Method of administering an Anti-soluble urokinase plasominogen activator receptor antibody for the treatment of kidney disease

Abstract

The present invention relates to a method of treating a glomerular kidney disease in a human patient in need thereof, comprising administering to the patient an isolated antibody or an antigen binding fragment thereof that binds to soluble urokinase plasminogen activator receptor (suPAR). The present invention also relates to a method of reducing proteinuria associated with a kidney disease in a patient in need thereof, comprising administering to the patient an isolated antibody or an antigen binding fragment thereof that binds to suPAR. The present invention also relates to a method of inhibiting suPAR in a patient in need thereof, having a glomerular kidney disease, with the same isolated antibody or fragment thereof.

Description

Attorney Docket No. A618-14.WO METHOD OF ADMINISTERING AN ANTI-SOLUBLE UROKINASE PLASOMINOGEN ACTIVATOR RECEPTOR ANTIBODY FOR THE TREATMENT OF KIDNEY DISEASE PRIORITY CLAIM

[0001] This application claims priority to United States Provisional Patent Application No. 63 / 658,365 filed on June 10, 2024 and titled “METHOD OF ADMINISTERING AN ANTI-SOLUBLE UROKINASE PLASOMINOGEN ACTIVATOR RECEPTOR ANTIBODY FOR THE TREATMENT OF KIDNEY DISEASE,” United States Provisional Application No. 63 / 658,394 filed on June 10, 2024 and titled “METHOD OF ADMINISTERING AN ANTI- SOLUBLE UROKINASE PLASOMINOGEN ACTIVATOR RECEPTOR ANTIBODY FOR THE TREATMENT OF KIDNEY DISEASE,” and United States Provisional Application No. 63 / 658,397 filed on June 10, 2024 and titled “METHOD OF ADMINISTERING AN ANTI- SOLUBLE UROKINASE PLASOMINOGEN ACTIVATOR RECEPTOR ANTIBODY FOR THE TREATMENT DIABETIC NEPHROPATHY,” the entire contents of all of which are hereby incorporated by reference herein. FIELD OF THE INVENTION

[0002] This application relates to methods of treating a kidney disease comprising administering an isolated antibody or an antigen binding fragment thereof that binds to soluble urokinase plasminogen activator receptor (suPAR). BACKGROUND

[0003] Glomerular kidney diseases are characterized by structural damage to the glomerular filtration barrier accompanied by proteinuria which is a key feature of complex disorders such as primary focal segmental glomerulosclerosis (FSGS), treatment-resistance minimal change disease (TR-MCD), primary immunoglobulin A nephropathy (IgAN), primary membranous nephropathy (PMN), and diabetic nephropathy (DN). Current therapeutics targeting glomerular diseases are aimed at symptom and sign management through diet, blood pressure medication, immunosuppression, and inflammation reduction. Standard of care therapies do not sufficiently address disease progression and management.Attorney Docket No. A618-14.WO

[0004] Current treatment options for glomerular diseases are directed at resolving proteinuria and delaying the progression to end stage kidney disease (ESKD). In general, patients with glomerular disorders receive sodium and protein restrictions, and antihypertensive treatment directed at inhibiting the renin-angiotensin system (e.g., angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB)), in attempts to provide kidney protective benefits through slowing the progressive loss of kidney function. Patients who have proteinuric kidney diseases (with or without diabetes) may also benefit in a similar manner from treatment with sodium glucose co-transporter-2 (SGLT2) inhibitors. While the majority of clinical trials with SGLT2 inhibitors demonstrating kidney protective benefits have been performed in proteinuric patients with diabetic kidney disease, there are data to suggest that these benefits may also extend to nondiabetic proteinuric patients.

[0005] Current therapeutics targeting glomerular diseases are aimed at symptom and sign management through diet, blood pressure medication, immunosuppression, and inflammation reduction. None of the currently available treatments for any of the glomerular disorders and proteinuria are curative. Standard of care therapies do not sufficiently address disease progression and management. Corticosteroid therapy has been associated with a multitude of adverse effects. Likewise, blood pressure lowering agents could be associated with kidney injury, immunosuppressant therapy typically results in health complications such as infections, and sodium-glucose cotransporter-2 (SGLT2) inhibitors that aid the kidneys in removing blood sugar through the urine can cause kidney disease and urinary tract infections. Therefore, there remains a high need for disease-modifying treatment options, including steroid-sparing options, to slow or halt disease progression of glomerular diseases. BRIEF SUMMARY OF THE INVENTION

[0006] In one aspect, the present application generally relates to a method of treating a glomerular kidney disease in a human patient in need thereof. The method comprises administering to the patient a therapeutically effective amount of an isolated antibody or an antigen binding fragment thereof that binds to soluble urokinase plasminogen activator receptor (suPAR). The antibody or the antigen binding fragment comprises a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, aAttorney Docket No. A618-14.WO LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6.

[0007] The present invention also generally relates to a method of reducing proteinuria associated with a kidney disease in a human patient in need thereof. The method comprises administering to the patient a therapeutically effective amount of an isolated antibody or an antigen binding fragment thereof that binds to suPAR, the antibody or the antigen binding fragment comprises a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6.

[0008] The present invention also generally relates to a method of inhibiting suPAR in a human patient in need thereof having a glomerular kidney disease. The method comprises administering to the patient a therapeutically effective amount of an isolated antibody or an antigen binding fragment thereof that binds to suPAR, the antibody or the antigen binding fragment comprises a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6.

[0009] In certain examples, the glomerular kidney disease is selected from the group consisting of diabetic nephropathy, primary focal segmental glomerulosclerosis, treatment- resistance minimal change disease, primary immunoglobulin A nephropathy, primary membranous nephropathy, and combinations thereof. In certain examples, the glomerular kidney disease is diabetic nephropathy. In certain examples, the glomerular kidney disease is primary focal segmental glomerulosclerosis. In certain examples, the glomerular kidney disease is treatment resistant-minimal change disease. In certain examples, the glomerular kidney disease is primary IgA nephropathy. In certain examples, the glomerular kidney disease is primary membranous nephropathy. In certain examples, the glomerular kidney disease is the combination of primary focal segmental glomerulosclerosis and treatment-resistance minimalAttorney Docket No. A618-14.WO change disease. In certain examples, the glomerular kidney disease is primary focal segmental glomerulosclerosis, or primary immunoglobulin A nephropathy.

[0010] In certain examples, the dose is from about 2 mg / kg to about 6 mg / kg. In certain examples, the dose is about 2 mg / kg. In certain examples, the dose is about 6 mg / kg. In certain examples, the antibody or the antigen binding fragment is intravenously administered to the patient. In certain examples, the antibody or the antigen binding fragment is intravenously administered to the patient once every 2 weeks. In certain examples, the antibody or the antigen binding fragment is intravenously administered to the patient once every 2 weeks for a treatment period of about 14 weeks.

[0011] In certain examples, the antibody is a humanized antibody. In certain examples, the antibody or the antibody binding fragment comprises a heavy chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 9. In certain examples, the antibody or the antibody binding fragment comprises a heavy chain variable region that is at least 97% identical to the amino acid sequence of SEQ ID NO: 9. In certain examples, the antibody or the antibody binding fragment comprises a heavy chain variable region that is at least 99% identical to the amino acid sequence of SEQ ID NO: 9. In certain examples, the antibody or the antibody binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9.

[0012] In certain examples, the antibody or the antibody binding fragment comprises a light chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10. In certain examples, the antibody or the antibody binding fragment comprises a light chain variable region that is at least 97% identical to the amino acid sequence of SEQ ID NO: 10. In certain examples, the antibody or the antibody binding fragment comprises a light chain variable region that is at least 99% identical to the amino acid sequence of SEQ ID NO: 10. In certain examples, the antibody or the antibody binding fragment comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10.

[0013] In certain examples, the antibody or the antibody binding fragment comprises a heavy chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 9 and / or a light chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10. In certain examples, the antibody or the antibody binding fragment comprises a heavy chain variable region that is at least 97% identical to the amino acid sequence of SEQ ID NO: 9 and / or a light chain variable region that is at least 97% identicalAttorney Docket No. A618-14.WO to the amino acid sequence of SEQ ID NO: 10. In certain examples, the antibody or the antibody binding fragment comprises a heavy chain variable region that is at least 99% identical to the amino acid sequence of SEQ ID NO: 9 and / or a light chain variable region that is at least 99% identical to the amino acid sequence of SEQ ID NO: 10. In certain examples, the antibody or the antibody binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10.

[0014] In certain examples, the antibody or the antibody binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 11. In certain examples, the antibody or the antibody binding fragment comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 12. In certain examples, the antibody or the antibody binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 11, a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 12.

[0015] In certain examples, the antibody or the antibody binding fragment comprises a heavy chain that is at least 95% identical to the amino acid sequence of SEQ ID NO: 7 and / or a light chain that is at least 95% identical to the amino acid sequence of SEQ ID NO: 8. In certain examples, the antibody or the antibody binding fragment comprises a heavy chain that is at least 97% identical to the amino acid sequence of SEQ ID NO: 7 and / or a light chain variable region that is at least 97% identical to the amino acid sequence of SEQ ID NO: 8. In certain examples, the antibody or the antibody binding fragment comprises a heavy chain that is at least 99% identical to the amino acid sequence of SEQ ID NO: 7 and / or a light chain that is at least 99% identical to the amino acid sequence of SEQ ID NO: 8. In certain examples, the antibody or the antibody binding fragment comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 7, and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

[0016] These and other aspects of the invention will become apparent to those skilled in the art after a reading of the following detailed description of the invention, including the figures and appended claims.Attorney Docket No. A618-14.WO BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1A provides data on a linear concentration scale for mean plasma WAL0921 concentration-time profiles obtained according to an exemplary Phase 1 study described in Example 4.

[0018] FIG.1B provides the data of FIG.1A on a logarithmic concentration scale.

[0019] FIG. 2 provides plasma free suPAR concentration data obtained according to the exemplary Phase 1 study described in Example 4.

[0020] FIG. 3A provides aggregate preliminary WAL0921 plasma concentration-time profiles for Cohort 1 and Cohort 2 of the Phase 2 Study described in Example 7 on a linear concentration scale.

[0021] FIG.3B provides the data of FIG.3A on a logarithmic concentration scale.

[0022] FIG. 4 provides aggregate preliminary mean percentage change in baseline plasma free suPAR over 12 weeks by dose from the Phase 2 study of Example 7.

[0023] FIG. 5 provides aggregate preliminary mean percentage change in baseline plasma free suPAR over 12 weeks for subjects who received WAL0921 in Cohorts 1 and 2 of the Phase 2 study of Example 7.

[0024] FIG.6 provides aggregate preliminary percent change in UACR over 36 weeks for subjects in Cohort 1 of the Phase 2 study of Example 7.

[0025] FIG. 7 provides preliminary percent change in UPCR for two subjects in Cohort 3 of the Phase 2 study of Example 7 that received 6 mg / kg of WAL0921. DETAILED DESCRIPTION

[0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set in the specification. All patents, published patent applications and publications cited herein are incorporated by reference as if set forth fully herein. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.Attorney Docket No. A618-14.WO Further, the dates of publication provided herein can be different from the actual publication dates.

[0027] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. When used herein the term “comprising” can be substituted with the term “containing” or “including” or sometimes when used herein with the term “having.” Moreover, each of the terms “by,” “comprising,” “comprises,” “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably.

[0028] When used herein “consisting of” excludes any element, step, or ingredient not specified in the claim element. When used herein, “consisting essentially of” does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. Any of the aforementioned terms of “comprising,” “containing,” “including,” and “having,” whenever used herein in the context of an aspect or embodiment of the application can be replaced with the term “consisting of” or “consisting essentially of” to vary scopes of the disclosure.

[0029] As used herein, the conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or.”

[0030] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound,” “a composition,” or “a disorder,” includes, but is not limited to, two or more such compounds, compositions, or disorders, and the like.

[0031] Unless otherwise stated, any numerical value, such as a concentration or a concentration range described herein, are to be understood as being modified in all instancesAttorney Docket No. A618-14.WO by the term “about.” As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. For example, a concentration of 1 mg / mL includes 0.9 mg / mL to 1.1 mg / mL. Likewise, a concentration range of 1 mg / mL to 10 mg / mL includes 0.9 mg / mL to 11 mg / mL. More particularly, the numerical value may include ± 1%, ± 3%, or ± 5% of the recited value.

[0032] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It can be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. When a range is expressed, a further example includes from the one particular value and / or to the other particular value. As used herein, the use of a numerical range expressly includes all possible subranges, all individual numerical values within that range, including integers within such ranges and fractions of the values unless the context clearly indicates otherwise. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g., the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g., ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’,” where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0033] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.Attorney Docket No. A618-14.WO

[0034] As used interchangeably herein, “subject,” “individual,” or “patient” refers to a vertebrate organism, such as a mammal (e.g., human) including a non-primate (e.g., a camel, donkey, zebra, cow, pig, horse, goat, sheep, cat, dog, rat, rabbit, guinea pig, marmoset or mouse) or a primate (e.g., a monkey, chimpanzee, or human). More particularly, the “subject,” “individual,” or “patient” is a human.

[0035] As used herein, the terms “treating” and “treatment” can refer generally to obtaining a desired pharmacological and / or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as a kidney disorder. The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder, or condition. The term “treatment” as used herein can include any treatment of a disorder in a subject, particularly a human and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and / or its symptoms or conditions. The term “treatment” as used herein can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and / or those in which the disorder is to be prevented. As used herein, the term “treating,” can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and / or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

[0036] The term “therapeutically effective amount” as used herein refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of one or more of the symptoms of the disease or disorder being treated; and / or reduction of the severity of one or more of the symptoms of the disease or disorder being treated.Attorney Docket No. A618-14.WO

[0037] As used herein, the term “antibody” or “antibodies” is used in a broad sense and includes immunoglobulin molecules including polyclonal antibodies, monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies and antibody fragments. In general, antibodies are proteins or peptide chains that exhibit binding specificity to a specific antigen. Immunoglobulins can be assigned to five major classes, namely IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified as the isotypes IgA1, IgA2, IgG1, IgG2, IgG3 and IgG4. Preferably, the antibodies of the present application are IgG1.

[0038] “Full antibody molecules” are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g., IgM). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CH1, CH2 and CH3). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). According to particular examples, the antibodies of the invention include heavy and / or light chain constant regions from murine antibodies or human antibodies.

[0039] As used herein, the term “antigen-binding fragment” refers to a portion of an immunoglobulin molecule that retains the heavy chain and / or the light chain antigen binding site, such as heavy chain complementarity determining regions (HCDR) 1, 2 and 3, light chain complementarity determining regions (LCDR) 1, 2 and 3, a heavy chain variable region (VH), or a light chain variable region (VL). Antibody binding fragments may include a diabody, a Fab, a Fab′, a F(ab′)2, a Fd and a Fv fragments, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, a bispecific dsFv (dsFv-dsFv′), a disulfide stabilized diabody (ds diabody), a single- chain antibody molecule (scFv), a single-chain antibody molecule (scFv), a single domain antibody (sdab), or any other antibody fragment that binds to an antigen but does not comprise a full antibody molecule.

[0040] A light or heavy chain variable region consists of a “framework” region interrupted by “antigen-binding sites.” The antigen-binding sites may be defined using various terms and numbering schemes as follows: (i) Kabat (Wu and Kabat, J Exp Med.132:211-50, 1970, (ii) Chothia (Chothia and Lesk, J Mol Biol.196:901-17, 1987 and Abhinandan and Martin, Mol Immunol.45:3832-9, 2008); (iii) ImMunoGeneTics (IMGT) (Lefranc et al., Dev Comp Immunol.27:55-77, 2003 and the IMGT database (http: / / www.imgt.org) provides a standardized numbering and definition of these regions); (iv) North numbering (North et al., AAttorney Docket No. A618-14.WO New Clustering of Antibody CDR Loop Conformations, Journal of Molecular Biology, 406:228-256 (2011)).

[0041] The terms “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2” and “LCDR3” may by defined by any of the methods described above, Kabat, Chothia, IMGT or North numbering, unless otherwise explicitly stated in the specification.

[0042] “Framework” or “framework sequence” is the remaining sequences within the variable region of an antibody other than those defined to be antigen-binding site sequences. Because the exact definition of an antigen-binding site can be determined by various delineations as described above, the exact framework sequence depends on the definition of the antigen-binding site.

[0043] “Monoclonal antibody” refers to an antibody population with single amino acid composition in each heavy and each light chain, except for possible well known alterations such as removal of C-terminal lysine from the antibody heavy chain. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population.

[0044] “Humanized antibodies” refers to antibodies in which the antigen binding sites are derived from non-human species and the variable region frameworks are derived from human immunoglobulin sequences. Humanized antibodies may include substitutions in the framework regions so that the framework may not be an exact copy of expressed human immunoglobulin or germline gene sequences.

[0045] “Human antibodies” refers to antibodies having heavy and light chain variable regions in which both the framework and the antigen binding site are derived from sequences of human origin. If the antibody contains a constant region or a portion of the constant region, the constant region also is derived from sequences of human origin.

[0046] 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% or 99% identical in amino acid sequence to an amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes. In some cases, human antibody comprises heavy or light chain variable regions that are derived from sequences of human origin if the variable regions of the antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Human antibody may contain amino acid differences when compared to the human germline or rearranged immunoglobulin sequences due to for example naturally occurring somaticAttorney Docket No. A618-14.WO mutations or intentional introduction of substitutions into the framework or antigen binding site, or both. Antibodies in which antigen binding sites are derived from a non-human species are not included in the definition of “human antibody”.

[0047] “Specific binding” or “specifically binds” or “binds” refers to antibody binding to an antigen or an epitope within the antigen with greater affinity than for other antigens. Typically, the antibody binds to the antigen or the epitope within the antigen with an equilibrium dissociation constant (KD) of about 1×10−8M or less, for example about 1×10−9M or less, or about 1×10−10M or less. The equilibrium dissociation constant (KD) is obtained from the ratio of kdto ka(i.e., kd / ka) and is expressed as a molar concentration (M). The KDvalues for antibodies can be obtained using methods in the art in view of the present application. Antibodies that specifically bind to the antigen or the epitope within the antigen may, however, have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs). While a monospecific antibody specifically binds one antigen or one epitope, a bispecific antibody specifically binds two distinct antigens or two distinct epitopes.

[0048] “uPAR” refers to urokinase plasminogen activator receptor (uPAR), all fragments thereof, and all post-translational glycosylation, genetic mutation, and different isoforms derived from alternative splicing, and encompasses a human urokinase plasminogen activator receptor (human uPAR). Human uPAR, also known as CD87, is encoded by the human PLAUR gene and belongs to the lymphocyte antigen-6 superfamily. The protein moiety consists of three Ly6 / uPAR / alpha-neurotoxin-like (LU) homologous domains denoted DI (residues 1–92), DII (residues 93–191) and DIII (residues 192–283), as numbered from the N- terminus. It is expressed and either tethered to a cell membrane as a glycosylphosphatidylinositol (GPI)-anchored membrane bound protein or cleaved at the GPI anchor by phospholipases to generate the soluble form of uPAR (suPAR).

