Bifunctional degraders

Abstract

A composition of matter including an IgM-binding moiety, a cellular receptor-binding moiety that binds to hepatocytes or other degrading cells through asialoglycoprotein receptors (ASGPR) on the surface of hepatocytes or other degrading cells in a subject or patient, and optionally, a linker moiety connecting the IgM-binding moiety and the cellular receptor-binding moiety, wherein the composition of matter is useful for removing in a subject or patient.

Description

BIFUNCTIONAL DEGRADERSFIELD OF THE INVENTION

[0001] The invention generally relates to medicinal preparations characterized by the non-active ingredients used, targeting or modifying agents chemically bound to the active ingredient, the nonactive ingredient being chemically bound to the active ingredient, the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e., the entire conjugate being a pharmacologically or therapeutically active compound, and particularly to bifunctional molecules which contain a circulating protein-binding moiety linked through a linker group to a cellular receptor-binding moiety for the treatment of Waldenstrom macroglobulinemia (WM) and other IgM-related disorders.BACKGROUND OF THE INVENTION

[0002] Waldenstrom macroglobulinemia is a form of non-Hodgkin lymphoma in which B-lymphocytes produce excessive immunoglobulin M. Waldenstrom macroglobulinemia often causes thickened blood (hyperviscosity), fatigue, peripheral neuropathy, symptomatic or bulky lymphadenopathy, and organ swelling. Although incurable, treatments such as targeted therapy, chemotherapy, and plasmapheresis can manage chronic symptoms. The clinical indications for initiating therapy for Waldenstrom macroglobulinemia include recurrent fever, night sweats, weight loss, and fatigue.

[0003] Thus, there remains a need in the biomedical art for new medicines capable of treating or slowing down the progression of Waldenstrom macroglobulinemia or other IgM-related disorders.SUMMARY OF THE INVENTION

[0004] In one embodiment, the invention provides a composition of matter (agent, a MODE™) comprising:a target-binding moiety that can bind to IgM,a cellular receptor-binding moiety that can bind to hepatocytes or other degrading cells through asialoglycoprotein receptors (ASGPR) of hepatocytes or other cell receptors on the surface of hepatocytes or other degrading cells in a subject or patient, and130131-WO-PCTa linker moiety connecting the target-binding moiety and the cellular receptor-binding moiety.

[0005] In another embodiment, the invention provides a composition of matter (agent, MODE™), where the composition of matter has the structure:wherein [CPBM] is a target-binding moiety that can bind to IgM;[CRBM] is a cellular receptor-binding moiety;each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [CRBM] or connects the [LINKER] to [CPBM] or to [CRBM], and[LINKER] is a chemical moiety that covalently attaches to one or more [CRBM] or [CPBM] groups, ora pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

[0006] In some embodiments, the invention provides a composition of matter (an agent, a MODE™) having a structure of:[AGN102],or a pharmaceutically acceptable salt thereof.In Formulas [AGN101] and [AGN102], each of a, b, and c is independently 1-200;each ABT is independently a target-binding moiety that can bind to IgM;L is a linker moiety; andeach TBT is independently a cellular receptor-binding moiety.230131-WO-PCT

[0007] In some embodiments, a is 1. In some embodiments, b is 1, 2, or 3. In some embodiments, c is 1. In some embodiments, each of a, b and c is 1.

[0008] In a particular embodiment, the composition of matter (agent, MODE™) has a structure selected from the Markush group consisting of AGN7557, AGN7558, AGN7559, AGN7560, AGN7561, AGN7562, and AGN7600.

[0009] In some embodiments, the target-binding moiety comprises ABT0101, a VHH moiety conjugated to the linker moiety, wherein one or two peptides comprising one or more epitopes are conjugated to one or each of the protein chains of the VHH moiety. In a particular embodiment, the VHH moiety with the peptide comprises the VHH nanobody of SEQ ID NO: 4. Target p-chain of IgM. Selectivity (binds to) Hu, Ms, Rt IgM. No cross-binding with human IgA, IgD, IgE, and IgG, free light chains (κ and λ), and Bv IgM. A 14 kDa recombinant single domain antibody fragment (VHH affinity ligand) that specifically binds to the p chain of human, rat, and mouse IgM antibodies. In some embodiments, the binding moiety has a structure selected from the Markush group consisting of ABT7229 (SEQ ID NO: 197), ABT7231 (SEQ ID NO: 199), ABT7232 (SEQ ID NO: 200), ABT7233 (SEQ ID NO: 201), ABT7322 (SEQ ID NO: 209), ABT7323 (SEQ ID NO: 210), and ABT7316 (SEQ ID NO: 203).

[0010] In some embodiments, the target-binding moiety comprises a fragment of the ~60 kDa human transmembrane protein Immunoglobulin mu Fc receptor (FcpR), also known as Fas apoptotic inhibitor molecule 3 (FAIM3) and Regulator of Fas-induced apoptosis (TOSO). Human FcpR is expressed predominantly by lymphocytes, binds IgM with specificity, and regulates IgM transport and homeostasis. The extracellular Ig-like domain of FcpR interacts specifically with the Fc portion of IgM with a KDof 1-2.5330131-WO-PCTpM and can be conjugated to an ASGPR ligand to generate a bifunctional degrader of IgM. See Kubagawa et al., J. Exp. Med., 206(12), 2779-93 (November 23, 2009); Skopnik et al., Front. Immunol. 11, 618327 (2021); Chen et al., Nature Struct. Mol. Biol., 30(7), 1033-1039 (July 2023); and Nyamboya, Sutton, and Calvert, Biochim. Biophys. Acta Proteins Proteom., 1868(1), 140266 (January 2020).

