasmon resonance.

Embodiment 16 A pharmaceutical composition comprising an antibody molecule according to any one of embodiments 1-15.

Embodiment 17 A nucleic acid molecule encoding an antibody molecule according to any one of embodiments 1-15.

Embodiment 18. A vector containing a nucleic acid molecule according to embodiment 17.

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Claims (21)

Embodiment 19 A cell transformed to express an antibody molecule according to any of embodiments 1-15. Embodiment 20. A method of treating a subject suffering from eosinophilic asthma, hypereosinophilic syndrome, eosinophilic nasal polyposis, eosinophilic granulomatosis with polyangiitis, atopic dermatitis, or eosinophilic esophagitis, comprising administering to the subject a therapeutically effective amount of an antibody molecule according to any one of embodiments 1-15 or a pharmaceutical composition according to embodiment 16 for the treatment of eosinophilic asthma, hypereosinophilic syndrome, eosinophilic nasal polyposis, eosinophilic granulomatosis with polyangiitis, atopic dermatitis, or eosinophilic esophagitis. Embodiment 21 Use of an effective amount of an antibody molecule according to any one of embodiments 1-15 or a pharmaceutical composition according to embodiment 16 for the treatment of eosinophilic asthma, hypereosinophilic syndrome, eosinophilic nasal polyposis, eosinophilic granulomatosis with polyangiitis, atopic dermatitis, or eosinophilic esophagitis. Embodiment 22 Use of an antibody molecule according to any one of embodiments 1-15 or a pharmaceutical composition according to embodiment 16 in the manufacture of a medicament for the treatment of eosinophilic asthma, hypereosinophilic syndrome, eosinophilic nasal polyposis, eosinophilic granulomatosis with polyangiitis, atopic dermatitis, or eosinophilic esophagitis. CLAIM 1. A human antibody molecule that immunospecifically binds to human IL-5, wherein the antibody molecule comprises: a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a heavy chain CDR3, comprising the amino acid sequence of SEQ ID NO: 8, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, 21, 24, 27, 30, 33, 36, 39 or 66, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7 , 42, or 45, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15, 48, 51, 54, 57, 60, or 63. 2. An antibody molecule according to claim 1, wherein the antibody molecule comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 8, and a) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15; b) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15; c) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 24, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15; d) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 27, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15; e) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 30, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15; f) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 33, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15; g) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 36, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15; h) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 39, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15; i) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 66, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15; j) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15; - 55 042576 k) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 45, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15; l) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 48; m) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 51; n) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 54; o) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 57; p) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 60; or q) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 63; where the position of the amino acid residues of the CDR is determined in accordance with AbM. 3. An antibody molecule according to claim 2, wherein the antibody molecule comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 8, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15. 4. An antibody molecule according to any one of the preceding claims, wherein the antibody molecule comprises a heavy chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 16 and a) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17; b) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 22; c) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 25; d) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 28; e) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 31; f) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 34; g) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 37; h) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 40; i) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 43; j) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 46; - 56 042576 j) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 49; l) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 52; m) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 55; n) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 58; o) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 61; p) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 64; or q) a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 67. 5. An antibody molecule according to any one of the preceding claims, wherein the antibody molecule comprises a heavy chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 16 and a light chain variable region comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:17. 6. An antibody molecule according to any one of the preceding claims, characterized in that the antibody molecule comprises: a) S228P mutation; b) M252Y mutation, S254T mutation and T256E mutation; c) deletion of the C-terminal heavy chain lysine residue; or e. any combination of a-c. 7. An antibody molecule according to claim 6, wherein the antibody molecule comprises an S228P mutation and a deletion of a C-terminal heavy chain lysine residue. 8. An antibody molecule according to claim 6, wherein the antibody molecule comprises an S228P mutation, an M252Y mutation, an S254T mutation, a T256E mutation, and a deletion of a C-terminal heavy chain lysine residue. 9. An antibody molecule according to any one of the preceding claims, wherein the antibody molecule comprises an IgG4 heavy chain constant region and a lambda light chain constant region. 10. An antibody molecule according to any one of the preceding claims, characterized in that the antibody molecule comprises a heavy chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18 and a) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19; b) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 23; c) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26; d) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 29; e) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 32; f) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 35; g) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 38; h) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 41; i) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 44; j) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 47; - 57 042576 j) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 50; l) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 53; m) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 56; n) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 59; o) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 62; p) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 65; or q) a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 68. 11. An antibody molecule according to any one of claims 1 to 9, characterized in that the antibody molecule comprises a heavy chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%. identical to the amino acid sequence of SEQ ID NO: 20 and a light chain containing an amino acid sequence that is at least 90, 95, 96, 97, 98, 99 or 100% identical to the amino acid acid sequence of SEQ ID NO: 19. 12. An antibody molecule according to claim 1 or 2, characterized in that the antibody molecule is a Fab fragment, a Fab2 fragment or a single chain antibody. 13. An antibody molecule according to any one of the preceding claims, characterized in that the antibody molecule has one or more of the following properties: a) reduces the binding of IL-5 to the IL-5 receptor; b) has a serum half-life of at least about 20 days; or c) binds human and cynomolgus monkey IL-5, but not mouse, rat or guinea pig IL-5. 14. An antibody molecule according to claim 1, wherein the antibody molecule binds to human IL-5 with an equilibrium affinity constant (K _D ) of at least about 40 pM as determined by surface plasmon resonance. 15. A pharmaceutical composition containing an antibody molecule according to any one of claims 1-14. 16. A nucleic acid molecule encoding an antibody molecule according to any one of claims 1-14. 17. A vector comprising a nucleic acid molecule according to claim 16. 18. A cell transformed to express an antibody molecule according to any one of claims 1 to 14, containing a vector according to claim 17 or a nucleic acid molecule according to claim 16. 19. A method of treating a subject suffering from eosinophilic asthma, hypereosinophilic syndrome, eosinophilic nasal polyposis, eosinophilic granulomatosis with polyangiitis, atopic dermatitis, or eosinophilic esophagitis, comprising administering to the subject a therapeutically effective amount of an antibody molecule according to any one of claims 1 to 14 or a pharmaceutical composition according to 15 for the treatment of eosinophilic asthma, hypereosinophilic syndrome, nasal polyposis with eosinophilic lesions, eosinophilic granulomatosis with polyangiitis, atopic dermatitis or eosinophilic esophagitis. 20. Use of an effective amount of an antibody molecule according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15 in the treatment of eosinophilic asthma, hypereosinophilic syndrome, nasal polyposis with eosinophilic involvement, eosinophilic granulomatosis with polyangiitis, atopic dermatitis or eosinophilic esophagitis. 21. The use of an antibody molecule according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15 in the manufacture of a medicament in the treatment of eosinophilic asthma, hypereosinophilic syndrome, nasal polyposis with eosinophilic involvement, eosinophilic granulomatosis with polyangiitis, atopic dermatitis or eosinophilic esophagitis. -