[0049] “suPAR” refers to soluble urokinase plasminogen receptor, all fragments thereof, and all post-translational glycosylation, genetic mutation, and different isoforms derived from alternative splicing. suPAR is derived from the cell membrane tethered receptor uPAR post enzymatic cleavage and initially comprises the identical three ectodomains of uPAR. suPAR is the soluble form of urokinase plasminogen activator receptor. As suPAR and uPAR can be cleaved at the linker region between DI and DII by a variety of enzymes, they may generate a DI fragment and a DIIDIII fragment. Circulating suPAR may, in turn, undergo proteolytic cleavage of the linker between DI and DII domains, thus generating free DI and DIIDIII domains with similar and / or different biologic properties.Attorney Docket No. A618-14.WO

[0050] As used herein, the term “isolated” means a biological component (such as a nucleic acid, peptide or protein) has been substantially separated, produced apart from, or purified away from other biological components of the organism in which the component naturally occurs, i.e., other chromosomal and extrachromosomal DNA and RNA, and proteins. Nucleic acids, peptides and proteins that have been “isolated” thus include nucleic acids and proteins purified by standard purification methods. “Isolated” nucleic acids, peptides and proteins can be part of a composition and still be isolated if such composition is not part of the native environment of the nucleic acids, peptides and proteins prepared by recombinant expression in a host cell.

[0051] An “isolated antibody that binds to suPAR” or an “isolated anti-suPAR antibody,” as used herein, is intended to refer to an antibody that specifically binds suPAR, more specifically, human suPAR. In some examples, the “isolated antibody that binds to suPAR” or “isolated anti-suPAR antibody” is an antibody that specifically binds suPAR and uPAR, and is substantially free of other antibodies having different antigenic specificities. For example, the “isolated antibody that binds to suPAR” or “isolated anti-suPAR antibody” is an antibody that specifically binds human suPAR and human uPAR, and is substantially free of other antibodies having different antigenic specificities. In one example, the “isolated antibody that binds to suPAR” or “isolated anti-suPAR antibody,” binds extracellular portions of suPAR and uPAR, more specifically, the extracellular portions of human suPAR and human uPAR.

[0052] The glomerular filtration barrier is composed of podocytes, the glomerular basement membrane, and the fenestrated endothelium, that together are responsible for solute clearance and large plasma protein retention. Podocytes form a critical component of the kidney’s filtration process. Podocytes are terminally differentiated epithelial cells lining the glomerular capillaries and extend foot processes terminating in specialized cell junctions bridged by slit diaphragms. The cells have a multitude of physiological functions which include: 1) providing a charge barrier to protein passage from intravascular compartment; 2) maintaining integrity of underlying glomerular capillaries; 3) generating extracellular matrix (ECM) proteins such as collagen; 4) maintaining glomerular basement membrane via integrin mediated adhesion; 5) secreting critical cell survival factors such as vascular endothelial growth factor (VEGF) and angiopoietin-1; and 6) formation of the ultrafiltrate of blood in the glomerular capillaries.

[0053] In glomerular kidney disease, injured podocytes undergo effacement whereby they lose their structure, including flattening and shortening of the highly arborised podocyteAttorney Docket No. A618-14.WO architecture, loss of podocyte negative charge, reduction in podocyte number and damage to the underlying endothelial cells, and glomerular basement membrane. Podocyte effacement is typically associated with the presence of proteinuria. In addition, damage to the underlying endothelial cells and glomerular basement membrane leads to abnormal thickening which further results in reduction of podocyte number via cell detachment, apoptosis, and autophagy response leading to development of tissue scarring and glomerulosclerosis.

[0054] suPAR and increased expression of cell surface uPAR has been shown to have a causative, pathological role in podocyte physiology. In human renal biopsy samples, higher uPAR expression was observed in a range of kidney diseases with highest levels in MCD, while higher serum suPAR levels correlating with proteinuria were noted especially in DN patients (Wu C-Z, Chang L-C, Lin Y-F, et al. Urokinase plasminogen activator receptor and its soluble form in common biopsy-proven kidney disease and in staging of diabetic nephropathy. Clin Biochem.2015;48(18):1324-1329). In addition, serum suPAR levels were found to be elevated in a majority of patients with FSGS and in a subset with MCD and membranous nephropathy (Wei C, Hindi SE, Li J, et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med.2011;17(8):952-960.; Wei C, Trachtman H, Li J, et al. Circulating suPAR in two cohorts of primary FSGS. J Am Soc Nephrol.2012;23:2051-2059). Presence of elevated urinary suPAR in both MCD and FSGS relapsing patients has been observed that provides additional support to distinct molecular mechanisms underlying proteinuria in the two conditions (Cara-Fuentes G. CD80 and suPAR in patients with minimal change disease and focal segmental glomerulosclerosis: diagnostic and pathogenic significance: response. Pediatr Nephrol. 2014;29(8):1467-1468). suPAR levels were also linearly related to estimated glomerular filtration rate (eGFR) and proteinuria after adjusting for age and multivariate regression (Saleem M. What is the role of soluble urokinase-type plasminogen activator in renal disease. Nephron.2018;139(4):334-341), as well as a higher incidence of chronic kidney disease, and hospitalization due to impaired kidney function (Schulz C-A, Persson M, Christensson A, et al. Soluble urokinase-type plasminogen activator receptor (suPAR) and impaired kidney function in the population-based Malmö Diet and Cancer Study. Kidney Int Rep. 2017;2(2):239-247). Additionally, suPAR levels have also been associated with the development of renal tubulointerstitial and glomerular lesions in the Boston Kidney Biopsy Cohort Study (Srivastava A, Schmidt IM, Palsson R, et al. The associations of plasma biomarkers in inflammation with histopathologic lesions, kidney disease progression, and mortality – The Boston Kidney Biopsy Cohort Study. Kid Int Rep.2021;6:685-694). Finally, itAttorney Docket No. A618-14.WO has also been suggested that elevated suPAR levels are predictive of eGFR decline in patients with or without kidney disease and associated with chronic kidney disease progression (Hayek SS, Sever S, Ko YA, et al. Soluble urokinase receptor and chronic kidney disease. N Engl J Med. 2015;373(20):1916-1925; Iversen E, Kallemose T, Hornum M, et al. Soluble urokinase plasminogen activator receptor and decline in kidney function among patients without kidney disease. Clin Kidney J.2022;15(8):1534-1541).

[0055] The present application is directed to methods for treating a glomerular kidney disease in a human subject in need thereof by administering a therapeutically effective amount of an isolated antibody or an antigen binding fragment thereof that binds to soluble urokinase plasminogen activator receptor (suPAR), in particular human suPAR. The isolated antibody or antigen binding fragment thereof is a monoclonal antibody or an antigen binding fragment thereof that binds to human suPAR. More particularly, the isolated antibody or antigen binding fragment thereof is a humanized monoclonal antibody or an antigen binding fragment thereof that binds to human suPAR. For example, the isolated antibody or antigen binding fragment thereof is a humanized IgG1 monoclonal antibody that binds to human suPAR.

[0056] In one example, the isolated antibody or antigen binding fragment thereof is a humanized IgG1 antibody comprising a covalently bonded pair of IgG heavy chains wherein each heavy chain is covalently bonded to one light chain.

[0057] More specifically, the isolated antibody or antigen binding fragment thereof is WAL0921. As used herein, the term “WAL0921” refers to an anti-suPAR humanized immunoglobulin IgG1 monoclonal antibody that binds to human suPAR having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10. WAL0921 comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising the amino acid sequences (provided based on each number scheme) in Tables 1 and 2. WAL0921 is an anti- soluble urokinase plasminogen activator receptor (anti-suPAR) humanized immunoglobulin (Ig)G1 monoclonal antibody. Table 1. Numbering HCDR1 HCDR2 HCDR3Attorney Docket No. A618-14.WO (SEQ ID NO: 13) (SEQ ID NO: 14) (SEQ ID NO: 15) IMGTGYTFTNYYIDHESGST ARGYDVDWFVY (SEQ ID NO: 19) (SEQ ID NO: 20) (SEQ ID NO: 21). Numbering LCDR1 LCDR2 LCDR3 Scheme

[0058] The heavy chain of WAL0921 comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 11, as provided in Table 3 below. In particular, the heavy chain of WAL0921 comprise the amino acid sequence of SEQ ID: 7. The light chain of WAL0921 comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 12, as provided in Table 3 below. In particular, the light chain of WAL0921 comprise the amino acid sequence of SEQ ID:8. Table 3. WAL0921 h QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYMHWVRQAPGQGLEWMGW LAttorney Docket No. A618-14.WO heavy ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV chain HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP constant KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS L

[0059] In some examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6. In another example, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 18. In a further example, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a HCDR1 comprising theAttorney Docket No. A618-14.WO amino acid sequence of SEQ ID NO: 19, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 20, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 21, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 22, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 23, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 24. In another example, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 25, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 27, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 28, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 29, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 30.

[0060] In some examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a heavy chain variable region that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 9. In other examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9.

[0061] In some examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a light chain variable region that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:10 In other examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10.

[0062] In some examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a heavy chain variable region that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 10. In a further example, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10.

[0063] In some examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a heavy chain variable region that is at least 95%, 96%,Attorney Docket No. A618-14.WO 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 9, and a heavy chain constant region that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 11. In other examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 11.

[0064] In some examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a light chain variable region that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 10, and a light chain constant region that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 12. In other examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 12.

[0065] In some examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a heavy chain variable region that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 9, a heavy chain constant region that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 11, a light chain variable region that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 10, and a light chain constant region that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 12. In other examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 11, a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 12.

[0066] In some examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a heavy chain that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:7. In other examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 7.Attorney Docket No. A618-14.WO

[0067] In some examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a light chain that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 8. In other examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a light chain comprising the amino acid sequence of SEQ ID NO: 8.

[0068] In some examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a heavy chain that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 7, and a light chain that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 8. In other examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 7, and a light chain comprising the amino acid sequence of SEQ ID NO: 8.

[0069] As discussed above, sequences of the present application may comprise amino acid sequences with at least 95% identity or homology to the sequences of the antibody or antigen binding fragment thereof, described above. In some examples, the sequence identity may be about 95%, 96%, 97%, 98% or 99% to the antigen binding domains that bind suPAR of the disclosure. Variants of the antigen binding domains that bind suPAR comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions in the antigen binding domain that bind suPAR are within the scope of the disclosure, as long as they retain or have improved functional properties when compared to the parent antigen binding domains. Functional equivalents or variants of the antigen binding domains that bind suPAR include one or more deletions and / or additions of one or more amino acid residues. Such an addition, substitution or deletion can be located at any position in the molecule. In the case where several amino acids have been added, substituted or deleted, any combination of addition, substitution or deletion can be considered, on condition that the resulting antibody still has at least the advantageous properties of the antibody of the disclosure.

[0070] The terms “identical” or percent “identity” in the context of two or more nucleic acids or polypeptide sequences (e.g., anti-suPAR antibodies and polynucleotides that encode them), refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same, when compared and aligned for maximum correspondence, as measured using one of the following sequence comparison algorithms or by visual inspection. The percent (%) amino acid sequence identity with respect to a reference polypeptide is defined as the percentage of amino acid residues in a givenAttorney Docket No. A618-14.WO sequence that are identical to the amino acid residues in the reference polypeptide sequence. The percent (%) identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity=number of identical positions / total number of positions), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The percent identity between two amino acid sequences may be determined using various the algorithms that are within the skill in the art, using publicly available software such as, e.g., BLAST.

[0071] A polypeptide is typically substantially identical to a second polypeptide, for example, where the two peptides differ only by conservative substitutions. The antibodies of the present disclosure also include those for which binding characteristics, functional or physical properties have been improved by direct mutations. In some examples, variant antigen binding domains that bind suPAR comprise one or two conservative substitutions in any of the CDR regions, while retaining desired functional properties of the parent antigen binding fragments that bind suPAR.

[0072] In a specific example, the substitution is a conservative amino acid substitution made at one or more predicted non-essential amino acid residues. “Conservative modifications” or “conservative substitution” refer to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid modifications. Conservative modifications include amino acid substitutions, additions and deletions. Conservative amino acid substitutions are those in which the amino acid is replaced with an amino acid residue having a similar side chain. The families of amino acid residues having similar side chains are well defined and include amino acids with acidic side chains (e.g., aspartic acid, glutamic acid), basic side chains (e.g., lysine, arginine, histidine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), uncharged polar side chains (e.g., glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine, tryptophan), aromatic side chains (e.g., phenylalanine, tryptophan, histidine, tyrosine), aliphatic side chains (e.g., glycine, alanine, valine, leucine, isoleucine, serine, threonine), amide (e.g., asparagine, glutamine), beta-branched side chains (e.g., threonine, valine, isoleucine) and sulfur-containing side chains (cysteine, methionine). Furthermore, any native residue in the polypeptide may also be substituted with alanine.

[0073] In some examples, the isolated antibody or antibody binding fragment thereof that binds to human suPAR may be any one or more of the suPAR binding antibodies orAttorney Docket No. A618-14.WO antibody binding fragments described in WO2023 / 168364, in particular, Example 13 of WO2023 / 168364, which is incorporated by reference in its entirety herein.

[0074] The isolated antibody or antibody binding fragment thereof described herein, specifically WAL0921, may be administered to a human subject in need thereof to treat a glomerular kidney disease. More specifically, the isolated antibody or antibody binding fragment thereof described herein, specifically WAL0921, may be administered to treat proteinuric glomerular kidney diseases induced and / or exacerbated by the uPAR-suPAR system. The glomerular kidney disease may be diabetic nephropathy (DN) or a primary glomerular kidney disease. The primary glomerular kidney disease may be selected from a group consisting of primary focal segmental glomerulosclerosis (FSGS), treatment-resistant minimal change disease (TR-MCD), primary immunoglobulin A nephropathy (IgAN), and primary membranous nephropathy (PMN). The glomerular kidney diseases may be characterized as primary (e.g., FSGS, TR-MCD, IgAN, and PMN) or secondary (e.g., DN) glomerulopathies.

[0075] In some examples, FSGS and TR-MCD may be grouped together and considered a spectrum of the same disease. Both FSGS and TR-MCD are characterized with podocyte injury and overlapping approach to treatment (Barisoni L, Schnaper HW, Kopp JB. A proposed taxonomy for the podocytopathies: a reassessment of the primary nephrotic diseases. Clin J Am Soc Nephrol.2007;2(3):529-542; Ozeki T, Gillespie BW, Larkina M, et al. Clinical Course of Adult FSGS and Minimal Change Disease in North American and Japanese Cohorts. Kidney360. 2023 Jul 1;4(7):924-934). Studies have shown support for TR-MCD being an early stage of FSGS (Maas RJ, Deegens JK, Smeets B, et al. Minimal change disease and idiopathic FSGS: manifestations of the same disease. Nat Rev Nephrol.2016;12(12):768- 776). The immunoexpression of synaptopodin in podocytes in patients with TR-MCD and FSGS results in a distinctly granular pattern in glomeruli, while the pattern and intensity in patients with steroid responsive MCD are similar to that in normal controls (Wagrowska- Danilewicz M, Danilewicz M. Synaptopodin immunoexpression in steroidresponsive and steroid-resistant minimal change disease and focal segmental glomerulosclerosis. Nefrologia. 2007;27(6):710-715). In addition, evaluation of protein C-C motif chemokine 22 (CCL22) levels in steroid-resistant disease also supports TR-MCD as an early and progressive stage of FSGS. Significantly elevated levels of CCL22 in patients have been attributed to the specific pathology of TR-MCD and FSGS (Zhaoyang P, Wei L, Yanyan J, et al. CCL22 and leptinAttorney Docket No. A618-14.WO associated with steroid resistance in childhood idiopathic nephrotic syndrome. Front Pediatr. 2023;11:1261034.

[0076] WAL0921 exhibits low nanomolar affinity to its molecular targets, suPAR and urokinase plasminogen activator receptor. WAL0921 binds to the extracellular portion of human uPAR and suPAR. The pharmacological profile of WAL0921 has been characterized in a series of in vitro studies demonstrating the binding affinity of WAL0921 to its target ligand, cell surface uPAR and circulating suPAR, and its activity related to its proposed mechanism of action in animal models of kidney disease. As demonstrated in Examples 1-3 below, in pharmacology studies, WAL0921 displayed strong affinity and selectivity to suPAR and uPAR proteins in vitro. Functional assessments with related antibodies, such as binding to Fc receptors, suggested that WAL0921 was specifically designed to not elicit immune effector response through Fc receptors or complement activation responses through C1q binding. WAL0921 does not affect interactions between uPAR and endogenous ligands vitronectin and urokinase-type plasminogen activator (uPA).

[0077] In certain examples, the WAL0921 is administered to a patient in need thereof for the treatment of glomerular kidney disease. In certain examples, the kidney disease is selected from the group consisting of diabetic nephropathy (DN), primary focal segmental glomerulosclerosis (FSGS), treatment-resistance minimal change disease (TR-MCD), primary immunoglobulin A nephropathy (IgAN), and primary membranous nephropathy (PMN). In some examples, the kidney disease is a primary glomerulopathy. The primary glomerulopathy is selected from the group consisting of primary focal segmental glomerulosclerosis (FSGS), treatment-resistance minimal change disease (TR-MCD), primary immunoglobulin A nephropathy (IgAN), and primary membranous nephropathy (PMN). In other examples, the kidney disease is a second glomerulopathy, such as, for example, diabetic nephropathy (DN).

[0078] In certain examples, the kidney disease is diabetic nephropathy (DN). In certain examples, the kidney disease is primary focal segmental glomerulosclerosis (FSGS). In certain examples, the kidney disease is treatment-resistance minimal change disease (TR-MCD). In certain examples, the kidney disease is primary immunoglobulin A nephropathy (IgAN). In certain examples, the kidney disease is primary membranous nephropathy (PMN). In certain examples, the kidney disease is selected from a combination of two or more of diabetic nephropathy (DN), primary focal segmental glomerulosclerosis (FSGS), treatment-resistance minimal change disease (TR-MCD), primary immunoglobulin A nephropathy (IgAN), and primary membranous nephropathy (PMN). In certain examples, the glomerular kidney diseaseAttorney Docket No. A618-14.WO is primary focal segmental glomerulosclerosis (FSGS) or treatment resistant-minimal change disease (TR-MCD). In other examples, the glomerular kidney disease is primary focal segmental glomerulosclerosis (FSGS) or treatment resistant-minimal change disease (TR- MCD) and primary immunoglobulin A nephropathy (IgAN).