[0011] In another embodiment, the cellular receptor-binding moiety comprises an ASGPR binding group according to the chemical structure:[TBT102],wherein the cellular receptor-binding moiety has additional elements described in this specification.

[0012] In a particular embodiment, the cellular receptor-binding moiety has a structure selected from the Markush group consisting of TBT6506, TBT3070, and TBT6544.

[0013] In another embodiment, the invention provides the composition of matter (agent, MODE™) for use a medicament.

[0014] In another embodiment, the invention provides the composition of matter (agent, MODE™) for use in removing IgM in a subject.

[0015] In another embodiment, the invention provides the composition of matter (agent, MODE™) for use in treating a disease state or condition associated with IgM upregulation in a subject.

[0016] In another embodiment, the invention provides a method of making the composition of matter (agent).30131-WO-PCT

[0017] In another embodiment, the invention provides a method of removing IgM in a subject by administering the agent to the subject.

[0018] In another embodiment, the invention provides a method for treating a disease state or condition associated with upregulation of IgM in a patient by administering an effective amount of the agent to the patient. In a particular embodiment, the invention provides a method for treating a disease state or condition selected from the Markush group consisting of IgM monoclonal gammopathy of undetermined significance (IgM MGUS), AL amyloidosis, anti-MAG neuropathy, Bing-Neel syndrome, CANOMAD syndrome, cold agglutinin disease, connective tissue diseases such as lupus, cryoglobulinemia, chronic lymphocytic leukemia (CLL), non-MAGPN, plasma cell dyscrasia, POEMS syndrome, Schnitzler syndrome, smoldering multiple myeloma, splenic marginal zone lymphoma, Tempi syndrome, and Waldenstrom macroglobulinaemia.

[0019] The selection of patients who can benefit from the administration of the IgM bifunctional degrader and the therapeutic progression of patients to whom the IgM bifunctional degrader was administered can be assayed by methods known in the biomedical art.

[0020] In another embodiment, the invention provides a composition including the agent, and at least one additional agent comprising a moiety capable of binding to that forms the antibody moiety of the first compound.

[0021] In another embodiment, the invention provides a composition including the agent and at least one pharmaceutically acceptable excipient.

[0022] Several objects, features, aspects, and advantages of the invention will become more apparent from the following detailed description of embodiments of the invention, along with the accompanying drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0023] For illustration, some embodiments of the invention are shown in the drawings described below. Like numerals in the drawings indicate like elements throughout. The invention is not limited to the precise arrangements, dimensions, and instruments shown.

[0024] FIG. 1 shows a process for preparing one embodiment of the bifunctional molecules (agents) from a full IgG antibody and a reagent having affinity for it by conjugating the IgG antibody to the reagent.

[0025] FIG. 2 is a table (TABLE 2) of R-Groups for MATE™ reagents and bifunctional MoDE™ final compounds.530131-WO-PCT

[0026] FIG. 3 is a sequence comparison of the constant heavy chains of human IgGl, lgG2, and lgG4, which can be therapeutic antibodies. Sequence differences in lgG2 and lgG4 from IgGl are noted. The hinge and lower hinge regions, with the N-glycosylation site, N297, are noted. Numbering is according to the European Union numbering scheme. Sequences important for FcgR binding, Clq, and FcRn are noted by shading. Some increased ADCC mutants are shown above or below the sequences, as noted: Xencor's S239D, A330L, I332E [above sequences], Genentech's S298A, E333A, K334A [below sequences], and Eli Lilly / AME's P247I, A339D / Q [above sequences]. Examples of FcRn-binding mutants for prolongation of half-life are also shown, as noted: Medlmmune's YTE mutant (M252Y, S254T, T256E), PDL's T250Q, M428L mutant, Sally Ward's H433K mutant, N434Y mutant, and Genentech's N434A mutant are shown boxes.

[0027] FIG. 4 is a set of diagrams showing exemplary bifunctional degrader embodiments, including AGN7557 (ABT7229-TBT6506), AGN7558 (ABT7229-TBT6506), AGN7559 (ABT7231-TBT6506), AGN7560 (ABT7233-TBT3070), AGN7562 (ABT7323-TBT6506), AGN7660 (ABT7316-TBT6506), and AGN17420 (hydrolysis of ABT7232-TBT6506).

[0028] FIG. 5 is a set of diagrams showing exemplary IgM-binding moieties, including ABT7518 (SEQ ID NO: 212) and ABT7519 (SEQ ID NO: 357).

[0029] FIG. 6 is a line graph showing that ASGPR ligand mediates internalization of IgM. Rank order of results was AGN7559 > AGN17420.

[0030] FIG. 7 is a line graph from the mouse pharmacodynamic assay, with the intravenous administration of several bifunctional degrader embodiments (AGN7559 (20:1), AGN7560 (20:1), and AGN7560 (4:1). See EXAMPLE 21.

[0031] FIG. 8 is a line graph from the mouse pharmacodynamic assay, with the intravenous administration of several bifunctional degrader embodiments (AGN7559 (8:1). See EXAMPLE 21.

[0032] FIG. 9 is a line graph showing the results of a ternary complex assay. Bifunctional degrader embodiments AGN7557, AGN7558, AGN7559, AGN7560, AGN7561, and AGN7562 were tested. See EXAMPLE 5.