[0079] Disease state and / or progression of a glomerular kidney disease may be correlated to with proteinuria in patients having the glomerular kidney disease. Therefore, treatment of a patient having a glomerular kidney disease may reduce proteinuria associated with a kidney disease. In certain examples, the WAL0921 is administered to a patient in need thereof for reducing proteinuria associated with a kidney disease, in particular, a glomerular kidney disease, in a patient. In certain examples, the kidney disease is selected from the group consisting of diabetic nephropathy (DN), primary focal segmental glomerulosclerosis (FSGS), treatment-resistance minimal change disease (TR-MCD), primary immunoglobulin A nephropathy (IgAN), and primary membranous nephropathy (PMN). In some examples, the kidney disease is a primary glomerulopathy. The primary glomerulopathy is selected from the group consisting of primary focal segmental glomerulosclerosis (FSGS), treatment-resistance minimal change disease (TR-MCD), primary immunoglobulin A nephropathy (IgAN), and primary membranous nephropathy (PMN). In other examples, the kidney disease is a second glomerulopathy, such as, for example, diabetic nephropathy (DN).

[0080] Proteinuria, and therefore, the disease state and / or progression of a glomerular kidney disease, may be quantified by a number of different measurements, such as, for example, urine albumin-creatinine ratio (UACR), urine protein-creatinine ratio (UPCR), estimated glomerular filtration rate (eGFR). For example, a patient having diabetic nephropathy may be associated with an elevated UACR of about 500 to about 3500 mg albumin / g creatinine. In another example, a patient having FSGS or TR-MCD may be associated with UPCR ≥ 1.0 g protein / g creatinine. For TR-MCD, there is also a lack of response to at least > 16 weeks of glucocorticoid therapy. In another example, a patient having IgAN may be associated with UPCR ≥ 0.75 g protein / g creatinine. In another example, a patient having PMN may be associated with i, ii, or iii below, and UPCR not decreasing > 50% in the last 6 months: i. UPCR ≥ 5 g protein / g creatinine after maximum tolerated standard of care (SoC) for ≥ 3 months, or ii. UPCR ≥ 4 g protein / g creatinine after maximum tolerated SoC for ≥ 6 months, or iii. UPCR ≥ 3.5 g protein / g creatinine and serum albumin ≤ 3.0 g / dL.Attorney Docket No. A618-14.WO

[0081] Furthermore, a glomerular kidney disease may be associated with a decline in kidney filtration, which can be measured and quantified using an estimated glomerular filtration rate (eGFR). A patient having a glomerular kidney disease (e.g., nephropathy (DN), primary focal segmental glomerulosclerosis (FSGS), treatment-resistance minimal change disease (TR-MCD), primary immunoglobulin A nephropathy (IgAN), and primary membranous nephropathy (PMN)) and / or proteinuria may have an eGFR, calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation method, ≥ 30 mL / min / 1.73 m2.

[0082] Therapeutically effective treatment of a glomerular kidney disease and / or proteinuria associated with the glomerular kidney disease may correspond to a decrease in UACR or UPCR. In one example, therapeutically effective treatment of a DN may be associated with a decrease in UACR or UPCR. In another example, therapeutically effective treatment of a primary glomerular kidney disease (e.g., FSGS, TR-MCD, IgAN, and PMN) may be associated with a decrease in UACR or UPCR. For each of the above describe diseases, the decrease in UACR or UPCR may be at least 30% from baseline, at least 40% from baseline or at least 50% from baseline. In some examples, the decrease in UACR or UPCR may reach a complete remission statement, e.g., UACR or UPCR <0.5 g / g. The above reductions may be achieved in any suitable timeframe to provide therapeutic improvement to the human patient, such as, for example, after at least about 12 weeks, at least about 18 weeks, at least about 24 weeks, at least about 30 weeks, or at least about 36 weeks of administering the isolated antibody or antibody binding fragment thereof described herein, specifically WAL0921, to the patient.

[0083] Therapeutically effective treatment of a glomerular kidney disease and / or reduction of proteinuria may be associated with a decrease in suPAR levels in the human patient. In one example, therapeutically effective treatment of a DN may be associated with a decrease in total and / or free suPAR concentration in the plasma or urine of the patient. More particularly, therapeutically effective treatment of a DN may be associated with a decrease in free suPAR concentration in the plasma of the patient. In another example, therapeutically effective treatment of a primary glomerular kidney disease (e.g., FSGS, TR-MCD, IgAN, and PMN) may be associated with a decrease in total and / or free suPAR concentration in the plasma or urine of the patient. More particularly, therapeutically effective treatment of a primary glomerular kidney disease (e.g., FSGS, TR-MCD, IgAN, and PMN) may be associated with a decrease in free suPAR concentration in the plasma of the patient. In a further example, a reduction in proteinuria in a human patient having a glomerular kidney disease (e.g., DN or aAttorney Docket No. A618-14.WO primary glomerular kidney disease, such as, for example, FSGS, TR-MCD, IgAN, and PMN) may be associated with a decrease in total and / or free suPAR concentration in the plasma or urine of the patient. More particularly, a reduction in proteinuria in a human patient having a glomerular kidney disease (e.g., DN or a primary glomerular kidney disease, such as, for example, FSGS, TR-MCD, IgAN, and PMN) may be associated with a decrease in free suPAR concentration in the plasma of the patient. For each of the above describe diseases, the decrease in free suPAR concentration in the plasma of the patient may be by at least 50% from baseline, at least 70% from baseline or at least 90% from baseline. In particular, for each of the above describe diseases, the decrease in free suPAR concentration in the plasma of the patient may be by about 50% to 70% or about 70% to about 90%. The decreases in suPAR levels may be achieved in any suitable timeframe to provide therapeutic improvement to the human patient, such as, for example, after at least about 12 weeks, at least about 18 weeks, at least about 24 weeks, at least about 30 weeks, or at least about 36 weeks of administering the isolated antibody or antibody binding fragment thereof described herein, specifically WAL0921, to the patient.

[0084] The isolated antibody or antibody binding fragment thereof described herein, specifically WAL0921, may be administered by any suitable administration route, such as, for example, parenterally (e.g., intravenously (IV)). In some examples, the isolated antibody or antibody binding fragment thereof described herein, specifically WAL0921, is parenterally administered to the subject. In particular examples, the isolated antibody or antibody binding fragment thereof described herein, specifically WAL0921, is intravenous administered to the subject.

[0085] Suitable compositions for parenteral (e.g., intravenous) administration include, for example, solutions. The isolated antibody or antibody binding fragment thereof described herein, specifically WAL0921, may be formulated as a pharmaceutical composition for parenteral (e.g., intravenous) administration to a human subject. Accordingly, a pharmaceutical composition may comprise (a) an effective amount of the isolated antibody or antibody binding fragment thereof described herein, specifically WAL0921, and (b) a pharmaceutically acceptable excipient. A “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith.Attorney Docket No. A618-14.WO

[0086] In one example, WAL0921 is formulated for intravenous administration as a sterile solution in a vial. The WAL0921 formulation includes WAL0921, 20 mM histidine buffer, 8% (w / v) sucrose, and 0.04% (w / v) polysorbate 80. More particularly, the intravenous formulation consists of or consists essentially of WAL0921, 20 mM histidine buffer, 8% (w / v) sucrose, and 0.04% (w / v) polysorbate 80. The formulation may be at a pH of or about 6.0. An intravenous formulation of WAL0921 is described in further detail in PCT Patent Application Publication No. WO2023 / 168364, which is incorporated by reference in its entirety herein.

[0087] The isolated antibody or antibody binding fragment thereof described herein, specifically WAL0921, may be administered to the human subject at a dose from about 0.3 mg / kg to about 30 mg / kg, about 2 mg / kg to about 6 mg / kg, about 2 mg / kg, about 6 mg / kg. In particular, the isolated antibody or antibody binding fragment thereof described herein, specifically WAL0921, may be parenterally administered (e.g., intravenously administered) to the human subject at a dose from about 0.3 mg / kg to about 30 mg / kg or about 2 mg / kg to about 6 mg / kg. In one example, the isolated antibody or antibody binding fragment thereof described herein, specifically WAL0921, may be administered, more particularly parenterally administered (e.g., intravenously administered), to the human subject having DN at a dose from about 0.3 mg / kg to about 30 mg / kg, about 2 mg / kg to about 6 mg / kg, about 2 mg / kg, about 6 mg / kg. In another example, the isolated antibody or antibody binding fragment thereof described herein, specifically WAL0921, may be administered, more particularly parenterally administered (e.g., intravenously administered), to the human subject having a primary glomerular kidney disease (e.g., FSGS, TR-MCD, IgAN, and PMN) at a dose from about 0.3 mg / kg to about 30 mg / kg, about 2 mg / kg to about 6 mg / kg, about 2 mg / kg, about 6 mg / kg.

[0088] In one example, the isolated antibody or antibody binding fragment thereof described herein, specifically WAL0921, may be administered to the human subject at a dosing frequencies once every 2 weeks. In particular, the isolated antibody or antibody binding fragment thereof described herein, specifically WAL0921, may be parenterally administered (e.g., intravenously administered) to the human subject at a dose from about 0.3 mg / kg to about 30 mg / kg or about 2 mg / kg to about 6 mg / kg every 2 weeks. In another example, the isolated antibody or antibody binding fragment thereof described herein, specifically WAL0921, may be administered, more particularly parenterally administered (e.g., intravenously administered), to the human subject having DN at a dose from about 0.3 mg / kg to about 30 mg / kg, about 2 mg / kg to about 6 mg / kg, about 2 mg / kg, about 6 mg / kg every 2 weeks. In another example, the isolated antibody or antibody binding fragment thereof described herein,Attorney Docket No. A618-14.WO specifically WAL0921, may be administered, more particularly parenterally administered (e.g., intravenously administered), to the human subject having a primary glomerular kidney disease (e.g., FSGS, TR-MCD, IgAN, and PMN) at a dose from about 0.3 mg / kg to about 30 mg / kg, about 2 mg / kg to about 6 mg / kg, about 2 mg / kg, about 6 mg / kg every 2 weeks. Each example of administering of the isolated antibody or antibody binding fragment thereof described in this paragraph, specifically WAL0921, may be continuously administered every 2 weeks for a treatment period of or longer than about 14 weeks. All dosage amounts mentioned herein, unless otherwise indicated, are calculated for an average body weight of about 70 kg and should be adjusted in case of pediatric applications, or when used with adult patients with a substantially diverting body weight. EXAMPLES

[0089] The following examples are to further illustrate the nature of the invention. It should be understood that the following examples do not limit the invention and that the scope of the invention is to be determined by the appended claims. Example 1: suPAR / uPAR binding

[0090] An anti-suPAR / uPAR antibody, WAb0014, was derived from a prototype via phage display technology. The heavy chain of WAb0014 is substantially the same as the heavy chain of WAL0921. The light chain of WAb0014 is the same as the light chain of WAL0921 described above. The WAb0014 is described in further detail in PCT Patent Application Publication No. WO2023 / 168364, which is incorporated by reference in its entirety herein.

[0091] The in vitro binding affinity of the anti-suPAR / uPAR antibody WAb0014 to human soluble urokinase plasminogen activator receptor (hsuPAR) isoforms and cell surface uPAR was assessed using biophysical and flow cytometry-based assays. The results showed that WAb0014 exhibited both an avidity-driven (sub-nanomolar) and affinity-driven (low nanomolar, KD = 0.69-2 nM) binding interaction with hsuPAR. An assessment of WAb0014 binding to cellular huPAR protein demonstrated a low nanomolar (KD= 2.1 nM) binding affinity.

[0092] In additional binding assessments, WAb0014 did not react with mouse urokinase plasminogen activator receptor (muPAR) but exhibited low nanomolar bindingAttorney Docket No. A618-14.WO affinity (KD = 10.5 nM) with cynomolgus monkey suPAR, confirming the nonhuman primate as the appropriate species model for the GLP toxicology study. Example 2: suPAR Biomarker Evaluation in Cynomolgus Monkeys

[0093] Repeated dose toxicology studies were conducted using WAL0921 and WAL0921-ΔK in cynomolgus monkeys. WAL0921-ΔK has the same target binding and functional properties as WAL0921. WAL0921 retains the codon for the C-terminal lysine on the heavy chain, which is not present in WAL0921-ΔK. However, during manufacturing, the majority of this C-terminal lysine from WAL0921 is removed by proteolytic processing yielding WAL0921-ΔK. The heavy chain of WAL0921-ΔK is the same as the heavy chain of WAL0921, except the heavy chain of WAL0921-ΔK does not include K448. The light chain of WAL0921-ΔK is the same as the light chain of WAL0921 described above. The WAL0921-ΔK is described in further detail in PCT Patent Application Publication No. WO2023 / 168364, which is incorporated by reference in its entirety herein.

[0094] The following exploratory toxicology studies assessed circulating plasma “total” suPAR biomarker (defined as a sum of free suPAR and antibody-bound suPAR) as an efficacy endpoint. A. Non-GLP 3-Week Repeated Dose, Dose Range Finding (DRF) Toxicology Study

[0095] An exploratory non-GLP-compliant 3-weeks repeated dose DRF toxicology study was conducted to determine the potential toxicity of WAL0921-ΔK (an antibody that is functionally identical to WAL0921) when administered via a 30-minute IV infusion once weekly for 3 weeks (dosing on Days 1, 8, and 15) to cynomolgus monkeys and to establish doses for a GLP 4-week repeated dose toxicology study (Example 2, B). In addition, the toxicokinetic (TK) characteristics of WAL0921-ΔK were determined.

[0096] This non-GLP 3-week study consisted of a total of 6 cynomolgus monkeys in 3 dose groups (1 monkey / sex / group). The monkeys were administered WAL0921-ΔK at 20, 60, or 150 mg / kg via a 30-minute IV infusion once weekly for 3 weeks. The doses of WAL0921- ΔK used for the non-GLP 3-week repeated dose DRF toxicology study were selected based on a range of published data and unpublished experience with the safety assessment of other antibody binding soluble antigens to cover a wide concentration range to comprehensively evaluate the safety of WAL0921.Attorney Docket No. A618-14.WO

[0097] Monkeys that were administered 150 mg / kg WAL0921-ΔK started dosing 7 days after the monkeys in the 20 and 60 mg / kg dose groups in accordance with an animal ethics requirement of staggering dose escalation for a novel molecule. Necropsy was performed on Day 31 for monkeys administered 20 or 60 mg / kg and on Day 24 for monkeys administered 150 mg / kg. A brief overview of the study design for the non-GLP 3-week repeated dose DRF toxicology study in cynomolgus monkeys is presented in Table 4. Table 4. Group Test Article Dose Dose Dose Number of Monkeys Level Concentration VolumeaMales Females nt.

[0098] Safety endpoints evaluated in the study included clinical observations, body weights, and clinical pathology parameters (hematology, coagulation, and chemistry), WAL0921-ΔK bioanalysis using LC-MS and TK parameters as well as biomarker (suPAR) analysis. At termination, gross observations and organ weights were recorded and tissues were collected for histopathological evaluations. In addition, measurement of glomerular integrity was undertaken in kidney tissues to assess the impact of WAL0921-ΔK on kidney function. Blood was sampled from monkeys for TK analyses pre-dose and at 30 minutes, 2, 6, 24, 72, 120, and 144-hours post the end of infusion on Days 1 and 15, and pre-dose and 30 minutes post the end of infusion on Day 8 to assess the exposure profile of WAL0921-ΔK.

[0099] All monkeys survived until scheduled euthanasia. There were no WAL0921- ΔK-related clinical observations or changes in body weights, gross pathology, organ weights, or microscopic pathology at any dose level. There were no WAL0921-ΔK-related hematology or clinical chemistry changes. There were higher levels of D-dimer in male and female monkeys at 150 mg / kg compared with pre-treatment, however the values were within normal range and there were no changes in prothrombin time (PT), activated partial thromboplastin time (aPTT), or fibrinogen which supported that there was no impact on coagulation. There were no WAL0921-ΔK-related microscopic findings in any tissues evaluated, including no WAL0921- ΔK-related changes in glomeruli. In conclusion, WAL0921-ΔK administered to male andAttorney Docket No. A618-14.WO female monkeys once weekly for 3 weeks (Days 1, 8, and 15) via a 30-minute IV infusion was well tolerated up to 150 mg / kg.

[0100] This non-GLP 3-week repeated dose DRF toxicology study showed a dose- dependent increase in total suPAR concentrations in both male and female cynomolgus monkeys following administration of WAL0921-ΔK at up to 150 mg / kg / dose. Elevated total suPAR reached saturation across all dose groups and either animal sex by Day 15 and were maintained until the day of necropsy for the 60 and 150 mg / kg doses. However, a 3- to 5-fold reduction in suPAR concentration was observed on the day of necropsy for the 20 mg / kg dose, when compared to the 144-hour post-dose sample from Day 15. These changes in total suPAR concentrations paralleled changes in WAL0921 concentrations in the non-GLP 3-week repeated dose DRF toxicology study. Importantly, there were no findings observed in any of the toxicology endpoints which included clinical signs, blood chemistries, hematology, or coagulation parameters. B. GLP-Compliant 4-Week Repeated Dose Toxicology Study

[0101] A GLP-compliant 4-week repeated dose toxicology study was conducted to evaluate the potential toxicity of WAL0921 when administered to cynomolgus monkeys via a 30-minute IV infusion once weekly for 4 weeks (dosing on Days 1, 8, 15, 22, and 29) at doses of 0, 15, 45, or 120 mg / kg followed by a 2-week recovery period to evaluate the reversibility of any findings. In addition, the TK characteristics of WAL0921 were determined.

[0102] This GLP 4-week study consisted of a total of 36 monkeys in 4 dose groups. The dose levels of WAL0921 were selected based on the results of the non-GLP 3-week DRF repeated dose study (Example 2, A) showing TK characteristics reflective of a conventional IgG1 antibody.

[0103] The monkeys assigned to the Main study were necropsied on Day 36 and the monkeys assigned to the Recovery phase were necropsied on Day 52 following a 2-week recovery period. A brief overview of the study design for the GLP 4-week repeated dose toxicology study in cynomolgus monkeys is presented in Table 5.Attorney Docket No. A618-14.WO Table 5. Group Test Dose Dose Dose Number of Monkeys Article Level Concentration volume Main Study Recovery (mg / kg) (mg / mL) (mL / kg)bMales Females Males Females nt.No recovery animals were designated in the 15 mg / kg group as aligned with the contract laboratory’s ethics policy for the responsible use of animals in research.

[0104] Safety endpoints evaluated in the study included mortality, clinical observations, incision site wound healing assessments, body weight, ophthalmological assessment, bioanalysis using LC-MS / MS, TK parameters, and clinical pathology parameters (e.g., hematology, coagulation, chemistry, urinalysis, and urine chemistry). In addition, potential immunogenicity of WAL0921 via measurement of anti-drug antibody (ADA), changes in target antigen (i.e., suPAR) and inflammatory cytokine levels, as well as cardiac activity (i.e., ECG) were assessed. At termination, gross observations and organ weights were recorded, and tissues were collected for microscopic evaluation that combined all anatomical features within each organ on the same slide (e.g., for lung slides trachea, bronchi, bronchioles, major blood vessels, and parenchymal tissue were assessed). Blood was sampled from all animals for WAL0921 pharmacokinetic (PK) and TK analyses pre-dose, 30 minutes, and 2, 6, 24, 72 and 144 hours post the end of infusion on Days 1 and 29 and from monkeys assigned to the Recovery phase on Day 52 to assess the exposure profile of WAL0921. The sampling times were designed to provide a TK profile to characterize WAL0921. ADA samples were assessed during the recovery period, where the likelihood of WAL0921 interference would be minimal as the WAL0921 concentrations decreased below the cut-point of the ADA screening assay. All dose formulations met the protocol-specified acceptance criteria for concentration and homogeneity.