[0033] FIG. 10 is a line graph showing the internalization of IgM using several bifunctional degrader embodiments into ASGR1 HEK293 cells. Bifunctional degrader embodiments AGN7557, AGN7558, AGN7559, AGN7560, AGN7561, and AGN7562 were tested.630131-WO-PCTDETAILED DESCRIPTION OF THE INVENTION

[0034] The following detailed description is provided to aid persons having ordinary skill in the biomedical art. Exemplary embodiments are described, but these embodiments are only exemplary. This disclosure is not limited thereto but is defined by the scope of the appended claims. Persons having ordinary skill in the biomedical art may make modifications and variations in the embodiments described in this specification without departing from the spirit or scope of this disclosure.Industrial Applicability

[0035] The invention provides a medically useful composition of matter (agent) for treating or slowing down the progression of IgM MGUS or and other diseases associated with an excess of IgM.

[0036] After the bifunctional degrader and the bound IgM protein are endocytosed, they are released from the ASGPR via calcium depletion of the endosome and changes in binding-site amino acid protonation due to decreased pH. The ASGPR is recycled back to the hepatocyte surface. Endocytosed proteins are trafficked to late endosomes, which are fused with lysosomes. Lysosomal proteases then degrade endocytosed proteins, permanently removing them from circulation.30131-WO-PCT30131-WO-PCTDefinitions

[0037] For convenience, the meaning of some terms and phrases used in the specification, examples, and appended claims are listed below. Unless stated otherwise or implicit from context, these terms and phrases shall have the meanings below. These definitions aid in describing embodiments but are not intended to limit the claimed invention.

[0038] As used in this specification, except as otherwise expressly provided in this specification, each of these terms shall have the meaning set forth below. Additional definitions are set forth throughout the specification. Where a term is not specifically defined in this specification, that term is given a biomedical art-recognized meaning, applying that term in context to its use in describing the invention.

[0039] The articles "a" and "an" have the plain meaning of one or more than one, i.e., at least one, of the grammatical object of the article unless the context indicates otherwise. For example, "an element" means one element or more than one element.

[0040] The term " ABT" as used in this specification means a binding moiety in a composition of interest (agent) that is an antibody, an antibody variant, or an antigen-binding fragment thereof that binds to an IgM of interest on a subject or patient.

[0041] The term "active Ingredient" has the United States Food & Drug Administration-provided meaning of any component that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of a human body or an animal body.

[0042] The term " ADCC" has the biomedical art-recognized meaning of antibody-dependent cell-mediated cytotoxicity, which is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system kills a target cell whose membrane-surface antigens have been bound by specific antibodies.930131-WO-PCT

[0043] The term " ADCP" has the biomedical art-recognized meaning of antibody-dependent cell-mediated phagocytosis. ADCP is an immunological mechanism of elimination whereby tumor cells are targeted with antibodies to promote their clearance from the body by phagocytic immune cells.

[0044] The term "agent" has the biomedical art-recognized meaning of a composition of matter useful for performing a function. Several biomedically useful functions are described in this specification.

[0045] The term " AL amyloidosis" has the biomedical art-recognized meaning of a complication of IgM MGUS caused by extracellular tissue deposition of misfolded immunoglobulins. Cao et al., Leuk Res., 46, 85–8 (2016). IgM-related AL amyloidosis less frequently presents with cardiac involvement than non-IgM AL amyloidosis but has a higher prevalence of peripheral neuropathy secondary to the amyloid deposition. See Sidana et al., Leukemia, 34(5), 1373-1382 (2020).

[0046] The term "alleviate" has the biomedical art-recognized meaning of a process by which the severity of a sign or symptom of a disorder is reduced. A sign or symptom can be alleviated without being eliminated. The administration of compositions or pharmaceutical compositions of the invention may or can lead to the elimination of a sign or symptom. However, elimination is not required. Effective dosages should be expected to decrease the severity of a sign or symptom.

[0047] The term "anti-MAG neuropathy" has the biomedical art-recognized meaning of the most common and best-defined IgM-related neuropathy. Subjects typically present with chronic-onset, distal, symmetric neuropathy, sensory ataxia and tremor. Subjects may be misdiagnosed as having chronic inflammatory demyelinating polyneuropathy. Atypical red flag symptoms not consistent with anti-MAG peripheral neuropathies include acute onset, rapid tempo of symptoms, pain, dysautonomia, weight loss, and cutaneous or central nervous system signs.

[0048] The term "antigen-binding fragment thereof" has the biomedical art-recognized meaning of (1) a fragment of an intact antibody that binds to the same antigen recognized by the full-length antibody, such as F(ab')2, F(ab)2, Fab', Fab, Fv, sFv, or other fragments consisting of the variable regions, or (2) any synthetic or genetically engineered protein that acts like an antibody by binding to a specific antigen to form a complex. The term antigen-binding portion of an antibody encompasses single-chain antibodies.

[0049] The term "asialoglycoprotein receptor (ASGPR) binding group" has the biomedical art-recognized meaning of a binding group that binds to a hepatocyte asialoglycoprotein receptor. The ASGPR binding group selectively binds to hepatocyte asialoglycoprotein receptors on the surface of hepatocytes. In several embodiments of this specification, an ASGPR binding group is a component of a1030131-WO-PCTbifunctional degrader as a cellular receptor-binding moiety covalently bound to the antibody-binding moiety through a linker group or directly. It is through this ASGPR moiety that bifunctional degrader complexes with a circulating protein, e.g., binds to hepatocytes. After the bifunctional degrader complexed with a circulating protein is bound to a hepatocyte or other cell, the circulating protein is taken into the hepatocyte or other cell via a phagocytosis mechanism, wherein the circulating protein is degraded through lysosomal degradation.

[0050] The term "asialoglycoprotein receptor (ASGPR) has the biomedical art-recognized meaning of lectins, which bind asialoglycoprotein and glycoproteins from which a sialic acid has been removed to expose galactose residues. These cellular receptors are located on mammalian hepatocytes and other cells, such as glandular cells of the gallbladder and the stomach. ASGPR removes target glycoproteins from circulation.

[0051] The term "at least one of," when preceding a list of elements, modifies the entire list of elements and does not modify the individual elements of the list.

[0052] The term " AT" as used in this specification means a moiety in the composition of matter (agent) that binds to a target of interest in a subject or patient. In some embodiments of this specification, the AT binds to IgM.

[0053] The term "binder to antibody ratio" (BAR) has biomedical art-recognized meaning when used in making antibody conjugates. In this specification, the terms DAR and BAR are interchangeable.

[0054] The term "binding moiety" has the biomedical art-recognized meaning of a moiety on a binding protein, e.g., an antibody, an antibody variant, or an antigen-binding fragment thereof, that binds to IgM,

[0055] The term " Bing-Neel syndrome" has the biomedical art-recognized meaning of a central nervous system infiltration by lymphoplasmacytic lymphoma; consensus guidelines on its diagnosis, treatment, and response criteria have been published. Minnema et al., Haematologica, 102(1), 43-51 (2017).

[0056] The term " CANOMAD syndrome" has the biomedical art-recognized meaning of a rare chronic progressive condition associated with antiganglioside antibodies.

[0057] The term "cellular receptor-binding moiety" has the biomedical art-recognized meaning. In several embodiments of this specification, the cellular receptor-binding moiety is an asialoglycoprotein receptor (ASGPR) binding group.

[0058] The term "cellular receptor" has the biomedical art-recognized meaning of a protein on the surface of a cell that binds to a compound, e.g., a ligand, e.g., a protein, in solution or on another cell.1130131-WO-PCTGenerally, ligand-receptor binding induces one or more biological responses. In this specification, an asialoglycoprotein receptor (ASGPR) is a cellular receptor on the surface of hepatocytes or other cells that binds to an asialoglycoprotein or a derivative thereof.

[0059] The term "chimerized" has a biomedical art-recognized meaning. Chimeric antibodies are made by fusing variable domains from one species, such as a mouse, with constant domains from another species, such as a human being. Through these biotechnical manipulations, chimeric antibodies retain the foreign antibody's antigen specificity and affinity.

[0060] The term "chronic lymphocytic leukemia" (CLL) has a biomedical art-recognized meaning. CLL arises from a pre- germinal or post-germinal center CD5+B cell. Fabbri & Dalla-Favera, Nature Rev., Cancer, 16(3), 145–62 (2016). CLL is preceded by monoclonal B-cell lymphocytosis (MBL) and monoclonal gammopathy of undetermined significance (MGUS), respectively. Landgren et al., N. Engl. J Med. 360(7), 659–67 (2009), Landgren et al., Blood, 113(22), 5412–7 (2009).

[0061] The term "cold agglutinin disease" has the biomedical art-recognized meaning. Cold agglutinin disease, leading to extravascular hemolytic anemia after cold exposure caused by IgM binding to red blood cell surface antigens and subsequent complement cascade activation, has been described in patients with IgM MGUS. Berentsen et al., Haematologica, 91(4), 460–6 (2006). Cold agglutinin has a monoclonal IgMK in more than 90% of cases. Cold agglutinin is produced by clonal lymphocytes in the bone marrow. The antibody binds erythrocyte antigens (typically type I) optimally at 4°C resulting in agglutination and classical complement pathway activation. Jäger et al., Blood Rev., 41 100648 (2020). The thermal amplitude describes the temperature range at which the antibodies are active, and only those with a thermal amplitude reaching higher than 28° C are considered pathogenic. In most cases, complement activation is incomplete, and extravascular hemolysis of C3b-opsonized erythrocytes occurs in the liver. Less frequently, the terminal pathway is initiated, the membrane attack complex (C5b-C9) is assembled, and intravascular hemolysis occurs, which can lead to acute, life-threatening anemia. Cold agglutinins in the context of infection, autoimmune disease and overt lymphoma (including chronic lymphocytic lymphoma, diffuse large B-cell lymphoma and Waldenstrom macroglobulinaemia) are referred to as cold agglutinin syndrome. CAD is a chronic disease. Clonality has been demonstrated in approximately 80% of cases. Berentsen et al., Blood, 136(4), 480-488 (2020).

[0062] The term "complementarity determining region (CDR)" has the biomedical art-recognized meaning of a polypeptide region of an antibody heavy chain or an antibody light chain that determines the antibody to antigen binding. Each antibody heavy chain contains three CDRs. Each antibody light chain contains three CDRs, usually different from the three CDRs on an antibody heavy chain. Persons1230131-WO-PCThaving ordinary skill in the biomedical art can calculate the CDR structure using a standardized numbering method known as the Kabat numbering scheme. Other numbering schemes, such as the Chothia, IMGT, Martin (enhanced Chothia), and other standard numbering schemes, are also used by persons having ordinary skill in the biomedical art.

[0063] The term "connective tissue disease such as lupus" has the biomedical art-recognized meaning. Larking-Pettigrew, Ranich, & Kelly, Immunol. Invest. 28 (4), 269–276 (1999).

[0064] The term "conservative substitution" has the biomedical art-recognized meaning. For example, Sequence identity can be measured using sequence analysis software, for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis. 53705, BLAST, BESTFIT, GAP, or PILEUP / PRETTYBOX programs. Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, or other modifications. Conservative substitutions include those within these groups: glycine, alanine, valine, isoleucine, leucine, aspartic acid, glutamic acid, asparagine, glutamine, serine, threonine, lysine, arginine, and phenylalanine and tyrosine. A residue having similar physicochemical characteristics can replace an amino acid, e.g., substituting one aliphatic residue for another, such as Ile, Val, Leu, or Ala for one another, or substitution of one polar residue for another, such as between Lys and Arg, Glu and Asp, or Gin and Asn. Other such conservative substitutions, e.g., substitutions of entire regions having similar hydrophobicity characteristics, are well known in the biomedical art. Numbering is according to the European Union numbering scheme. Polypeptides comprising conservative amino acid substitutions can be tested in any of the assays to confirm the desired activity.