[0105] All monkeys survived until scheduled euthanasia. There were no WAL0921- related changes in body weight, ophthalmological status, clinical pathology parameters (including hematology, coagulation, clinical chemistry, and urinalysis), gross pathology, or organ weights during the dosing or recovery periods at any dose level. There were no WAL0921-related ECG findings. There was no evidence of toxicity in monkeys assigned toAttorney Docket No. A618-14.WO the Main study or Recovery phases at any dose level. Three of 4 monkeys and 4 of 4 monkeys in the 45 mg / kg and 120 mg / kg groups, respectively, assigned to the Recovery phase, showed detectable anti-WAL0921 antibodies in samples collected pre-dose on Day 29 and on Day 52.

[0106] This GLP 4-week repeated dose toxicology study in cynomolgus monkeys showed a dose-dependent increase in total suPAR levels following WAL0921 administration at 15 and 45 mg / kg / dose, and a suggestion of saturation of the observed total suPAR increase at 120 mg / kg / dose. At the end of recovery (3 weeks after the last dose), total suPAR levels remained elevated in most animals and were similar to the values observed at the end of termination for the respective treatment group. Like the non-GLP 3-week repeated dose DRF toxicology study (Example 2, A), changes in total suPAR concentrations paralleled changes in WAL0921 concentrations in the GLP 4-week repeated dose toxicology study as well.

[0107] In conclusion, WAL0921 administered to male and female monkeys once weekly for 4 weeks (Days 1, 8, 15, 22, and 29) via a 30-minute IV infusion was well tolerated up to 120 mg / kg. There was no evidence of toxicity in monkeys assigned to the Main study or Recovery phases at any dose level. Therefore, the no-observed-effect-level (NOEL) was considered to be 120 mg / kg. C. GLP-Compliant 13-Week Repeated Dose Toxicology Study

[0108] A GLP 13-week repeated dose toxicology study was conducted to evaluate the potential toxicity of WAL0921 when administered to cynomolgus monkeys via 30-minute IV infusion once weekly for 13 weeks (dosing on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85) at doses of 0, 15, 45, or 120 mg / kg followed by a 7-week recovery period to evaluate the reversibility of any findings. In addition, the TK characteristics of WAL0921 were determined.

[0109] This GLP 13-week study consisted of a total of 40 monkeys in 4 dose groups. The dose levels of WAL0921 were selected based on the results of the GLP 4-week repeated dose toxicology study showing TK characteristics reflective of a conventional IgG1. It was anticipated that the doses selected for the GLP 13-week repeated dose toxicology study would provide a sufficient range of exposures for evaluation of PK properties and potential toxicities and to assess the formation of anti-drug antibodies (ADAs). The study design of this GLP 13- week repeated dose toxicology study in cynomolgus monkeys is provided in Table 6.Attorney Docket No. A618-14.WO Table 6. Group Test Dose Dose Dose Number of Monkeys Article Level Concentrat- Volume Main Study Recovery (m / k ) i n (m / mL) (mL / k )bM l F l M l F le

[0110] This GLP 13-week repeated dose toxicology study in cynomolgus monkeys included the evaluation of biomarker (suPAR) analysis. Blood was sampled from all animals for WAL0921 TK analyses pre-dose, 30 minutes, and 1.5, 2.5, 6.5, 24.5, 72.5, and 144.5 hours post the end of infusion on Days 1 and 85 as well as pre-dose on Days 29, 36, and 43. In addition, blood was also sampled from monkeys assigned to the Recovery phase on Days 99, 106, 113, 120, 127, 133, and 142 to assess the exposure profile of WAL0921.

[0111] All monkeys survived until scheduled euthanasia. There were no WAL0921- related changes in clinical observations, body weight, ophthalmological assessments, clinical pathology parameters (including hematology, coagulation, clinical chemistry, and urine chemistry [N-acetyl-β-D-glucosaminidase / creatinine ratio]), gross pathology, cardiac activity (ECG), body temperature, neurobehavior, and respiration rate at any dose level.

[0112] The suPAR biomarker analysis for this GLP 13-week repeated dose monkey study showed a dose-dependent increase in total suPAR levels following WAL0921 administration up to 120 mg / kg in the main phase of the study with a saturation of the observed total suPAR increase between Days 71 and 99. During the study recovery period, total suPAR levels across all treatment groups exhibited a return towards baseline in the recovery animals starting on Day 99 up until the end of the recovery period (Day 142). Like the non-GLP 3-week and GLP-compliant 4-week repeated dose toxicology studies, changes in total suPAR concentrations paralleled changes in WAL0921 concentrations in the GLP-compliant 13-week repeated dose toxicology study as well. D. Free suPAR and WAL0921 Concentrations in Plasma

[0113] Plasma samples were analyzed for free suPAR in the non-GLP 3-week repeated dose DRF (Example 2, A), as well as the GLP 4-week and 13-week repeated dose toxicologyAttorney Docket No. A618-14.WO studies (Example 2, B and C), to confirm the effect of WAL0921 on lowering of free suPAR. The data showed a dose-dependent reduction in free suPAR concentrations in the study main phase following administration of WAL0921-ΔK in the non-GLP 3-week repeated dose DRF study (Example 2, A) and WAL0921 administration in the GLP 4-week and 13-week repeated dose toxicology studies (Example 2, B and C).

[0114] Plasma WAL0921 concentrations observed in the non-GLP 3-week repeated dose DRF study (Example 2, A) and both the GLP 4-week and 13-week repeated dose toxicology studies (Example 2, B and C) are at least 50-fold molar excess of KD of WAL0921. Examples 3: Mouse Nephrotoxic Serum Model of Glomerular Nephritis

[0115] Three independent studies were conducted investigating the effect of two anti- suPAR antibodies (WAb0008 and WAL0921mu) versus IgG control on nephrotoxic serum induced albuminuria in hsuPAR isoform 1 transgenic mice.

[0116] The WAb0008 is described in further detail in PCT Patent Application Publication No. WO2023 / 168364, which is incorporated by reference in its entirety herein. The amino acid sequences for VHand VLof WAL0921mu are the same as WAL0921. However, the human IgG1 heavy chain and kappa light chain constant regions of WAL0921 are replaced with mouse versions in WAL0921mu.

[0117] Administration of these anti-suPAR antibodies at 1.2 mg / kg (dosed twice, with 4 days between doses) was well tolerated, with no observed significant effects on body weight or clinical observations with WAb0008 in the first 2 sub-studies or with WAL0921mu in the final sub-study. The results from these studies successfully demonstrated the ability of these anti-suPAR antibodies to lower peak and overall albuminuria. Example 4: Phase 1 Study in Healthy Subjects – Safety Data

[0118] The Phase 1 study describe herein in Example 4 was a first-in-human, single- center, randomized, double-blind, placebo-controlled, Phase 1 single ascending dose (SAD) study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of WAL0921. This study randomized subjects in a 3:1 ratio in 5 sequential cohorts of 8 subjects each (i.e., 6 active: 2 placebo) and included sentinel dosing in all cohorts, i.e., 2 subjects (1 active, 1 placebo). Sentinel subjects received study drug and were observed for 48 hours priorAttorney Docket No. A618-14.WO to dosing the remaining subjects of each sequentially enrolled cohort. Subjects in the study completed safety assessments (e.g., physical examination, safety laboratory tests, electrocardiogram, concomitant medication collection and adverse event monitoring), and blood sampling for PK, PD, and anti-drug antibody (ADA) measurements and were followed until Day 64 post study drug administration.

[0119] Eight subjects were enrolled in each cohort (total n=40) and received the following doses of study drug: • Cohort 1 received 0.3 mg / kg of WAL0921 intravenously or placebo intravenously; • Cohort 2 received 1 mg / kg of WAL0921 intravenously or placebo intravenously; • Cohort 3 received 3 mg / kg of WAL0921 intravenously or placebo intravenously; • Cohort 4 received 10 mg / kg of WAL0921 intravenously or placebo intravenously; and • Cohort 5 received 30 mg / kg of WAL0921 intravenously or placebo intravenously.

[0120] All subjects completed the treatment and were evaluable for the duration of the study. No safety signals related to WAL0921 were identified, and no safety stopping rules were triggered in any cohort. Safety laboratory testing included blood chemistry, complete blood count (CBC) with differential, prothrombin time (PT), partial thromboplastin time (PTT), international normalized ratio (INR) PT / PTT / INR, D-dimer, and urinalysis. Vitals signs were stable throughout the evaluation period. All ECGs obtained during the dose limiting toxicity (DLT) period were without clinically significant interval (including QTcF) prolongation compared with baseline values, and no clinically significant findings were identified. A summary of treatment emergent adverse events (AEs) in the Phase 1 study of Example 4 are presented in Table 7.Attorney Docket No. A618-14.WO Table 7. Pooled 0.3 1 3 10 30 Overall Placebo mg / kg mg / kg mg / kg mg / kg mg / kg n=40 n 8 n 8 n 8 n 8 n 8 n 8Attorney Docket No. A618-14.WO Table 7. Pooled 0.3 1 3 10 30 Overall Placebo mg / kg mg / kg mg / kg mg / kg mg / kg n=40 n 8 n 8 n 8 n 8 n 8 n 8 / kg

[0121] All AEs have been reported as mild in severity, and AE-directed physical exams and vital signs have been unremarkable. There have been no serious AEs (SAEs) reported in this study. Overall, there were 16 subjects who experienced at least 1 treatment emergent adverse event (TEAE). Headache was the most commonly reported TEAE (n=1 placebo subject, n=6 WAL0921 subjects). Treatment-related TEAEs (placebo or WAL0921) for the Phase 1 study of Example 4 are summarized in Table 8. Table 8. Pooled 0.3 1 3 10 30 OverallAttorney Docket No. A618-14.WO Nervous system 2 1 2 0 0 0 5 disorders H d h 1 1 2 0 0 0 4 IV

[0122] All AEs have resolved. There are no safety concerns or potential signals resulting from AEs in any cohort. Example 5: Phase 1 Study in Healthy Subjects: Pharmacokinetic Data Analysis

[0123] Single dose pharmacokinetic (PK) data from the Phase 1 study of Example 4 was analyzed for the following WAL0921 dose groups: 1 mg / kg (n=6); 3 mg / kg (n=6); and 10 mg / kg (n=6). FIGS. 1A and 1B summarizes the mean plasma WAL0921 concentration-time profiles by cohort (PK data available for Cohorts 2, 3, and 4 of the Phase 1 study of Example 4). A linear concentration scale was used for FIG. 1A and a logarithmic concentration scale was used for FIG. 1B. In both FIGS. 1A and 1B, concentrations below the lower limit of quantification (LLOQ) were set to 0 ng / mL in the analysis.

[0124] The pharmacokinetic data from the Phase 1 study of Example 4 indicates that WAL0921 exhibits bi-phasic distribution following single 30 min IV infusions. There is evidence of pharmacokinetic nonlinearity at lower plasma WAL0921 concentrations in the distal terminal phases of the mean concentration-time profiles at the 1 and 3 mg / kg doses. Example 6: Phase 1 Study in Healthy Subjects: Pharmacodynamic Data Analysis

[0125] Pharmacodynamic (PD) data from the Phase 1 study of Example 4 were analyzed using a bioanalytical method to quantitate plasma suPAR concentrations. In the presence of WAL0921, plasma suPAR exists as WAL0921-unbound suPAR (hereinafter, free suPAR) and WAL0921-bound suPAR. Plasma free suPAR was measured using a commercially available enzyme linked immunoassay (ELISA) kit (suPARnostic®, ViroGates) in accordance with the manufacturer specifications. A custom suPAR ELISA method (referred to as HybridAttorney Docket No. A618-14.WO suPAR ELISA) was also developed to detect plasma total suPAR (defined as the sum of free and antibody-bound suPAR species) in the presence of WAL0921. Total suPAR primarily reflects WAL0921-bound suPAR and its clearance to occur via WAL0921 elimination pathways. Thus, the PD effect that is most likely to be clinically relevant is the effect of WAL0921 on free suPAR concentrations. A summary of plasma free suPAR concentration data from the Phase 1 study of Example 4 in healthy subjects is provided in FIG.2. Aggregate study data in FIG.2 are presented as mean ± SD. The triangle trace indicates subjects in the placebo group, while the other tracers indicate subjects in the WAL0921 groups.

[0126] The mean (± SD) baseline plasma free suPAR concentration was 1.63 ± 0.34 ng / mL and plasma free suPAR concentrations following single WAL0921 IV administrations indicate a rapid reduction of baseline suPAR concentrations to the assay lower limit of quantitation (LLOQ) (0.38 ng / mL) within 15 minutes, supporting successful target engagement by WAL0921. The plasma free suPAR concentrations stayed at LLOQ levels for increasing duration of time proportional to administered WAL0921 dose. In Cohorts 1 (0.3 mg / kg), 2 (1 mg / kg), and 3 (3 mg / kg), a subsequent return of the plasma free suPAR concentrations to baseline was observed with a saturating transient increase in mean plasma free suPAR concentrations to ≤ 4 ng / mL. In Cohorts 4 (10 mg / kg) and 5 (30 mg / kg), the lowered plasma free suPAR concentrations remained below baseline levels for duration of the observation period. Equivalent changes in baseline plasma free suPAR concentrations were not observed in the placebo subjects.

[0127] The planned dose levels for the Phase 2 study (Example 7) are 2 and 6 mg / kg administered once every 2 weeks for 7 doses. Doses for WAL0921 in Example 7 were selected by considering pharmacologically meaningful target engagement and adequate drug exposure safety margins.

[0128] Pharmacokinetic nonlinearity was observed in the distal terminal phases of the WAL0921 concentration-time profiles for the 1 and 3 mg / kg dose groups in the Phase 1 study of Example 4. When considered together with WAL0921’s known molecular binding targets in systemic circulation (suPAR) as well as on cell surface (uPAR), the data suggest an underlying and well described target mediated drug disposition (TMDD) effect. Thus, a pharmacokinetic- pharmacodynamic (PK / PD) model was developed to comprehensively describe the observed WAL0921 PK and PD relationship in the Phase 1 study of Example 4 and predict profiles for the Phase 2 study (Example 7). PK / PD simulations were undertaken using 500 virtual subjects with elevated baseline plasma free suPAR concentrations of 4.5 ± 2 ng / mL (mean ± SD), thatAttorney Docket No. A618-14.WO are anticipated in diabetic nephropathy patients. The simulations also modeled PK and PD changes over an extended sampling period post last administered WAL0921 dose. Example 7: Ongoing Phase 2 Study

[0129] Example 7 describes an ongoing Phase 2 clinical study of WAL0921. This Phase 2 clinical study is an adaptive, prospective, multi-center, randomized, double-blind, placebo- controlled study to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of WAL0921 in subjects with glomerular kidney diseases and proteinuria, including DN and rare glomerular kidney diseases (FSGS, TR-MCD, IgAN, and PMN). The rare glomerular kidney diseases described in Example 7 are primary glomerulopathies, as described above. In this study, the FSGS subgroup will include FSGS and TR-MCD since it has been considered a spectrum of the same disease.

[0130] Subjects in this study will be randomized to receive the investigational drug WAL0921 or placebo as an intravenous infusion once every 2 weeks for 7 total infusions. All subjects will be followed for 24 weeks after their last infusion. A. Study Objectives and Endpoints Study Objectives

[0131] This Phase 2 clinical study described herein in Example 7 is designed to evaluate a number of Primary, Secondary, and Exploratory objectives.

[0132] The Primary objectives of this study is to evaluate the safety of WAL0921 in at least 2 multiple ascending dose (MAD) levels in subjects with diabetic nephropathy (DN); and evaluate the safety of WAL0921 following multiple doses in subjects with rare glomerular kidney diseases (FSGS, TR-MCD, IgAN, and PMN).

[0133] The Secondary objectives of this study is to evaluate the efficacy of WAL0921 following multiple doses in subjects with DN and subjects with rare glomerular kidney diseases; evaluate WAL0921 pharmacokinetics (PK) following multiple doses in subjects with DN and subjects with rare glomerular kidney diseases; and evaluate WAL0921 pharmacodynamics (PD) following multiple doses in subjects with DN and subjects with rare glomerular kidney diseases.

[0134] An Explorative objective of this study is to evaluate the impact of WAL0921 exposure on select renal biomarkers relevant to disease indication(s), such as, for example, anyAttorney Docket No. A618-14.WO one or more of diabetic nephropathy (DN) and rare glomerular kidney diseases (FSGS, TR- MCD, IgAN, and PMN). Endpoints

[0135] This Phase 2 clinical study described herein in Example 7 is designed with safety and efficacy endpoints. The Primary Endpoint, Secondary Endpoints, and Exploratory Endpoint are provided detailed further below.

[0136] The Primary Endpoint is related to the safety of WAL0921 in at least 2 multiple ascending dose (MAD) levels in subjects with diabetic nephropathy (DN) or subjects with rare glomerular kidney diseases (FSGS, TR-MCD, IgAN, and PMN). The Primary Endpoint is incidence of treatment-emergent adverse events (TEAEs).

[0137] The Secondary Endpoints include endpoints related to safety, efficacy, PK and PD of WAL0921 following multiple doses in subjects with diabetic nephropathy (DN) or subjects with rare glomerular kidney diseases (FSGS, TR-MCD, IgAN, and PMN). This study includes a single Secondary Endpoint related to safety, which is clinically significant changes in safety laboratory parameters, PE findings, vital signs, or electrocardiograms (ECGs) (including QTcF). The efficacy Secondary Endpoints include: • Percentage change from baseline in UACR or UPCR based on quantitative 24-hour urine collections at baseline, 12, 18, 24, 30, and 36 weeks; and spot urine UACR or UPCR assessed at baseline, 4, and 8 weeks in subjects with DN or rare glomerular disease, respectively; • Percentage change from baseline in eGFR from baseline renal function at 12, 18, 24, 30, and 36 weeks; • Slope of eGFR at 12, 18, 24, 30, and 36 weeks; • Proportion achieving a complete remission (CR) as UACR or UPCR < 0.5 g / g at 12, 18, 24, 30, and 36 weeks in subjects with DN or rare glomerular disease, respectively; • Proportion with a UACR or UPCR decrease of at least 30% from baseline at 12, 18, 24, 30, and 36 weeks in subjects with DN or rare glomerular disease, respectively; • Proportion with a UACR or UPCR decrease of at least 40% from baseline at 12, 18, 24, 30, and 36 weeks in subjects with DN or rare glomerular disease, respectively; andAttorney Docket No. A618-14.WO • Proportion with a UACR or UPCR decrease of at least 50% from baseline at 12, 18, 24, 30, and 36 weeks in subjects with DN or rare glomerular disease, respectively.

[0138] There are two (2) Secondary Endpoints related to pharmacokinetics (PK) of WAL0921. For PK Secondary Endpoints, WAL0921 concentrations will be assessed at the timepoints identified in Tables 9A and B Schedule of Assessments (SoA) below; and an analysis of the relationship between positive anti-drug antibodies (ADA), if any, and WAL0921 exposure will be performed.

[0139] There are four (4) Secondary Endpoint related to pharmacodynamics (PD): • Plasma total and free suPAR concentrations will be assessed at the timepoints identified in Tables 9A and B SoA; • Assessment of urine total and free suPAR concentrations at the timepoints identified in Tables 9A and B SoA; • Analyses of relationships between plasma and urine suPAR concentrations with WAL0921 exposure; • Analysis of plasma free suPAR percent reduction from baseline at 4, 8, 12, 18, 24, 30, and 36 weeks; and • Analysis of urine suPAR / creatinine ratios and percent reduction from baseline at 12, 18, 24, 30, and 36 weeks. Exploratory Endpoint

[0140] As an Exploratory Endpoint, the impact of WAL0921 exposure on select biomarkers reported in the scientific / medical literature that is associated with CKD may be considered for assessment (e.g., urine podocin RNA, urine epidermal growth factor receptor (EGFR), and protein levels). Table 9A provides a schedule of assessments from -28 days to Day 56 and Table 9B provides a schedule of assessments from Day 70 to Day 252. Table 9A. Day Day 0Attorney Docket No. A618-14.WO Study Drug X X X X X (WAL0921 or Placebo)Attorney Docket No. A618-14.WO disease Hep. B, C / HIV Pr n n X13X X X X XTable 9B: Schedule of Assessments (Day 70 to Day 252) Days Da 85 87 Da 1Attorney Docket No. A618-14.WO Informed Consent Eli ibilitAttorney Docket No. A618-14.WO Pregnancy X X X testing (POCBP) FSH [antibody; AE = adverse event; aPTT = activated partial thromboplastin clotting time; CBC = complete blood count; DN = diabetic nephropathy; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; FSH = follicle stimulating hormone; HEENT = head, ears, eye, nose and throat; HIV = human immunodeficiency virus; IP = investigational product; IV = intravenous; PD = pharmacodynamic(s); PK = pharmacokinetic(s); POCBP = person of child-bearing potential; and PT = prothrombin timeAttorney Docket No. A618-14.WO

[0142] Tables 9A and 9B include a number of footnotes, which are further explained below. Footnote 1 denotes that in the event of early withdrawal from the study, complete end of study assessments (Day 252). Footnote 2 denotes that WAL0921 will be administered as a 30 min ± 5 min infusion. An infusion administration window of 5 min is allowed so that the duration of WAL0921 administration can range from 25 - 35 min. Subjects should remain in clinic for observation for 2 hours after the first dose of study drug (WAL0921 or placebo) and 1 hour after remaining doses. Footnote 3 denotes that demographics are collected at Screening to include age, sex, race, and ethnicity. Footnote 4 denotes that weight is to be obtained before each dose and on Day 252, and height is only needed at Screening. Footnote 5 denotes that a full physical examination is required at Screening and on Day 0; and thereafter, symptom- driven limited physical assessments that include head, ears, eye, nose, and throat (HEENT), respiratory, cardiovascular, and gastrointestinal assessments may be performed by a qualified health care provider. Footnote 6 denotes that two 24-hour urine sample collections must be provided during the Screening period (Day -28 to Day 0), within 10 days pre-dose of Day 84, and Day 126 ± 7 days. A single 24-hour urine sample collection must be provided on Days 168, 210, and 252. Footnote 7 denotes that spot urine samples will be taken from each 24-hour urine collection, and that spot urine samples will be collected at Screening and Days 84, 126, 168, 210, and 252. Footnote 8 denotes that first morning void samples will be collected before Doses 2, 3, 4, 5, and 6. Footnote 9 denotes that after vital signs are measured and prior to collection of blood sample, triplicate 12-lead ECG will be collected (after subject is resting quietly in the supine position for approximately 10 min) immediately before and approximately 40 min after the start of each of the 7 planned IV infusions. Footnote 10 denotes that if any infusion goes past 30 min ± 5 min or is interrupted and then restarted, the 40-min post-start of infusion ECG collection should be taken approximately 10 min post the completion of the infusion (and not collected during the infusion or within the first 10 min after the end of the infusion), but before any coincident blood collection. Footnote 11 denotes that at Screening and Day 0 pre-dose, test for alcohol (e.g., breathalyzer, saliva test, depending on availability of type of test per clinical site), and urine sample to test for drugs of abuse (e.g., methamphetamine, amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, and tetrahydrocannabinol [THC], substances tested may depend on tests available per the standard panel for screening for drugs of abuse at that clinical site). Legal drugs in geographical area are permissible. Urine sample to test for drugs of abuse at Screening will be sent to the laboratory for testing, but on Day 0 pre-dose, the urine sample will be tested at the clinical site with results available and reviewed prior to study drug administration.Attorney Docket No. A618-14.WO Footnote 12 denotes that for persons of child-bearing potential (POCBP), serum pregnancy tests to be performed at Screening (Day -28) and urine pregnancy tests to be performed pre- dose (before each study drug administration). Footnote 13 denotes that postmenopausal status may be confirmed through testing for FSH at Screening only. Footnote 14 denotes that for DN subjects only (Cohorts 1 and 2), blood samples for measurement of plasma WAL0921 concentrations (PK) and WAL0921 biomarkers (PD) will be collected before Dose 1 IV infusion (up to 2 hr before first dose infusion on Day 0), and at 15 min ±5 min (Day 0), 45 min ±5 min (Day 0), 24 hr ±2 hr (Day 1), 72 hr ±26 hr (Day 3), 120 hr ±26 hr (Day 5), and 168 hr ±26 hr (Day 7) post start of Dose 1 IV infusion; prior to the start of IV infusion of Doses 2 (Day 14), 3 (Day 28), 4 (Day 42), 5 (Day 56), and 6 (Day 70); and prior to the start of IV infusion of Dose 7 (Day 84) and at 15 min ±5 min (Day 84), 45 min ±5 min (Day 84), 24 hr ±2 hr (Day 85), 72 hr ±26 hr (Day 87), 120 hr ±26 hr (Day 89), 168 hr ±26 hr (Day 91), 336 hr ±26 hr (Day 98), 672 ±26 hr (Day 112), 1008 hr ±72 hr (Day 126), 2016 hr ±72 hr (Day 168), 3024 hr ±72 hr (Day 210), and 4032 hr ±72 hr (Day 252; last clinic visit) post start of Dose 7 IV infusion. Scheduling of blood sample collection for PK and PD on Study Days 84, 85, 87, 89, 91, 98 and 112 will be in accordance with actual Dose 7 (or last scheduled dose) study visit to maintain the intended separations in sample collection. Blood samples for measurement of plasma WAL0921 concentrations (PK) and WAL0921 biomarkers (PD) will also be collected on Study Days 126 ±7, 168±7, 210 ±7 and 252 ±7 (last clinic visit) respectively counting from the original Study Day 0 date. The 15 min blood sample should always be taken during the infusion and the 45 min blood sample should always be taken after the infusion completion regardless of whether the actual infusion duration is 30 min. WAL0921 biomarkers (PD) will be total and free suPAR. Footnote 15 denotes that for DN subjects only (Cohorts 1 and 2), blood samples for plasma WAL0921 concentrations (PK) and WAL0921 biomarkers (PD). Blood samples may be drawn by a home phlebotomist. Footnote 16 denotes that for rare glomerular kidney disease subjects (Cohorts 3 and 4) and any additional cohorts, blood samples for measurement of plasma WAL0921 concentrations (PK) and WAL0921 biomarkers (PD) will be collected before Dose 1 (up to 2 hr before first dose infusion on Day 0), and at 15 min ±5 min (Day 0), 45 min ±5 min (Day 0); prior to the start of IV infusion of Doses 2 (Day 14), 3 (Day 28), 4 (Day 42), 5 (Day 56), 6 (Day 70), and Dose 7 (Day 84); and at 15 min ±5 min and 45 ±5 min post start of Dose 7 (or last scheduled dose) IV infusion. Scheduling of blood sample collection for PK and PD on Study Day 84 will be in accordance with actual Dose 7 (or last scheduled dose) study visit to maintain the intended separations in sample collection. Blood samples for measurement of plasma WAL0921 concentrations (PK) and WAL0921Attorney Docket No. A618-14.WO biomarkers (PD) will also be collected on Study Days 126 ±7, 168 ±7, 210 ±7 and 252 ±7 (last clinic visit) respectively counting from the original Study Day 0 date. The 15-min blood sample should be taken during the infusion and the 45-min blood sample should be taken after the infusion completion regardless of whether the actual infusion duration is 30 min. WAL0921 biomarkers (PD) will be total and free suPAR. Footnote 17 denotes that for all subjects, blood samples for measurement of plasma WAL0921 anti-drug antibodies (ADAs) will be assessed before IV infusion of Doses 1, 2, 3, 4, 5, 6, and 7; and during visits on Day 126, Day 168, Day 210, and Day 252 (EOS, last clinic visit). Footnote 18 denotes urine and blood sampling for measuring exploratory biomarkers; and urine and blood samples to be stored for future analysis for research purposes, and that whole blood samples will also be taken for exploratory biomarkers preferably at pre-dose Day 0, or on predose Day 84, or on Day 252. Footnote 19 denotes blood sample only at Day 0 pre-dose. Footnote 20 denotes urine and blood sampling only in DN subjects at these timepoints. Footnote 21 denotes that smoking assessment to be included with assessment of concomitant medications. Footnote 22 denotes that AEs will be collected from the time of informed consent through EOS (Day 252). Footnote 23 denotes that vital signs include systolic / diastolic blood pressure, pulse, respiratory rate, and body temperature. Footnote 24 denotes that safety Laboratory tests include hematology / CBC with differential, clinical chemistry, urinalysis, coagulation panel (PT / aPTT, D-dimer). B. Study Design

[0143] The safety, efficacy, PK, and PD results in at least 2 MAD levels of WAL0921 (Cohort 1: 2 mg / kg once every 2 weeks [Q2W] and Cohort 2: 6 mg / kg Q2W) will be evaluated in subjects with DN. At least 2 intravenous (IV) MAD levels of WAL0921, informed by cumulative safety data and modeling of PK / PD data from Phase 1 study of Example 4-6, will be evaluated in subjects with DN. Cohorts 1 and 2 are enrolled sequentially. Initiation of Cohort 2 is based on Clinical Steering Committee (CSC) review of the dose-limiting toxicity (DLT) period of Cohort 1 including cumulative safety and available PK and PD data. Dose levels to be evaluated in rare glomerular kidney diseases will be based on data from the DN cohorts.

[0144] The study will enroll up to 96 subjects randomized in a 3:1 ratio (active:placebo; 6:2 for DN, IgAN, and PMN; and 9:3 for FSGS / TR-MCD). Initially 44 subjects in 3 sequential cohorts (DN Cohort 1 (8); DN Cohort 2 (8); and Rare Cohort 3 (28) will be enrolled. Up to 52 additional subjects may be adaptively enrolled to further explore safety, efficacy, PK, and PD of WAL0921 by expanding or adding cohorts of subjects (e.g., Cohort 4 to explore anAttorney Docket No. A618-14.WO alternative dose level in 2 rare glomerular kidney diseases). The different study cohorts are summarized below in Table 10. Table 10. Cohort Subgroup N Study Drug V D pnephropathy; Q2W = once every 2 weeks; TBD = to be determined; TR-MCD = treatment- resistant minimal change disease.1One or more rare glomerular diseases (e.g., Cohort 4a, 4b) based on CSC review of cumulative safety, and available PK, PD, and efficacy data of Cohorts 1, 2, and 3.2Dose level will not exceed 6 mg / kg and will be selected based on CSC review of cumulative safety data, and available PK and PD data of Cohorts 1, 2 and 3.

[0145] Subjects will be administered 7 sequential, IV doses of WAL0921 or placebo every 14 days (Days 0, 14, 28, 42, 56, 70, and 84) over a 12-week treatment period. All subjects will be followed for 24 weeks after their last dose of study drug with follow-up visits on Days 126, 168, 210, and 252. The placebo is sodium chloride 0.9% (normal saline), United States Pharmacopeia (USP), administered as an IV infusion.

[0146] Subject safety, efficacy, PK, and PD will be reviewed by the Clinical Steering Committee (CSC) in an ongoing and cumulative manner for the duration of the study. The CSC will confirm / determine the dose level for all subsequent cohorts after Cohort 1.

[0147] DLTs are defined in this study as any event found to meet dose stopping or discontinuation criteria. The DLT population is the first 8 subjects enrolled in each of Cohorts 1 and 2 to complete the 14-day DLT evaluation period. The DLT period is defined as 14 days post the first dose of study drug in the last subject in the DN cohorts. DLTs will be considered related to study drug if they cannot be explained alternatively by underlying disease, comorbidities, intercurrent illness, or concomitant medication(s).Attorney Docket No. A618-14.WO

[0148] The preliminary safety, PK, PD and ADA data for Cohort 1 and a portion of Cohort 2 in this Phase 2 study are provided below. Dose Rationale

[0149] The 2 dose levels studied in DN subjects, i.e., DN Cohort 1: 2 mg / kg once every 2 weeks (Q2W), and DN Cohort 2: 6 mg / kg Q2W, were selected based on PK / PD modeling to provide population averages of 50-70% and 70-90% plasma free suPAR reductions from baseline, respectively, averaged over a steady-state dosing interval in subjects.

[0150] Cohort 2 was initiated based on the CSC review of the DLT period of Cohort 1 and cumulative safety and available PK and PD data from Cohort 1.

[0151] Dose selection and initiation of Cohort 3 was based on the CSC review of the DLT period of Cohort 2 and cumulative safety, and available PK and PD data of Cohorts 1 and 2. Consideration will also be given to choosing a dose that takes into account any significant impact of proteinuria level on WAL0921 PK parameters (e.g., increased renal clearance). End-of-Study Definition

[0152] The end of the study is defined as the date of the last visit of the last subject in the study or last scheduled procedure shown in the SoA for the last subject in the study globally. A subject is considered to have completed the study if the subject has completed all periods of the study including the last visit or the last scheduled procedure shown in the SoA. C. Study Population

[0153] The study will enroll up to 96 subjects randomized in a 3:1 ratio (active:placebo; 6:2 for DN, IgAN, and PMN; and 9:3 for FSGS / TR-MCD). Initially 44 subjects in 3 sequential cohorts (DN Cohort 1 (8); DN Cohort 2 (8); and Rare Cohort 3 (28, 18 subjects with FSGS or TR-MCD, 8 subjects with IgAn and 8 subjects with PMN) will be enrolled. Up to 52 additional subjects may be adaptively enrolled to further explore safety, efficacy, PK, and PD of WAL0921 by expanding or adding cohorts of subjects (e.g., Cohort 4 to explore an alternative dose level in 2 rare glomerular kidney diseases).

[0154] Subjects will be assigned to study drug only if they meet all the inclusion criteria and none of the exclusion criteria Inclusion CriteriaAttorney Docket No. A618-14.WO

[0155] Each potential participant must satisfy all of the following criteria to be enrolled on the study:

[0156] (1) Adults of any race, age 18 to 75 years;

[0157] (2) Diagnosis of one of the following glomerular kidney diseases with elevated UACR or UPCR based on 24-hour urine during the Screening period: a. For DN, a clinical diagnosis of DN; Type 1 or Type 2 diabetes mellitus with chronic kidney disease (CKD) not secondary to other etiologies; UACR 500- 3500 mg albumin / g creatinine; b. For FSGS or TR-MCD, diagnosis based on renal biopsy within 7 years of Screening or with UPCR ≥ 1.0 g protein / g creatinine at Screening. For FSGS, as disease-causing genetic mutation may be considered instead of renal biopsy. TR-MCD lack response to at least ≥ 16 weeks of glucocorticoid therapy. c. For IgAN, a diagnosis based on renal biopsy within 7 years of Screening with UPCR ≥ 0.75 g protein / g creatinine at Screening. d. For PMN, a diagnosis based on renal biopsy within 7 years of Screening with i, ii, or iii below, and UPCR not decreasing > 50% in the last 6 months: i. UPCR ≥ 5 g protein / g creatinine after maximum tolerated standard of care (SoC) for ≥ 3 months, or ii. UPCR ≥ 4 g protein / g creatinine after maximum tolerated SoC for ≥ 6 months, or iii. UPCR ≥ 3.5 g protein / g creatinine and serum albumin ≤ 3.0 g / dL prior to Screening;

[0158] (3) Estimated glomerular filtration rate (eGFR), calculated by the Chronic Kidney Disease- Epidemiology Collaboration (CKD-EPI 2021) equation method, ≥ 30 mL / min / 1.73 m2at Screening;

[0159] (4) If receiving an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), endothelin and angiotensin II receptor antagonist, sodium-glucose co-transporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and / or aldosterone antagonists, subjects should be stable on maximum tolerated dailyAttorney Docket No. A618-14.WO dose as per local standard for at least 12 weeks prior to Screening and maintain prescribed dose for the duration of the study unless a safety issue is associated with that medication;

[0160] (5) No longer receiving budesonide and completed a 9-month course of treatment, or unable to tolerate budesonide treatment or agree not to initiate budesonide for the duration of study, except budesonide administered by inhalation is allowed;

[0161] (6) If taking corticosteroid therapy (i.e., prednisone), stable dose of ≤ 15 mg / day or ≤ 30 mg on alternate days for ≥ 8 weeks prior to Screening with no plan to change the dose or regimen during the study;

[0162] (7) Persons of child-bearing potential must have a negative pregnancy test and must agree to either abstain from sex or to use highly effective method(s) of birth control based on the subject’s preferred and usual lifestyle from the date of dosing through the duration of the study and for at least 24 weeks after their last dose of study treatment;

[0163] (8) Persons of non-childbearing potential are at least 12 months postmenopausal confirmed by follicle stimulating hormone (FSH) > 40 IU or 6 weeks after surgical bilateral oophorectomy with or without hysterectomy OR post-hysterectomy;

[0164] (9) All biological male subjects of childbearing potential who are heterosexually active must agree to use a highly effective method of barrier contraception for the duration of the study and for at least 24 weeks after their last dose of study treatment; and

[0165] (10) Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

[0166] The association between glomerular kidney diseases with proteinuria and elevated baseline suPAR levels and urine albumin-creatinine ratio (UACR) or urine protein- creatinine ratio (UPCR) will be explored in patients with glomerular kidney disease associated with any of the specific diseases being studied (e.g., DN, FSGS, TR-MCD, IgAN, PMN). Therefore, an inclusion criterion for baseline suPAR level is not specified in the study. Exclusion Criteria

[0167] Any potential participant who meets any of the following criteria will be excluded from the study:

[0168] (1) Currently pregnant, breast-feeding, or planning to become pregnant within 12 months of Screening;Attorney Docket No. A618-14.WO

[0169] (2) History of organ or bone marrow transplantation, including renal transplantation;

[0170] (3) Currently on an organ transplant waiting list or there is a reasonable possibility of undergoing an organ transplant within 10 months of Screening;

[0171] (4) Body Mass Index (BMI) ≥ 40 kg / m2;

[0172] (5) History of malignancy, unless in remission for at least 2 years other than basal cell or squamous cell skin carcinoma, cervical carcinoma in situ, or prostate cancer not expected to require treatment over the course of the study;

[0173] (6) History of alcohol or substance use disorder within 12 months prior to Screening;

[0174] (7) Uncontrolled systemic hypertension with systolic blood pressure >160 mmHg and diastolic blood pressure ≥ 100 mmHg at Screening;

[0175] (8) Acute dialysis or acute kidney injury within 6 months prior to Screening;

[0176] (9) Histological FSGS subtype of collapsing variant;

[0177] (10) On renal biopsy, rapidly progressive glomerulonephritis (RPGN) and / or > 25% crescents and / or > 50% tubulointerstitial fibrosis on biopsy;

[0178] (11) Secondary FSGS that develops as an adaptive response to glomerular hypertrophy or hyperfiltration including disorders associated with a reduced renal mass and / or renal vasodilation, such as unilateral renal agenesis. Other secondary FSGS associated with drugs and toxins (i.e., heroin, interferon, pamidronate) and viral infections (i.e., human immunodeficiency virus [HIV]);

[0179] (12) Diagnosis of IgA vasculitis;

[0180] (13) Secondary IgAN associated with cirrhosis, celiac disease, HIV infection, dermatitis herpetiformis, seronegative arthritis, small cell carcinoma, lymphoma, disseminated tuberculosis, bronchiolitis obliterans, inflammatory bowel disease, familial Mediterranean fever, etc;

[0181] (14) Secondary membranous nephropathy associated with a history of drug use (such as excessive use of nonsteroidal anti-inflammatory drugs [NSAIDs]), infections (such as hepatitis B or C), autoimmune diseases (such as systemic lupus erythematosus [SLE]), or cancer;Attorney Docket No. A618-14.WO

[0182] (15) Hospitalization for congestive heart failure (CHF) within 6 months, or cerebrovascular accident (CVA) or myocardial infarction (MI) within 3 months of Screening;

[0183] (16) Life expectancy of less than 1 year at Screening;

[0184] (17) Liver transaminase levels > 2 × ULN, active hepatobiliary disease, jaundice, and / or hepatitis. Gilbert’s syndrome is acceptable if direct bilirubin is ≤ ULN;

[0185] (18) History of seizures or history of epilepsy;

[0186] (19) History of serious mental illness;

[0187] (20) Positive serology for HIV type 1 or 2, hepatitis B surface antigen, or hepatitis C;

[0188] (21) Active or chronic tuberculosis.