[0065] The term "cryoglobulinemia" has the biomedical art-recognized meaning of a family of rare vasculitis conditions causing inflammation of the blood vessels. Cryoglobulinemia patients have cryoglobulin proteins that clump together at body temperatures below 37°C. Cryoglobulinemia is manifested by acrocyanosis, Raynaud phenomenon, urticaria, peripheral neuropathy, renal failure, or vasculitis resulting from IgM immune-complex precipitation in cold temperatures, which has been associated with IgM MGUS as well. Ramos-Casals et al., Lancet, 379(9813), 348–60 (2012).

[0066] The term "drug to antibody ratio" (DAR) has biomedical art-recognized meaning when used in making antibody conjugates. In this specification, the terms DAR and BAR are interchangeable.

[0067] The term " Fab" has the biomedical art-recognized meaning.

[0068] The term " Fc" has the biomedical art-recognized meaning of the fragment crystallizable region (Fc region), the tail region, of an antibody.1330131-WO-PCT

[0069] The term " FcgR" has the biomedical art-recognized meaning of a polypeptide region in the fragment crystallizable region (Fc region), the tail region, of an antibody.

[0070] The term " FcRn" has the biomedical art-recognized meaning of a polypeptide region in the fragment crystallizable region (Fc region), the tail region, of an antibody.

[0071] The term " FcRy" has the biomedical art-recognized meaning of a polypeptide region in the fragment crystallizable region (Fc region), the tail region, of an antibody.

[0072] The term "hepatocyte" has the biomedical art-recognized meaning of a cell of the main parenchymal tissue of the liver. Hepatocytes make up 55-65% of the liver's mass.

[0073] The term "humanized" has the biomedical art-recognized meaning that a protein, e.g., an antibody, is genetically engineered to closely resemble the polypeptide structure of the human homologue. A variable domain of a rodent antibody can be fused to a constant domain of human origin, thus retaining the specificity of the rodent antibody. The human origin domain need not originate directly from a human when it is first synthesized in a human. Human domains can be generated in rodents whose genome incorporates human immunoglobulin genes. The antibody can be partially or completely humanized. In one approach, four general steps are used to humanize a monoclonal antibody. These steps are (1) determining the nucleotide and predicted amino acid sequence of the starting antibody light and heavy variable domains; (2) designing the humanized antibody, i.e., deciding which antibody framework region to use during the humanizing process; (3) the actual humanizing methodologies / techniques; and (4) the transfection and expression of the humanized antibody.

[0074] The term " IC50" has the biomedical art-recognized meaning of an amount, concentration, or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.

[0075] The term " IgG" antibody has the biomedical art-recognized meaning. Each IgG molecule consists of the basic four-chain immunoglobulin structure— two y (gamma) heavy chains and two identical light chains (either κ or λ)— and carries two identical antigen-binding sites. There are four subclasses of IgG, each with minor differences in its H chains but with distinct biological properties.

[0076] The term " IgGl" antibody has the biomedical art-recognized meaning of an IgG antibody where the Ig gamma-1 chain C region is a protein encoded by the IGHG1 gene in humans.

[0077] The term "lgG2" antibody has the biomedical art-recognized meaning of an IgG antibody where the Ig gamma-2 chain C region is a protein encoded by the IGHG2 gene in humans.1430131-WO-PCT

[0078] The term "lgG4" antibody has the biomedical art-recognized meaning of an IgG antibody where the Ig gamma-4 chain C region is a protein encoded by the IGHG4 gene in humans. lgG4 has little effector function. lgG4 cannot fix complement.

[0079] The term " IgM gammopathy" has the biomedical art-recognized meaning of a condition selected from the Markush group consisting of IgM monoclonal gammopathy of undetermined significance (MGUS) and monoclonal gammopathy of clinical significance (MGCS).

[0080] The term " IgM monoclonal gammopathy of undetermined significance" (IGM MGUS) has the biomedical art-recognized meaning, has the biomedical art-recognized meaning. The Mayo Clinic criteria of IgM MGUS characterize the condition as a serum IgM monoclonal protein of less than 3 g / dL, bone marrow lymphoplasmacytic lymphoma (LPL) involvement of less than 10%, and no evidence of signs or symptoms secondary to the lymphoplasmacytic infiltrative process. Kyle et al., Clin. Lymphoma Myeloma, 9(1), 17-8 (2009). The Second International Workshop on Waldenstrom macroglobulinaemia consensus defined IgM MGUS as a serum IgM monoclonal protein of any size without bone marrow involvement by an LPL. Owen et al., Semin. Oncol., 30(2), 110-5 (2003). See also the 2016 revision of the World Health Organization classification of lymphoid neoplasms. Swerdlow et al., Blood, 127(20), 2375-2390 (2016).

[0081] The term " IgM-related disorders" has the biomedical art-recognized meaning that encompasses not only IgM MGUS and Waldenstrom macroglobulinaemia, but any underlying condition associated with a monoclonal IgM paraprotein. Owen et al., Semin. Oncol., 30(2), 110-5 (2003). Immune thrombocytopenic purpura and acquired von Willebrand disease are uncommonly seen in IgM MGUS. Rossi et al., British J. Haematol., 138(2), 249–52 (2007).