[0189] (22) History of inadequate venous access and / or experience of difficulty donating blood;

[0190] (23) History of angioedema and / or anaphylactic reactions;

[0191] (24) Any prior or current medical condition that, in the judgment of the Investigator, would prevent the subject from safely participating in and / or completing all study requirements;

[0192] (25) Positive test for alcohol or illegal drugs of abuse at Screening or Day 0;

[0193] (26) Treated with rituximab within 24 weeks of Screening, or cyclophosphamide, mycophenolate mofetil, azathioprine, calcineurin inhibitors, budesonide or abatacept within 12 weeks prior to Screening;

[0194] (27) Participation in other interventional clinical studies within 30 days or 5 half-lives of experimental treatment (whichever is greater) prior to Screening. D. Study Intervention(s) And Concomitant Therapy

[0195] Subjects will receive either WAL0921 or placebo (sodium chloride 0.9% (normal saline) USP, sterile grade). WAL0921 is provided as a clear to opalescent, colorless to yellow, sterile solution for IV infusion with a pH 5.5-6.5. It is supplied in a 10 mL vial with a 5.2 mL fill. WAL0921 is compatible with polyvinylchloride (PVC) and non-polyvinylchloride (non-PVC) IV bags and IV infusion sets (PVC and non-PVC). Dosing solutions diluted inAttorney Docket No. A618-14.WO normal saline are stable at room temperature or 2-8 °C for up to 4 hours. WAL0921 should be used within 4 hours of preparation. WAL0921 vials should be stored at -20 °C (-15 to -25 °C).

[0196] Placebo will be sodium chloride 0.9% (normal saline) USP, sterile grade. The placebo will be provided and prepared by the investigational site in a manner that maintains site-specific blinding.

[0197] Subjects who are determined to be eligible for the study will be randomized on Day 0 to WAL0921 or placebo by an unblinded pharmacist. Dose Modification

[0198] All Grade 3 (or higher) infusion-related reactions will be investigated by the CSC to determine whether dosing may continue or whether dosing modifications are required for that subject, subjects at the same dose level, or all subjects in the study.

[0199] If a dose reduction is necessary, the study drug will be administered as determined by the CSC. Prior and Concomitant Therapy

[0200] Throughout the study, the subjects may be prescribed concomitant medications or treatments deemed necessary to provide the standard of care, with the exception of other investigational agents.

[0201] Permitted concomitant medications include standard of care medications established within 3 months prior to Screening for treatment of glomerular kidney disease, oral contraceptives, and other medications per inclusion and exclusion criteria provided above, and summarized below:

[0202] Concomitant use of nicotine or nicotine containing products should be maintained throughout the study at the rate of usage captured at Screening.

[0203] Per inclusion criteria described above, treatment parameters for select concomitant medications listed below are allowed as noted: • if receiving an ACE inhibitor, an ARB, endothelin and angiotensin II receptor antagonist, SGLT2 inhibitors, GLP-1 agonists, and / or aldosterone antagonists subjects should be stable on maximum tolerated daily dose as per local standard for at least 12 weeks prior to Screening (with no increases in the dose or regimen anticipated for the next 24 weeks);Attorney Docket No. A618-14.WO • if taking corticosteroid therapy (i.e., prednisone), excluding budesonide, stable dose of ≤ 15 mg / day or ≤ 30 mg on alternate days for ≥ 8 weeks prior to Screening with no plan to change the dose or regimen during the study; and • oral contraception.

[0204] Per exclusion criteria described above, the following concomitant medications are prohibited: • rituximab within 24 weeks of Screening and throughout the duration of the study; • cyclophosphamide, mycophenolate mofetil, azathioprine, calcineurin inhibitors, or abatacept within 12 weeks prior to Screening and throughout the duration of the study; and • budesonide treatment.

[0205] Concomitant medication information will be collected for all eligible subjects at the time of enrollment through the subject’s last study visit. Additionally, use of any non- drug procedural therapies will be recorded for each subject. Concomitant medication information taken at the time of a SAE will also be collected during the safety data follow-up. E. Study Assessments And Procedures

[0206] Study procedures and their timing are summarized in the SoA (Table 9A and B). Protocol waivers or exemptions are not allowed. Adherence to the study design requirements, including those specified in the SoA, is essential and required for study conduct.

[0207] All screening evaluations must be completed and reviewed to confirm that potential subjects meet all eligibility criteria. The Investigator will maintain a screening log to record details of all subjects screened and to confirm eligibility or record reasons for screening failure, as applicable.

[0208] Procedures conducted as part of the subject’s routine clinical management (e.g., blood count) and obtained before signing of the ICF may be utilized for Screening (Day -28) or baseline purposes provided the procedures met the protocol-specified criteria and were performed within the timeframe defined in the SoA.

[0209] In the event of a significant study-continuity issue (e.g., caused by a pandemic), alternate strategies for subject visits, assessments, medication distribution and monitoring may be implemented, as per local health authority / ethics requirements.Attorney Docket No. A618-14.WO

[0210] Safety results (e.g., laboratory) that could unblind the study will not be reported to investigative sites or other blinded personnel until the study has been unblinded, as applicable.

[0211] The total volume of blood that will be taken over the duration of the study for subjects enrolled into Cohorts 1 and 2 will not be more than 790 mL. For subjects enrolled in Cohort 3 and subsequent cohorts, the total amount of blood taken over the duration of the study will not exceed 590 mL. The total volume of blood per subject for planned study samples does not exceed 550 mL or 10.5 mL / kg (whichever is smaller) per any 8-week period.

[0212] All samples will be retained according to local regulations following the last subject’s last visit for the study to enable further analysis. Safety Assessments

[0213] Safety will be monitored by the assessments described below as well as the collection of AEs at every visit after Screening. Planned timepoints for all safety assessments are provided in the SoA of Tables 9A and B. AEs are collected from the time of informed consent until the completion of the subject’s last study visit. Physical Examinations (PEs)

[0214] PEs (when conducted by a physician, or other medically qualified Investigator) or limited physical assessments (when performed by a nurse or other qualified individual) should include at a minimum an assessment of the head, eyes, ears, nose and throat (HEENT), respiratory, cardiovascular, and gastrointestinal systems, and any symptom-related body system as is consistent per site’s standard practice.

[0215] A full PE should be conducted at Screening, while limited physical assessments may be conducted at other timepoints and must also be inclusive of the relevant organ or body system of interest for assessing the AE. Vital Signs, Height, and Weight

[0216] Vital signs (including blood pressure, pulse, respiration, and temperature) will be measured at Screening, prior to and after study drug administration dosing day(s), and at each study visit. Vital signs should be collected while the subject is in a seated position and after resting for approximately 10 min for all measurements. Temperature will only be collected when noted specifically in the SoA. Height will be collected only at Screening. Weight will be obtained at Screening and prior to dosing.Attorney Docket No. A618-14.WO Electrocardiograms (ECGs)

[0217] Standard 12-lead ECG(s) will be obtained as outlined in the SoA of Tables 9A and B. All ECGs will be collected in triplicate. The following parameters will be assessed: interpretation, ventricular rate, PR interval, QRS duration, QT, and QTcF.

[0218] Subjects should be allowed to rest quietly in the supine position for at least 10 min prior to their ECG. Additional ECGs may be collected if an issue or safety concern is noted. At each timepoint at which triplicate ECGs are required, 3 individual ECG tracings should be obtained as closely as possible in succession, but no more than 2 min apart.

[0219] A subject with an abnormal, clinically significant ECG during Screening does not qualify for the study. A subject with an abnormal, non-clinically significant ECG does not qualify for dosing without physician evaluation and comment on the ECG. A physician may request that additional ECGs be performed at any time (unscheduled ECGs). Unscheduled ECGs should also be collected in triplicate. Clinical Safety Laboratory Tests

[0220] Clinical laboratory assessments will be performed by a central lab, unless otherwise specified. Reference ranges will be used by the Investigator to assess the laboratory data for clinical significance and changes relative to baseline measurements. Clinical laboratory assessments will include COVID-19 testing on days of study drug administration. COVID-19 positive subjects may have treatment delayed until the subject is asymptomatic. COVID-19 testing will be performed locally. Any abnormal laboratory test results (hematology, chemistry, or urinalysis) or other safety assessments (e.g., physical examination, vital signs measurements), including those that worsen from baseline, deemed clinically significant in the medical and scientific judgement of a physician are to be recorded as AEs or SAEs. See Table 11 below for the protocol-required safety laboratory tests, which is the list of clinical laboratory tests to be performed and the SoA (Tables 9A and B) for the timing and frequency. Unscheduled laboratory assessments for safety issues are permitted as deemed necessary by a physician. All laboratory tests may be performed non-fasting. All laboratory tests with values considered clinically significantly abnormal during participation in the study or within 4 weeks after the last dose of study drug should be repeated until the values return to normal, return to baseline, or are no longer considered clinically significant.Attorney Docket No. A618-14.WO Table 11. Hematology• Platelet Count• Red blood cell (RBC) count ) ) l ty l)Attorney Docket No. A618-14.WO • International normalized ratio (INR) • D-dimer e s fPharmacokinetics

[0221] Plasma WAL0921 concentrations will be assessed at the timepoints identified in the SoA in Tables 9A and B. Plasma WAL0921 concentrations will be analyzed via noncompartmental analysis (NCA), compartmental analysis, and / or population pharmacokinetic (PopPK) analysis techniques to estimate individual and population systemic drug exposure and PK using Phoenix WinNonlin (Certara, Inc.) and / or similar software. Samples collected for analyses may also be used to evaluate safety or efficacy aspects related to concerns arising during or after the study. Pharmacodynamics

[0222] Plasma total and free suPAR concentrations and urine total and free suPAR concentrations will be assessed at the timepoints identified in the SoA of Tables 9A and B. Samples collected for analyses may also be used to evaluate safety or efficacy aspects related to concerns arising during or after the study.Attorney Docket No. A618-14.WO Genetics

[0223] Targeted analysis of high-risk genes and their variants associated with kidney disease (e.g., PLAUR, APOL1, etc.) is planned in the study. Biomarkers

[0224] Biomarkers will be evaluated in the serum and / or plasma samples collected from all subjects according to the schedule described in the SoA in Tables 9A and B. suPAR (free and total) will be measured as a WAL0921 PD biomarker.

[0225] Exploratory biomarkers associated with CKD (e.g., urine podocin RNA, urine EGFR and protein levels) may be assessed in the study from the collected research blood and / or urine samples. Serum and / or plasma samples collected in the study may be stored for future research purposes related to the subjects’ condition(s). Immunogenicity Assessments

[0226] Antibodies to WAL0921 will be evaluated in plasma samples collected from all subjects according to the SoA of Tables 9A and 9B. Additionally, blood samples for plasma ADA evaluation will also be collected at the final visit from subjects who discontinue study drug or are withdrawn from the study.

[0227] Plasma samples will be screened for antibodies binding to WAL0921 and the titer of confirmed positive samples will be reported. Other analyses may be performed to verify the persistence of antibodies to WAL0921 and / or further characterize the immunogenicity of WAL0921.

[0228] The detection and characterization of antibodies to WAL0921 will be performed using an assay method. Antibodies may be further characterized and / or evaluated for their ability to neutralize the activity of WAL0921.

[0229] The impact of positive plasma WAL0921 ADA on safety measures, efficacy measures, and plasma WAL0921 exposure will be evaluated. F. Adverse Events: Definitions And Procedures For Recording, Evaluating, Follow-Up And Reporting

[0230] An adverse event (AE) is any untoward medical occurrence in a subject, temporally associated with the use of a study drug, whether or not considered related to WAL0921. An AE can therefore be any unfavorable and unintended sign (including anAttorney Docket No. A618-14.WO abnormal, clinically significant laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of WAL0921.

[0231] An AE may include any of: • Exacerbation of a pre-existing illness; • Subjective or objective symptoms spontaneously offered by the subject and / or observed by the Investigator or study staff; • Increase in frequency or intensity of a pre-existing episodic event or condition; • Condition detected or diagnosed after study drug administration even though it may have been present prior to the start of the study (unless it can be demonstrated by medical record review that the onset of the event preceded the date / time of informed consent). • Continuous persistent disease or symptoms present at baseline that worsen following the start of the study; • Symptoms associated with disease not previously reported by the subject; • Untoward medical occurrences considered by the Investigator to be related to study- mandated procedures; • Abnormal assessments (e.g., change on PE, ECG findings), if they represent a clinically significant finding, that were not present at baseline or worsened during the course of the study; or • Laboratory test abnormalities, if they represent a clinically significant finding, symptomatic or not, which were not present at baseline or worsened during the course of the study.

[0232] An AE would NOT include a / an: • Elective medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, transfusion); • Pre-existing diseases or conditions present or detected at Screening that do not worsen; • Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for cosmetic elective surgery, social and / or convenience admissions);Attorney Docket No. A618-14.WO • Overdose of either study drug or concurrent medication without any signs or symptoms; or • Pregnancy.

[0233] An unsolicited AE is an AE that was not solicited. Unsolicited AEs include serious and nonserious AEs. Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses requiring a hospitalization, emergency room visit, or visit to / by a healthcare provider). Unsolicited AEs that are not medically attended will be collected at the next visit.

[0234] Examples of events that meet the AE definition described above include: • Any abnormal laboratory test results (e.g., hematology, clinical chemistry, urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen from baseline, considered clinically significant in the medical and scientific judgment of a physician (i.e., not related to progression of underlying disease, or more severe than expected for the subject’s condition). • Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and / or intensity of the condition. • New condition detected or diagnosed after study drug administration even though it may have been present before the start of the study. • Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. • Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or a concomitant medication. Overdose per se will not be reported as an AE / SAE unless it is an intentional overdose taken with possible suicidal / self-harming intent. Such overdoses should be reported regardless of sequelae.

[0235] Examples of events that do not meet the AE definition described above are as follows: • Any abnormal laboratory findings or other abnormal safety assessments that are associated with the underlying disease, unless judged by the Investigator to be more severe than expected for the subject’s condition.Attorney Docket No. A618-14.WO • The disease / disorder being studied or expected progression, signs, or symptoms of the disease / disorder being studied, unless more severe than expected for the subject’s condition. • Medical or surgical procedure (e.g., endoscopy). • Situations in which an untoward medical occurrence did not occur (social and / or convenience admission to a hospital). • Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.

[0236] An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of the criteria listed below: • Results in death; • Is life-threatening; • Requires inpatient hospitalization or prolongation of existing hospitalization; • Results in persistent or significant disability / incapacity; • Is a congenital anomaly / birth defect; and / or • Other situations.

[0237] The term life-threatening in the definition of serious refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.

[0238] In general, hospitalization signifies that the subject has been admitted (usually involving at least an overnight stay) at the hospital or emergency ward for observation and / or treatment that would not have been appropriate in the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether hospitalization occurred or was necessary, the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

[0239] The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences ofAttorney Docket No. A618-14.WO relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or prevent everyday life functions but do not constitute a substantial disruption.

[0240] With respect to other situations, medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other situations such as important medical events that that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These events should usually be considered serious. Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, convulsions not resulting in hospitalization, or development of intervention dependency or intervention abuse. AE and SAE Recording

[0241] AEs will be collected from the time of informed consent through Day 252 (± 3 days), according to the SoA of Tables 9A and 9B.

[0242] For abnormal clinically significant laboratory findings, the clinical manifestation (diagnosis) should be noted as an AE (e.g., anemia instead of low hemoglobin). Should a clinically significant lab abnormality occur that is not part of a diagnosis, the abnormality itself may be reported as an AE. Laboratory abnormalities that meet the criteria for an AE should be followed until they have returned to normal or an adequate explanation of the abnormality is determined. When an abnormal laboratory result corresponds to a sign / symptom of an already reported AE it is not necessary to separately record the lab result as an additional AE. Assessment of Severity

[0243] The AEs may be classified based on the perceived clinical significance of the event and / or laboratory finding in the subject.

[0244] The severity for each AE and SAE reported during the study will be assessed and assigned it to one of the following categories: Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated;Attorney Docket No. A618-14.WO Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting age- appropriate instrumental Activities of Daily Living (ADL); Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL; Grade 4: Life-threatening consequences; urgent intervention indicated; and Grade 5: Death related to AE.

[0245] The term severe is often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as severe headache). This is not the same as serious, which is based on subject / event outcome or action criteria usually associated with events that pose a threat to a subject’s life or functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. Assessment of Causality

[0246] A physician will use clinical judgment to assess the relationship between study drug and each occurrence of each AE / SAE. A reasonable possibility of a relationship conveys that there are facts, evidence, and / or arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the temporal relationship of the event to study drug administration, will be considered and investigated.

[0247] If a subject dies during participation in the study or during a recognized follow- up period, a physician will provide any postmortem findings including histopathology. Clinical Steering Committee

[0248] The study will be overseen by a CSC whose members will include the clinical trial Sponsor’s Chief Medical Officer, a clinical pharmacologist, a statistician, and an external independent clinician. The CSC will be unblinded to treatment assignment as required for safety evaluation, PK, PD, and / or efficacy assessments. Subject safety, including safety signal detection at any time during the study, will be monitored by the CSC.

[0249] The safety information to be reviewed by CSC include the overall numbers and percentages of subjects who experienced any TEAEs, where AEs will be presented by system organ class and preferred term by treatment group, cohort, and disease population. ClinicalAttorney Docket No. A618-14.WO laboratory results will be listed. Clinically significant PE findings or clinically significant clinical laboratory abnormalities will be reported as AEs.

[0250] All safety data collected will be summarized and reviewed by the CSC for agreement of next steps. In particular, data will be reviewed by the Sponsor for identification of events that would potentially contribute to a requirement to stop the study.

[0251] Stopping rules are provided in below. If a stopping rule is met, a decision will be made, based on the review, as to whether enrollment in the study will be allowed to resume. G. Discontinuation Of Study Intervention And Subject Discontinuation / Withdrawal

[0252] The discontinuation of specific site(s) or of the study as a whole is detailed below.

[0253] In the event that a subject meets the criteria described in this section, dosing will be paused for the individual subject. Subjects who meet the criteria for dose pausing will continue to be followed, and additional interventions will be administered as needed.

[0254] As part of its investigation, the CSC will review the subject’s treatment assignment to establish if WAL0921 or placebo was administered. In cases in which placebo was administered, dosing will continue for that subject as described in the SoA (Tables 9A and 9B). If WAL0921 was administered, dosing for only that subject will be paused until the CSC completes an investigation and makes 1 of the following recommendations: continue at the current dose level; modify or discontinue the dose level for that subject or subjects at the same dose level; or modify or discontinue the dose for all subjects in the study. Temporarily Delaying Administration of Study Intervention

[0255] Should a Stopping Rule be met, dosing activities will be paused; however, active subjects will remain in the study for ongoing safety follow-up. A meeting will be convened promptly with the CSC in accordance with the CSC charter to discuss the event(s) and determine a follow-up action plan, including any changes to study conduct.

[0256] Instances of temporarily delaying enrollment or randomization are to be determined by the CSC.Attorney Docket No. A618-14.WO Discontinuation of Study Intervention

[0257] In rare instances, it may be necessary for a subject to permanently discontinue study drug. If the study drug is permanently discontinued, the subject should, if at all possible, remain in the study to be evaluated for safety. See the SoA for data to be collected at the time of discontinuation of study drug and follow-up and for any further evaluations that need to be completed. Grade 3 or Higher AEs during the First Infusion

[0258] If a subject has a study drug-related serious or severe (Grade 3 or higher) AE that occurs during the first infusion, dosing will be paused for that subject. All Grade 3 (or higher) infusion-related reactions will be investigated by the CSC to determine whether dosing may continue or whether dosing modifications are required for that subject, subjects at the same dose level, or all subjects in the study. Clinical Laboratory Stopping Rules

[0259] If a subject has an abnormal liver or renal test that meets 1 of the conditions outlined below at any time during the 12-week treatment period, dosing in that subject will be paused: • AST and / or ALT > 5 × Upper Limit of Normal (ULN) that is confirmed by repeat testing within 72 hours; • AST and / or ALT > 3 × ULN, and total bilirubin > 2 × ULN that is confirmed by repeat testing within 72 hours; • AST or ALT > 3 × ULN (confirmed by repeat testing within 72 hours) with the appearance or worsening of symptoms suspected by the Investigator to be related to hepatic inflammation (e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, or eosinophilia); or\ • Serum creatinine > 2 × subject’s baseline serum creatinine level that is confirmed by repeat testing within 72 hours and deemed related to study drug and not alternative etiologies (e.g., underlying disease, concomitant medications, intercurrent illness).

[0260] Additional unscheduled laboratory testing may be performed to investigate alternative etiologies of the event and / or to follow the duration and resolution of the event. TheAttorney Docket No. A618-14.WO CSC will investigate these events before additional subjects are dosed on the study. The CSC will decide how to proceed with discontinuation or dose escalation. Within Cohort Stopping Rules

[0261] Should a subject within a dose level develop a Grade 4 or higher AE, that is considered related to study drug by the CSC, dosing will be stopped for that subject and for all other subjects at the same or higher dose level.

[0262] The CSC will review the subject’s treatment assignment to establish if WAL0921 or placebo was administered. In cases in which placebo was administered, dosing will resume for that subject and for all subjects at the same or higher dose level.

[0263] In cases of Grade 4 or higher AEs in which the subject received WAL0921, the CSC will review available data and may recommend that the study be stopped, or that the subject and the remaining subjects resume treatment. Treatment may be resumed at the same dose level, a prior dose level, or an alternative dose level that is less than or equal to the level implicated in the event. Study Progression Stopping Rules

[0264] Should 2 or more subjects within a dose level experience a Grade 3 or higher event that is considered related to study drug by the CSC, the event(s) will be evaluated, and a determination made by the CSC if dose escalation or study progression will occur or stop, and / or if dosing will continue at the same dose level, a prior dose level, or an alternative dose level that is less than or equal to the level implicated in the event. Reversibility of the condition will be considered as well as the treatment options for the event. H. Statistical Considerations

[0265] The SAP will be finalized prior to the database lock, and it will include a more technical and detailed description of the statistical analyses described in this section. This section is a summary of the planned statistical analyses of the most important endpoints including primary and key secondary endpoints.

[0266] The null hypothesis of no treatment effect (no difference between baseline and 12 weeks for each WAL0921 dose) will be tested against alternative hypothesis of a beneficial treatment effect (improvement from baseline to 12 weeks for each WAL0921 dose individually, not compared to placebo) for each efficacy endpoint in each treatment groupAttorney Docket No. A618-14.WO (WAL0921 dose) and each disease population (DN and rare glomerular kidney disease subgroups). Analysis Sets

[0267] The following analysis sets will be defined in the study and will be applicable to each WAL0921 dose level and disease population (DN and each of the rare glomerular kidney disease dose level subgroups): • The enrolled analysis set (ENR), consisting of all subjects who met all eligibility criteria irrespective of whether they received the study drug; • The safety analysis set (SAS), consisting of randomized ENR subjects who received at least 1 dose of study drug (WAL0921 or placebo) and provided at least 1 safety assessment after dosing. The analyses using this set will be based upon the actual treatment assignment; • The full analysis set (FAS), consisting of SAS subjects who had at least 1 valid post- baseline efficacy or PD assessment. The analyses using this set will be based upon the actual treatment assignment; • The per protocol analysis set (PPS), consisting of FAS subjects who did not have major protocol violations during the 12-week treatment period; and • The dose-determining analysis set (DDS), consisting of PPS subjects who experienced a DLT or in the absence of a DLT, received at least 100% of the planned WAL0921 dose and completed the 12-week treatment period. Should a subject be excluded from the DDS, they may be replaced. Statistical Analyses

[0268] The statistical methods will be aimed at deriving point estimates of relevant quantities as well as appropriate measures of variability (using one-sided 90% confidence intervals). Continuous variables will be summarized by reporting the number of observations, mean, standard deviation, median, minimum, and maximum. Categorical variables will be summarized using frequency tables showing the number and percentage of subjects within each category. A detailed statistical analysis plan (SAP) will be finalized and signed before the database locks. Any deviations from the analyses described below will be described in the SAP and the clinical study report. All statistical analyses will be performed using SAS (SAS Institute Inc.; Cary, NC) and / or similar software.Attorney Docket No. A618-14.WO Safety Analysis

[0269] AEs will be coded using the most current version of Medical Dictionary for Regulatory Activities (MedDRA). The system organ class and preferred term for each AE by treatment group (placebo or WAL0921 dose levels), cohort, and disease population will be available, along with the verbatim reported term, event start and stop dates / times, seriousness, severity, relationship to treatment, action taken, and event outcome. Serious Adverse Events (SAEs) will also be documented in a case narrative format.

[0270] The overall numbers and percentages of subjects who experienced any TEAEs will be presented. Clinically significant PE findings and / or clinical laboratory abnormalities will also be reported as AEs. All AE data will be listed for each subject.

[0271] Descriptive statistics of the absolute values and changes from baseline will be presented for each continuous laboratory parameter in each treatment group and disease population by visit. In addition, each value will be classified as below, within, or above the normal range, based on ranges supplied by the laboratory used. Shift tables for changes from baseline to the end of the treatment period will be presented. All laboratory parameter data will be listed for each subject.

[0272] Vital signs and ECG parameters will be summarized using the same approach as continuous laboratory parameters, including relevant descriptive statistics and shift tables in each treatment group and disease population. In addition, a tabulation of QTcF interval data will be performed by absolute value (> 450 ms and ≤ 470 ms, >470 ms and ≤ 500 ms, >500 ms) as well as by change from baseline (>30 ms and ≤ 60 ms, >60 ms). All vital signs and ECG data will be listed. Efficacy Analysis

[0273] The efficacy endpoints will be summarized by treatment group (placebo or WAL0921 dose levels) and disease population (DN and rare glomerular kidney disease subgroups). Interim analyses (IA) for efficacy and safety will be performed on all accumulated data when the last subject within a disease group for each dose level has completed 12 weeks of treatment.

[0274] Adequately collected 24-hour urine samples will be used for efficacy analysis. The assessment for adequacy of sample collection, based on the calculated creatinine value most proximal to predicted creatinine value, will be performed prior to any unblinding.Attorney Docket No. A618-14.WO

[0275] All efficacy assessments will be performed at a one-sided α = 0.1 significance level. PK / PD Analysis

[0276] Plasma WAL0921 PK parameters defined under the PK endpoints will be estimated using NCA, compartmental, and / or PopPK analysis. Plasma WAL0921 PK parameters may include, but are not limited to, maximum observed drug concentration (Cmax), time of Cmax(Tmax), area under the drug concentration-time curve (AUC), elimination half-life (t1 / 2), and Cmin / Ctrough.

[0277] The relationship between WAL0921 PK parameters and safety, PD, and ADA will be evaluated. Additional analysis may include: • Assessment of the relationship between measures of WAL0921 exposure and level of proteinuria; • Assessment of the relationship between measures of WAL0921 exposure and select covariates / demographics; and • Assessment of the relationship between measures of WAL0921 exposure and clinical response.

[0278] The PD endpoints will be summarized by treatment group (placebo or WAL0921 dose levels) and disease population (DN and rare glomerular kidney disease subgroups). Exploratory Endpoint(s) Analysis

[0279] As an exploratory analysis, advanced statistical models (e.g., repeated measures models) may be applied to the continuous efficacy endpoints with longitudinal measurements, sample size permitting. The models may include fixed terms (treatment, visit, endpoint’s baseline value, treatment-by-visit interaction and baseline-by-visit interaction) and subject as a random term. These models may be used for evaluating the significance of the treatment effect on the continuous efficacy endpoints at all post-baseline timepoints (e.g., 4, 8, 12, 18, 24, 30, and 36 weeks). Sample Size Determination

[0280] The numbers of subjects with each disease in each WAL0921 cohort (6 subjects randomized to WAL0921 in the DN, IgAN, PMN subgroups and 9 subjects randomized toAttorney Docket No. A618-14.WO WAL0921 in the FSGS / TR-MCD subgroup ) were chosen to allow detection of statistically significant reductions in UACR (DN 36%) or UPCR (FSGS / TR-MCD 36%, IgAN 28%, PMN 29%) over 12 weeks of the treatment duration from baseline at a one-sided α = 0.1 significance level. Interim Analyses

[0281] Interim efficacy analyses will occur after each disease population (DN and each of the rare glomerular kidney disease subgroups) completes 12 weeks of dosing at an assigned dose level. Subjects and Investigators will remain blinded until all subjects in a DN or rare glomerular kidney disease subgroup have completed the follow-up period.

[0282] The IAs will be conducted such that the ongoing study integrity is maintained. Only the independent statistical support group, who is responsible for providing the interim analysis results, will be unblinded to the individual treatment assignments. Cohort Expansion / Addition

[0283] The primary objective of Cohort 4 will be to evaluate the safety, efficacy, PK, and PD of a dose level not to exceed 6 mg / kg Q2W), and / or a less frequent regimen (e.g., a monthly dosing schedule at the previously evaluated dose, in the selected subgroup. Dose selection and initiation of Cohort 4 (4a, 4b, etc.) will be based on CSC review of cumulative safety, efficacy, and available PK and PD data of Cohorts 1, 2, and 3 subgroup(s), as well as preliminary evidence of efficacy based on reduction in UACR in Cohorts 1 and 2 or UPCR in Cohort 3 for any given subgroup.

[0284] Additional subjects may be enrolled in Cohort 4 to further explore safety, efficacy, PK, and PD of WAL0921 by expanding or adding cohorts of subjects (e.g., Cohort 4 to explore an alternative dose level in 2 rare glomerular kidney diseases or additional cohort(s) in the study population), based on interim analyses of existing cohorts.

[0285] In the event variable baseline suPAR levels and UACR or UPCR reductions are observed within a cohort (e.g., specific glomerular disease[s]), a cohort may be expanded to better understand these variables. For example, a cohort may be expanded to increase the number of subjects with FSGS and variable baseline suPAR levels, to further inform / explore the relationship between baseline suPAR levels and UPCR reduction.

[0286] Cohort expansion is defined as the inclusion of individual or groups of subjects in an existing cohort. Cohort expansion decisions will be made by indication and by dose.Attorney Docket No. A618-14.WO

[0287] Expansion of any cohort may occur for the following reasons:

[0288] (1) In certain instances, a randomized subject may not be evaluable for efficacy (e.g., a subject is found to have insufficient net creatinine in the baseline 24-hour urine collection compared to predicted as per body weight based published calculations). In these instances, additional subjects(s) may be enrolled in a cohort. The originally enrolled subjects who may not be evaluable for efficacy will not count towards the cohort / subgroup sample size in the study;

[0289] (2) To increase sample size where there is preliminary evidence of activity, but assumptions used for power calculations to allow detection of statistically significant reductions in UACR or UPCR at 12 weeks are not supported by an interim analysis (e.g., the magnitude of effect of reduction in UACR or UPCR is lower than predicted). Cohorts, or disease subgroups within a cohort, may be expanded to increase confidence in the magnitude of effect observed in any given cohort or disease subgroup. Cohort expansion will not exceed 2 times the number of evaluable subjects originally planned per cohort or disease subgroup. A doubling of the number of evaluable subjects in a cohort or disease subgroup will increase the power and result in a confidence interval approximately 30% narrower than that with the original cohort size. The doubling of a cohort size and / or disease subgroup within a cohort would allow detection of statistically significant reductions in UACR (DN 25% if chosen for expansion) or UPCR (FSGS / TR-MCD 25%, IgAN 20%, PMN 21% if chosen for expansion) at 12 weeks of the treatment duration from baseline at a one-sided α = 0.1 significance level; and / or

[0290] (3) To enrich for subjects in a subset with a potentially favorable relevant prognostic or response-predictive baseline characteristic (e.g., subjects with elevated baseline suPAR levels), in the event a relevant subset shows greater reductions in UACR or UPCR than the overall cohort (e.g., 30% reduction in subjects with elevated baseline suPAR levels) but has limited sample size. Cohort or disease subgroup expansion in the subset will be limited to at most adding the same number of evaluable subjects in the clinically relevant subset as originally planned for the disease cohort or disease subgroup. I. Summary of Phase 2 Study Interim Data Phase 2 Study Cohort 1 Overview

[0291] All 8 subjects in Cohort 1 in the Phase 2 study have completed the 36-week study. Six of the 8 Cohort 1 subjects have received all 7 of their planned infusions. One subjectAttorney Docket No. A618-14.WO missed their infusion at Week 10 (6thdose) due to a treatment emergent adverse event (TEAE) (considered not related to the study drug), and 1 subject missed their infusion at Week 8 (5thdose) due to a TEAE (considered not related to study drug). Preliminary safety and PK / PD data are described below. Phase 2 Study Cohort 1 Safety Data

[0292] In Cohort 1 there were no observed trends in protocol-specified laboratory evaluations, and protocol-specified safety assessments were unremarkable (e.g., vital signs, physical examinations, ECGs). Table 12 provides data for TEAEs in Cohort 1 of the Phase 2 Study. Table 12. Subject ID AE Term Severity Relations Action Outcome to Study Taken withAttorney Docket No. A618-14.WO Acute Grade 2 Not related Study drug Recovered / bronchitis (moderate) dose missed Resolved 7 Dizzin Gr d 1 N t r l t d N h n R v rin /

[0293] Two subjects had study drug treatment interruptions (i.e., missed their subsequent scheduled study drug dose) due to TEAEs, which were considered not related to the study drug by both the Investigator and Sponsor. Additional details on these TEAEs are provided below.

[0294] One TEAE was deemed possibly related to study drug. The subject reported a constant headache to the study staff that commenced on the day following the first administration of study drug. The subject reported a change in intensity of the headache pain to 8 / 10 on Day 2 which decreased to 5 / 10 pain upon returning to bed and improving after taking acetaminophen on Day 3. The TEAE has resolved, and there was no interruption of study drug. This report of headache following the administration of WAL0921 is consistent with observations in the Phase 1 study where headache was the most commonly reported TEAE (n=1 / 2 placebo subject, n=6 / 6 WAL0921 subjects).