[0082] The term " IgM-related peripheral neuropathy" or " IgM-associated peripheral neuropathy" has the biomedical art-recognized meaning of an array of entities including immune-mediated neuronal damage, such as that caused by antibodies to myelin-associated glycoprotein (MAG), or direct neurotoxicity with infiltration by lymphoma (neurolymphomatosis), light chains (amyloidosis) or cryoglobulins. Peripheral neuropathy has been found to occur in IgM MGUS and Waldenstrom macroglobulinaemia cases, but the prevalence is likely affected by selection bias and variable neurological evaluation in patients as part of a work up of IgM M-protein. See Tomkins et al., Blood, 136(Suppl 1), 1-2.32430499 (2020).

[0083] The term "immunoglobulin M (IgM) MGUS" (IgM MGUS) has the biomedical art-recognized meaning of a particular form of MGUS, where the antibody is an IgM antibody.1530131-WO-PCT

[0084] The term "immunoglobulin M" (IgM) has the biomedical art-recognized meaning. See The American Heritage® Medical Dictionary (Houghton Mifflin Company, 2007).

[0085] The term " I VIG" has the biomedical art-recognized meaning of administering intravenous immunoglobulin (I VIG).

[0086] The term " Kd" has the biomedical art-recognized meaning of the measured equilibrium dissociation constant between a compound or ligand and a protein or binding domain of a protein.

[0087] The term "linker moiety" has the biomedical art-recognized meaning of a moiety of a chemical compound that links one moiety of the chemical compound to another moiety of the same compound.

[0088] The term "lymphoplasmacytic lymphoma" (LPL) has the biomedical art-recognized meaning. This lymphoma is characterized by bone marrow infiltration with malignant cells ranging from small mature-appearing B cells to lymphoplasmocytes and plasma cells. Naderi & Yang, Arch. Pathol. Lab. Med., 137(4), 580–5 (2013). Presence of lymphoplasmacytic lymphoma is a requirement for the diagnosis of Waldenstrom macroglobulinaemia but can also be identified in patients with IgM MGUS depending on the diagnostic criteria used. Owen et al., Semin. Oncol., 30(2), 110-5 (2003); Kyle et al., Blood, 102(10), 3759–64 (2003).

[0089] The term "lymphoplasmocytic lymphoma" has the biomedical art-recognized meaning of a form of non-Hodgkin lymphoma. Murakami et al., Am. J. Hematol. 56 (3), 173–178 (1997).

[0090] The term " MGUS polyneuropathy" has the biomedical art-recognized meaning.

[0091] The term " MoDE™" has the proprietary meaning of an agent for the targeted removal of aberrant protein, such as a bifunctional degrader. See Inti. Pat. Publ. WO 2019 / 199634 (Yale University) and WO 2019 / 199621 (Yale University).

[0092] The term "moiety" has the biomedical meaning of a defined chemical group or entity with a particular structure or activity. A moiety generally refers to a part of a molecule. In some embodiments, a binding moiety maintains one or more desired structural features, properties, functions, or properties, e.g., 3-dimension structure, antigen specificity, antigen-binding capacity, or immunological functions, etc., comparable to its corresponding binding protein, e.g., an antibody. In some embodiments, a moiety is monovalent. In some embodiments, a moiety is bivalent. In other embodiments, a moiety is polyvalent.

[0093] The term "monoclonal gammopathy of undetermined significance" (MGUS), also known as monoclonal gammopathy of unknown significance, monoclonal gammopathy of renal significance, or benign monoclonal gammopathy, has the biomedical-art recognized meaning of a plasma cell dyscrasia1630131-WO-PCTin which plasma cells or other types of antibody-producing cells secrete a myeloma protein, i.e., an antibody, into the blood. Kaushansky, Williams Hematology (United States, McGraw Hill, 2016), pp. 1723-1727. In IgM MGUS, the antibody is an IgM antibody. MGUS resembles multiple myeloma and similar diseases, but the levels of antibodies are lower, the number of plasma cells in the bone marrow is lower, and MGUS rarely has symptoms or major problems. Agarwal & Ghobrial, Clinical Cancer Research, 19(5), 985-94 (March 1, 2013). However, MGUS can progress to multiple myeloma. Paludo & Ansell (December 13, 2017).

[0094] The term "monoclonal gammopathy" has the biomedical art-recognized meaning.International Myeloma Working Group, British J. Haematol., 121(5), 749-57 (2003).

[0095] The term "monotherapy" has the biomedical art-recognized meaning of administering a single active or therapeutic compound to a subject or patient in need. Monotherapy usually involves administering a therapeutically effective amount of an active composition.

[0096] The term "monotherapy" is a biomedical art-recognized term for administering a single active or therapeutic compound to a subject or patient in need. Monotherapy usually involves administering a therapeutically effective amount of an active composition.

[0097] The term " Multimodal Antibody Therapy Enhancers (MATE™)" has the proprietary meaning. See Inti. Pat. Publ. WO 2021 / 102052 (Kleo Pharmaceuticals).

[0098] The term "multiple myeloma" (MM) has the biomedical art-recognized meaning. The cell of origin in MM is a B cell that has fully differentiated into a plasma cell. Matsui et al., Cancer Res., 68(1), 190–7 (2008). MM is always preceded by monoclonal B-cell lymphocytosis (MBL) and monoclonal gammopathy of undetermined significance (MGUS), respectively. Landgren et al., N. Engl. J Med. 360(7), 659–67 (2009), Landgren et al., Blood, 113(22), 5412–7 (2009).

[0099] The term "nanobody" has the biomedical art-recognized meaning. The term "antibody" refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site that specifically binds an antigen. The term also refers to antibodies comprised of two immunoglobulin heavy chains and two immunoglobulin light chains as well as forms including full-length antibodies and antigen-binding portions thereof, including immunoglobulin molecules, monoclonal antibodies, chimeric antibodies, CDR-grafted antibodies, humanized antibodies, Fab, a Fab', F(ab')2, Fv, disulfide-linked Fv, scFv, single domain antibody, diabody, nanobody, multi-specific antibody, e.g., tri-specific antibody, dual specific antibody, bispecific antibody, anti-idiotypic antibody, functionally active epitope-binding portion thereof, or bifunctional hybrid antibodies.1730131-WO-PCT

[0100] The term "non-Hodgkin lymphoma" has the biomedical art-recognized meaning. Murakami et al., Am. J. Hematol., 56(3), 173–178 (1997).

[0101] The term "non-MAGPN" as used in this specification means an IgM gammopathy where the autoantigen is not the myelin-associated glycoprotein (MAG). The more frequent autoantigen in IgM monoclonal immunoglobulin-associated neuropathy is the myelin-associated glycoprotein (MAG). See Jaccard, Blood, 136 (21), 2366–2367 (November 19, 2020).

[0102] The term "on" has the plain meaning. When an element is referred to as being on another element, it can be directly in contact with the other element, or intervening elements may be present therebetween. When an element is referred to as being "directly on" another element, no intervening elements are present.

[0103] The term "or" as used in this specification, means "or." The term "or" as used in this specification, includes all combinations of one or more of the associated listed items.

[0104] The term "other degrading cells" has the biomedical art-recognized meaning.Asialoglycoprotein receptors (ASGPRs) are found on hepatocytes and the glandular cells of the gallbladder and stomach.

[0105] The term "partially humanized" has the biomedical art-recognized meaning that a protein, e.g., an antibody, is genetically engineered to resemble the polypeptide structure of the human homologue more closely. A variable domain of an antibody of rodent origin can be fused to a constant domain of human origin, thus retaining the specificity of the rodent antibody. The domain of human origin need not originate directly from a human in that it is first synthesized in a human. Human domains can be generated in rodents whose genome incorporates human immunoglobulin genes. The antibody can be partially or completely humanized.

[0106] The term "pharmaceutically acceptable excipient" has the biomedical art-recognized meaning of an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use and human pharmaceutical use. A "pharmaceutically acceptable excipient," as used in the specification and claims, includes both one and more than one such excipient. A thorough discussion of pharmaceutically acceptable excipients is available in Remington's Pharmaceutical Sciences 23rd edition (Elsevier, 2020).

[0107] The term "pharmaceutically acceptable" has the biomedical art-recognized meaning of those compounds, anions, cations, materials, compositions, carriers, or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of humans and animals1830131-WO-PCTwithout excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0108] The term "plasma cell dyscrasia" has the biomedical art-recognized meaning of group of diseases characterized by the proliferation of a single clone of cells producing a monoclonal immunoglobulin or immunoglobulin fragment (a serum M component). The cells usually have plasma cell morphology but may have lymphocytic or lymphoplasmacytic morphology. This group includes multiple myeloma, Waldenstrom macroglobulinaemia, the heavy chain disease, benign monoclonal gammopathy, and immunocytic amyloidosis. See Farlex Partner Medical Dictionary (2012).

[0109] The term " POEMS syndrome" has the biomedical art-recognized meaning. Go & Rajkumar, Blood, 131(2), 163-173 (January 11, 2018). POEMS is an acronym for Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder, and Skin changes.

[0110] The term "protein-binding moiety" has the biomedical art-recognized meaning of a region of a chemical composition, e.g., a polypeptide region of a chemical composition, that specifically binds to a protein, e.g., a specific protein.

[0111] The term "rlgG" has the biomedical art-recognized meaning of recombinant human IgG.

[0112] The term " ROC" has the biomedical art-recognized meaning of the receiver operating characteristic curve.

[0113] The term " Schnitzler syndrome" has the biomedical art-recognized meaning of an auto-inflammatory disorder characterized by an IgM monoclonal gammopathy and chronic recurrent urticarial rash. See the Mayo Clinic experience described by Sokumbi, Drage, & Peters, J Am. Acad. Dermatol., 67(6), 1289–95 (2012). The Strasbourg criteria outline minor criteria of recurrent fever, abnormal bone remodeling with or without bone pain, neutrophilic dermal infiltrate, leukocytosis and elevated C-reactive protein. The upregulation of the IL-1 pathway plays a pivotal role. Simon et al., Allergy, 68(5), 562–8 (2013), Terpos et al., Haematologica, 97(11), 1699–703 (2012).

[0114] The term "smouldering multiple myeloma" has the biomedical art-recognized meaning.

[0115] The term "splenic marginal zone lymphoma" has the biomedical art-recognized meaning of a form of non-Hodgkin lymphoma. Murakami et al., Am. J. Hematol. 56 (3), 173-178 (1997).

[0116] The term " TBT" has the biomedical art-recognized meaning of an IgM-binding moiety, a cellular receptor-binding moiety. In some embodiments of this specification, the TBT binds to ASGPR.

[0117] The term " Tempi syndrome" has the biomedical art-recognized meaning. Sykes, Schroyens, & O'Connell, N. Engl. J. Med., 365(5), 475–477 (2011).1930131-WO-PCT

[0118] The term " Type I cryoglobulinemia has the biomedical art-recognized meaning.Cryoglobulinemia is characterized by immunoglobulins that precipitate at temperatures below 37°C and redissolve on warming. Type I cryoglobulinemia consists of monoclonal immunoglobulins only. The symptoms of type I cryoglobulinemia are caused by vascular occlusion. Cutaneous involvement is most frequent in type I cryoglobulinemia. Cutaneous manifestations range from purpura, livedo reticularis, acrocyanosis to cold urticaria, digital ischemia, ulcers and necrosis.