[0295] All 8 subjects completed the 14-day DLT evaluation period and no DLTs were observed. No stopping rules have been triggered in any of the Cohort 1 subjects have been triggered for these 8 subjects during the 14-day DLT evaluation period. Clinical Steering Committee Assessment of Phase 2 Study Cohort 1 DLT Period

[0296] Upon review of the study data, the CSC concluded that there were no safety concerns or potential signals observed and recommended that the study continue unmodified and proceed with enrolling and dosing Cohort 2 at 6 mg / kg Q2W WAL0921.Attorney Docket No. A618-14.WO Phase 2 Study Cohort 2 Overview

[0297] Eight subjects were initially enrolled in Cohort 2 in the Phase 2 Study. All 8 subjects completed 24 weeks of the study. Three subjects missed at least one treatment visit. Three subjects were replaced due to inadequate baseline urine collection. These replacement subjects have completed 12 weeks of the study. Phase 2 Study Cohort 2 Safety Data

[0298] In Cohort 2, there were no observed trends in protocol-specified laboratory evaluations and protocol-specified safety assessments were unremarkable (e.g., vital signs, physical examinations, ECGs). Table 13 provides data for TEAEs in Cohort 2 of the Phase 2 Study. Table 13. Subject AE Term Severity Relations to Action Outcome ID Study Drug Taken with / / / / / / / Attorney Docket No. A618-14.WO 16 Hypotension Grade 2 Not related No Recovered / (moderate) applicable Resolved H t i G d 2 N t l t d N R d / / ereobserved. No study stopping rules have been triggered in Cohort 2 subjects. Pharmacokinetic Data for Cohorts 1 and 2

[0300] Preliminary PK data from the MAD phase of the ongoing Phase 2 study in DN subjects were analyzed using a validated LC-MS / MS bioanalytical method for the 2 mg / kg (n=6 subjects; Cohort 1) and 6 mg / kg (n=2 subjects; Cohort 2) WAL0921 dose groups. FIG. 3A (linear concentration scale) and FIG. 3B (logarithmic concentration scale) summarize the preliminary available mean plasma WAL0921 concentration-time profiles. For FIGS.3A and 3B, aggregate preliminary blinded data are presented as mean ± standard error of the mean (SEM). The symbols / lines indicate subjects in the WAL0921 treated groups. The arrows indicate WAL0921 dosing events. Concentrations below the lower limit of quantitation (LLOQ; 150 ng / mL) were set to 0 ng / mL in the analysis.

[0301] Following the 1st 30-minute IV infusion, WAL0921 exhibits a bi-phasic distribution over the 14 days prior to administration of the 2nd dose, as expected of a monoclonal antibody. Preliminary mean (± SEM) maximal plasma WAL0921 concentration following the 1st dose is 46000 (± 3552) ng / mL for Cohort 1 and 167000 (± 36000) ng / mL for Cohort 2. WAL0921 exhibits an accumulation ratio of < 2-fold and an observed effective half- life of about 10-14 days based on data from 1 subject in Cohort 1 for whom PK data from 7 doses of WAL0921 are currently available. Single, transient ADA-positive samples were observed in some subjects, but no impact of the observed ADA responses on WAL0921 PK is apparent.

[0302] Table 14 provides the ratio of observed change in Plasma WAL0921 levels to predicted change (based on the Phase 1 PK and PD data as described above in Examples 5 and 6) in plasma WAL0921 levels at week 12 for subjects in Cohort 1 and Cohort 2 that received WAL0921. PK and PK / PD analyses are ongoing.Attorney Docket No. A618-14.WO Table 14. Cohort 1 Observed / Predicted Cohort 2 Observed / Predicted Subject No. Plasma WAL0921 Subject No. Plasma WAL0921 1 080 9 047

[0303] Preliminary PD data from the MAD phase of the Phase 2 study in DN subjects were analyzed using a validated bioanalytical method to quantitate plasma suPAR concentrations. In the presence of WAL0921, plasma suPAR exists as WAL0921-unbound suPAR (hereinafter, free suPAR) and WAL0921-bound suPAR. Plasma free suPAR was measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (suPARnostic®, ViroGates) in accordance with the manufacturer specifications. A custom suPAR ELISA method (referred to as hybrid suPAR ELISA) was also developed to detect plasma total suPAR (defined as the sum of free and antibody-bound suPAR species) in the presence of WAL0921. Total suPAR primarily reflects WAL0921-bound suPAR and its clearance is believed to occur via WAL0921 elimination pathways. The WAL0921-bound suPAR is believed to be non-pathogenic as WAL0921 completely neutralizes suPAR-induced Src kinase phosphorylation in vitro. Thus, the PD effect that is most likely to be clinically relevant is the effect of WAL0921 on free suPAR concentrations.

[0304] The mean (± SEM) baseline plasma free suPAR concentration was 3.42 ± 0.4 ng / mL (n=8) and 3.55 ± 0.05 ng / mL (n=2) for Cohort 1 (2 mg / kg WAL0921) and Cohort 2 (6 mg / kg WAL0921) subjects, respectively. In both cohorts, plasma free suPAR concentrations following the first WAL0921 IV administration show a rapid reduction of baseline suPAR concentrations to below the assay LLOQ (0.38 ng / mL) within 15 minutes, supporting successful target engagement by WAL0921 in DN subjects.

[0305] FIG.4 provides the aggregate preliminary mean percentage change in baseline plasma free suPAR by dose from the Phase 2 study. Aggregate preliminary blinded data isAttorney Docket No. A618-14.WO presented as mean ± standard error of the mean (SEM). The top symbols / lines indicate subjects presumed to be in the placebo group. The lower symbols / lines indicate subjects presumed to be in the WAL0921 treated groups. The arrows indicate WAL0921 dosing events. Concentrations below the lower limit of quantitation (LLOQ; 0.38 ng / mL) were set to 0.38 ng / mL in the analysis. The plasma free suPAR concentrations stayed at or below LLOQ levels for increasing duration of time post-dose, proportional to the first administered WAL0921 dose (FIG.4), consistent with PD data from the Phase 1 SAD study (Study WAL0921-01) in healthy subjects. In Cohort 1 (2 mg / kg), available data suggest a subsequent return of the initially reduced plasma free suPAR concentrations towards baseline. Administration of subsequent doses of WAL0921 resulted in a progressive increase in reduction of the plasma free suPAR concentrations with an average of 75 (± 8) % at the 10-week treatment period likely resulting from the observed PK accumulation of WAL0921 and consistent with PD simulations undertaken by the Sponsor from the PK data from the Phase 1 SAD study in healthy subjects. While the study remains blinded, based on review of the preliminary data, equivalent changes in baseline plasma free suPAR concentrations were not observed in 2 Cohort 1 subjects, consistent with the assumption that these were placebo subjects.

[0306] FIG.5 provides the aggregate preliminary mean percentage change in baseline plasma free suPAR over 12 weeks for subjects who received WAL0921 in Cohorts 1 and 2 of the Phase 2 Study. As illustrated in FIG. 5, preliminary data from the Phase 2 study indicates that the 2 mg / kg dose of WAL0921 maintains free suPAR in a physiological range, while the 6 mg / kg dose lowers free suPAR to a sub-physiological range for an extended period of time. Physiological levels of suPAR maintain homeostatic functions including podocyte adhesion.

[0307] Overall, analysis of preliminary WAL0921 PD data from the Phase 2 Study suggest that WAL0921 doses of 2 mg / kg administered Q2W as the effective minimal dose level predicted to achieve the targeted lower bound 50-70% reduction in plasma free suPAR concentrations from baseline in >75% of population and normalize elevated suPAR to ≤2 ng / mL levels in 86% of the subjects at 2 mg / kg Q2W at steady state.

[0308] Preliminary data shows that WAL0921 reduces proteinuria with a substantial duration of response, as illustrated in Table 15 and Table 16 below. Table 15 shows change in UACR for Cohort 1 from this Phase 2 study. Similarly, Table 16 shows change in UACR for Cohort 2 from this Phase 2 study.Attorney Docket No. A618-14.WO Table 15. Subject 12-week 18-week 24-week 30-week 36-week 1 -4% -23% -31% -15% 24% 2 1 2 1 ned onTable 16. Subject 12-week 18-week 24-week 9* -37% 126% 30%AKI; ** Subject 11 reflects UPCR change from baseline; *** Subject 15 had stopped taking Enalapril at week 10.

[0309] FIG. 6 provides the aggregate preliminary percent change in UACR over 36 weeks for subjects in Cohort 1 of the Phase 2 study. The arrows indicate WAL0921 dosing events. The “WAL0921 vs Placebo” row indicates the difference between the average percent change in UACR for patients that received placebo and patients that received WAL0921. The “WAL0921 vs Baseline: row indicates the average percent change in UACR compared to baseline. The effect of WAL0921 reducing proteinuria with a substantial duration of response is also shown in FIG.6. Study WAL0921-02 Cohort 3 Preliminary Data

[0310] Four subjects have been enrolled and received WAL0921 in Cohort 3. One subject in the FSGS arm received 6 mg / kg of WAL0921 and has completed their planned seven treatment visits. Another subject in the FSGS arm received 2 mg / kg of WAL0921 and has completed two treatment visits in the study. One subject in the IgAN arm received 6 mg / kg ofAttorney Docket No. A618-14.WO WAL0921 and has completed their planned seven treatment visits. Another subject in the IgAN arm received 2 mg / kg of WAL0921 and has completed three treatments in the study. Overall, the 2 mg / kg and 6 mg / kg WAL0921 doses have been well tolerated in the above-identified Cohort 3 subjects. Table 17 provides the change in UPCR, based on two sequential 24-hour urine collections, at 12 weeks for the Cohort 3 subjects that have received 6 mg / kg of WAL0921. FIG.7 provides the preliminary percent change in UPCR for two subjects in Cohort 3 of the Phase 2 study that received 6 mg / kg of WAL0921. Each subject was dosed as 6 mg / kg and completed their seven planned treatment visits. Two sequential 24-hour urine collections were collected and plotted for each subject. The “placebo range – DN subjects” indicates the range of percent change in UPCRs found in Cohort 1 and Cohort 2 of the Phase 2 study. The subject in the FSGS arm of Cohort 3 that received 6 mg / kg of WAL0921 achieved a mean reduction in urine protein-creatinine ratio (UPCR) of 50% vs baseline. The subject in the IgAN arm of Cohort 3 that received 6 mg / kg of WAL0921 achieved a mean reduction in UPCR of 35% vs baseline. Table 17. Subject 12-week 1 (IgAN) -28%

[0311] The invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed since these embodiments are intended as illustrations of several aspects of this invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All publications cited herein are incorporated by reference in their entirety.

Claims

Attorney Docket No. A618-14.WO CLAIMS What is claimed is:

1. A method of treating a glomerular kidney disease in a human patient in need thereof, the method comprising: administering to the patient a therapeutically effective amount of an isolated antibody or an antigen binding fragment thereof that binds to soluble urokinase plasminogen activator receptor (suPAR), the antibody or the antigen binding fragment comprises a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:

6.

2. The method of claim 1, wherein the glomerular kidney disease is selected from the group consisting of diabetic nephropathy, primary focal segmental glomerulosclerosis, treatment-resistance minimal change disease, primary immunoglobulin A nephropathy, primary membranous nephropathy, and combinations thereof.

3. The method of claim 2, wherein the glomerular kidney disease is diabetic nephropathy.

4. The method of claim 2, wherein the glomerular kidney disease is primary focal segmental glomerulosclerosis.

5. The method of claim 2, wherein the glomerular kidney disease is treatment-resistance minimal change disease.Attorney Docket No. A618-14.WO 6. The method of claim 2, wherein the glomerular kidney disease is primary immunoglobulin A nephropathy.

7. The method of claim 2, wherein the glomerular kidney disease is primary membranous nephropathy.

8. The method of claim 2, wherein the glomerular kidney disease is the combination of primary focal segmental glomerulosclerosis and treatment-resistance minimal change disease.

9. The method of claim 2, wherein the glomerular kidney disease is primary focal segmental glomerulosclerosis, or primary immunoglobulin A nephropathy.

10. The method of claim 1, wherein the glomerular kidney disease is a primary glomerulopathy.

11. The method of claim 10, wherein the primary glomerulopathy is selected from the group consisting of primary focal segmental glomerulosclerosis, treatment-resistance minimal change disease, primary immunoglobulin A nephropathy, primary membranous nephropathy, and combinations thereof.

12. The method of any one of claims 1-11, wherein the dose is from about 2 mg / kg to about 6 mg / kg.

13. The method of any one of claims 1-11, wherein the dose is about 2 mg / kg.

14. The method of any one of claims 1-11, wherein the dose is about 6 mg / kg.Attorney Docket No. A618-14.WO 15. The method of any one of claims 1-11, wherein the antibody or the antigen binding fragment is intravenously administered to the patient.

16. The method of claim 15, wherein the antibody or the antigen binding fragment is intravenously administered to the patient once every 2 weeks.

17. The method of claim 16, wherein the antibody or the antigen binding fragment is intravenously administered to the patient once every 2 weeks for a treatment period of about 14 weeks.

18. A method of reducing proteinuria associated with a glomerular kidney disease in a human patient in need thereof, the method comprising: administering to the patient a therapeutically effective amount of an isolated antibody or an antigen binding fragment thereof that binds to soluble urokinase plasminogen activator receptor (suPAR), the antibody or the antigen binding fragment comprises a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:

6.

19. The method of claim 18, wherein the glomerular kidney disease is selected from the group consisting of diabetic nephropathy, primary focal segmental glomerulosclerosis, treatment-resistance minimal change disease, primary immunoglobulin A nephropathy, primary membranous nephropathy, and combinations thereof.

20. The method of claim 19, wherein the glomerular kidney disease is diabetic nephropathy.Attorney Docket No. A618-14.WO 21. The method of claim 19, wherein the glomerular kidney disease is primary focal segmental glomerulosclerosis.

22. The method of claim 19, wherein the glomerular kidney disease is treatment- resistance minimal change disease.

23. The method of claim 19, wherein the glomerular kidney disease is primary immunoglobulin A nephropathy.

24. The method of claim 19, wherein the glomerular kidney disease is primary membranous nephropathy.

25. The method of claim 19, wherein the glomerular kidney disease is the combination of primary focal segmental glomerulosclerosis and treatment-resistance minimal change disease.

26. The method of claim 19, wherein the glomerular kidney disease is primary focal segmental glomerulosclerosis, or primary immunoglobulin A nephropathy.

27. The method of claim 18, wherein the glomerular kidney disease is a primary glomerulopathy.

28. The method of claim 27, wherein the primary glomerulopathy is selected from the group consisting of primary focal segmental glomerulosclerosis, treatment-resistance minimal change disease, primary immunoglobulin A nephropathy, primary membranous nephropathy, and combinations thereof.

29. The method of any one of claims 18-28, wherein the dose is from about 2 mg / kg to about 6 mg / kg.Attorney Docket No. A618-14.WO 30. The method of any one of claims 18-28, wherein the dose is about 2 mg / kg.

31. The method of any one of claims 18-28, wherein the dose is about 6 mg / kg.

32. The method of claim 18, wherein the antibody or the antigen binding fragment is intravenously administered to the patient.

33. The method of claim 32, wherein the antibody or the antigen binding fragment is intravenously administered to the patient once every 2 weeks.

34. The method of claim 33, wherein the antibody or the antigen binding fragment is intravenously administered to the patient once every 2 weeks for a treatment period of about 14 weeks.

35. A method of inhibiting soluble urokinase plasminogen activator receptor (suPAR) in a human patient in need thereof having a glomerular kidney disease, the method comprising: administering to the patient a therapeutically effective amount of an isolated antibody or an antigen binding fragment thereof that binds to soluble urokinase plasminogen activator receptor (suPAR), the antibody or the antigen binding fragment comprises a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:

6.

36. The method of claim 35, wherein the glomerular kidney disease is selected from the group consisting of diabetic nephropathy, primary focal segmental glomerulosclerosis, treatment-resistance minimal change disease, primary immunoglobulin A nephropathy, primary membranous nephropathy, and combinations thereof.Attorney Docket No. A618-14.WO 37. The method of claim 36, wherein the glomerular kidney disease is diabetic nephropathy.

38. The method of claim 36, wherein the glomerular kidney disease is primary focal segmental glomerulosclerosis.

39. The method of claim 36, wherein the glomerular kidney disease is treatment- resistance minimal change disease.

40. The method of claim 36, wherein the glomerular kidney disease is primary immunoglobulin A nephropathy.

41. The method of claim 36, wherein the glomerular kidney disease is primary membranous nephropathy.

42. The method of claim 36, wherein the glomerular kidney disease is the combination of primary focal segmental glomerulosclerosis and treatment-resistance minimal change disease.

43. The method of claim 36, wherein the glomerular kidney disease is primary focal segmental glomerulosclerosis, or primary immunoglobulin A nephropathy.

44. The method of claim 35, wherein the glomerular kidney disease is a primary glomerulopathy.

45. The method of claim 44, wherein the primary glomerulopathy is selected from the group consisting of primary focal segmental glomerulosclerosis, treatment-resistance minimal change disease, primary immunoglobulin A nephropathy, primary membranous nephropathy, and combinations thereof.Attorney Docket No. A618-14.WO 46. The method of any one of claims 35-45, wherein the dose is from about 2 mg / kg to about 6 mg / kg.

47. The method of any one of claims 35-45, wherein the dose is about 2 mg / kg.

48. The method of any of one claims 35-45, wherein the dose is about 6 mg / kg.

49. The method of claim 35, wherein the antibody or the antigen binding fragment is intravenously administered to the patient.

50. The method of claim 49, wherein the antibody or the antigen binding fragment is intravenously administered to the patient once every 2 weeks.

51. The method of claim 50, wherein the antibody or the antigen binding fragment is intravenously administered to the patient once every 2 weeks for a treatment period of about 14 weeks.

52. The method of any one of claims 1-51, wherein the antibody is a humanized antibody.

53. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a heavy chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO:

9.

54. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a heavy chain variable region that is at least 97% identical to the amino acid sequence of SEQ ID NO: 9.Attorney Docket No. A618-14.WO 55. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a heavy chain variable region that is at least 99% identical to the amino acid sequence of SEQ ID NO:

9.

56. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

9.

57. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a light chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO:

10.

58. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a light chain variable region that is at least 97% identical to the amino acid sequence of SEQ ID NO:

10.

59. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a light chain variable region that is at least 99% identical to the amino acid sequence of SEQ ID NO:

10.

60. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:

10.

61. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a heavy chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3 and a light chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10.Attorney Docket No. A618-14.WO 62. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a heavy chain variable region that is at least 97% identical to the amino acid sequence of SEQ ID NO: 3 and a light chain variable region that is at least 97% identical to the amino acid sequence of SEQ ID NO:

10.

63. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a heavy chain variable region that is at least 99% identical to the amino acid sequence of SEQ ID NO: 9 and a light chain variable region that is at least 99% identical to the amino acid sequence of SEQ ID NO:

10.

64. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

10.

65. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a heavy chain constant region comprising the amino acid sequence of SEQ ID NO:

11.

66. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a light chain constant region comprising the amino acid sequence of SEQ ID NO:

12.

67. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 39 a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 11, a light chain variable region comprising the amino acid sequence of SEQ ID NO: 4, and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 12.Attorney Docket No. A618-14.WO 68. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a heavy chain that is at least 95% identical to the amino acid sequence of SEQ ID NO:

7.

69. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a heavy chain that is at least 97% identical to the amino acid sequence of SEQ ID NO:

7.

70. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a heavy chain that is at least 99% identical to the amino acid sequence of SEQ ID NO:

7.

71. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:

7.

72. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a light chain that is at least 95% identical to the amino acid sequence of SEQ ID NO:

8.

73. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a light chain that is at least 97% identical to the amino acid sequence of SEQ ID NO:

8.

74. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a light chain that is at least 99% identical to the amino acid sequence of SEQ ID NO: 8.Attorney Docket No. A618-14.WO 75. The method of any one of claims 1-51, wherein the antibody or the antibody binding fragment comprises a light chain comprising the amino acid sequence of SEQ ID NO: 8.

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