[0119] The term " Type II cryoglobulinemia has the biomedical art-recognized meaning.Cryoglobulinemia is characterized by immunoglobulins that precipitate at temperatures below 37°C and redissolve on warming. In type II "mixed" cryoglobulinemia there is a monoclonal component possessing avidity for the polyclonal component of a different isotype (most frequently IgM with rheumatoid factor activity, the ability to bind to the Fc portion of IgG). The rheumatoid factor detected in type II cryoglobulinemia is a monoclonal IgMK in over 85% of cases. Kolopp-Sarda, Nombel, & Miossec, Arthritis Rheumatol., 71(11), 1904-1912 (2019). While most cases of type II cryoglobulinemia are related to hepatitis C, some are monoclonal IgM. The symptoms of type II cryoglobulinemia are due to small and medium vessel vasculitis. No studies are known to have reported specific presenting features of type II cryoglobulinemia in patients with circulating monoclonal IgM. Khwaja et al., Haematologica, 107(9), 2037-2050 (June 30, 2022).

[0120] The term "universal antibody-binding moiety" has the biomedical art-recognized meaning of a polypeptide region of an antibody-binding protein that binds a class of antibodies rather than a specific set of antibodies.

[0121] The term "variant" has the biomedical art-recognized meaning of an alteration in a polynucleotide sequence or a polypeptide sequence. The term variant can be used to describe an alteration that may be significant or of unknown significance. The term variant is often used for the term mutation. See NCI Dictionary of Genetics Terms.

[0122] The term " VHH" has the biomedical art-recognized meaning. VHH has 9 beta-sheets forming a cylindric structure.

[0123] The term " Waldenstrom macroglobulinaemia" (WM) has the biomedical art-recognized meaning of a pre-malignant condition for multiple B-cell non-Hodgkin lymphomas. Paludo & Ansell (December 13, 2017). Waldenstrom macroglobulinaemia arises from a post-germinal center B cell that has undergone somatic hypermutation but not heavy-chain class switch. Sahota et al., Blood, 100(4), 1505–7 (2002).2030131-WO-PCT

[0124] The terms "an effective amount" and "a therapeutically effective amount" have the biomedical art-recognized meaning of an amount effective to achieve its intended purpose. The effect can be detected by any assay method known in the art. The precise effective amount for a subject depends on the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0125] The terms "combination therapy" and "co-therapy" have the biomedical art-recognized meaning of the administration of a composition described in this specification and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the coaction of these therapeutic agents. The beneficial effect of the combination may include but is not limited to pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. These therapeutic agents are typically administered in combination over a defined time, usually minutes, hours, days, or weeks, depending on the combination selected. The term combination therapy" includes the administration of the therapeutic agents described above in combination with other biologically active ingredients and non-drug therapies, e.g., surgery or radiation treatment. Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time if a beneficial effect from the co-action of the combination of the therapeutic agents is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

[0126] The terms "comprises," "comprising," "includes," and "including" specify the presence of stated features, regions, integers, steps, operations, elements, or components but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, or groups thereof.

[0127] The terms "first," "second," "third," etc., have the plain meaning of describing several elements, components, regions, layers, or sections. These terms should not limit these elements, components, regions, layers, or sections. These terms are only used to distinguish one element, component, region, layer, or section from another element, component, region, layer, or section. A first element, component, region, layer, or section could be called a second element, component, region, layer, or section without departing from the teachings of the present embodiments.2130131-WO-PCT

[0128] The terms "subject" and "patient" have the biomedical art-recognized meanings. The term "patient" includes human and other mammalian subjects receiving prophylactic or therapeutic treatment.

[0129] The terms "treating" and "treat" have the biomedical art-recognized meaning of managing and caring for a patient to combat a disease, condition, or disorder. Treating includes administering a composition described in this specification to alleviate the symptoms or complications of a disease, condition, or disorder or to eliminate the disease, condition, or disorder.

[0130] Additional embodiments are described below by referring to structures and schemes to explain aspects of the description.

[0131] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by persons having ordinary skill in the biomedical art.

[0132] This specification does not concern a process for cloning humans, methods for modifying the germ line genetic identity of humans, uses of human embryos for industrial or commercial purposes, or procedures for modifying the genetic identity of animals likely to cause them suffering with no substantial medical benefit to humans or animals resulting from these processes.The chemical structure of the composition of matter (agent, MoDE™).

[0133] In an embodiment, the invention provides a composition of matter (agent) comprising:a binding moiety that can bind to IgM,a cellular receptor-binding moiety that binds to hepatocytes or other degrading cells through asialoglycoprotein receptors (ASGPR) of hepatocytes or other cell receptors on the surface of degrading cells in a subject or patient, anda linker moiety linking the antibody moiety and the cellular receptor-binding moiety.

[0134] In some embodiments, the invention provides a composition of matter (agent) having a structure selected from the Markush group of structures consisting of:[AGN101], or2230131-WO-PCT[AGN102]or a pharmaceutically acceptable salt thereof.

[0135] In Formulas [AGN101] and [AGN102], each of a, b and c is independently 1-200;each ABT is independently a target-binding moiety that can bind to IgM;L is a linker moiety; andeach TBT is independently a cellular receptor-binding moiety.

[0136] In some embodiments of Formulas [AGN101] and [AGN102], a is 1. In some embodiments, b is 1, 2, or 3. In some embodiments, c is 1. In some embodiments, each of a, b and c is 1.

[0137] In these Formulas, a, b, and c may independently be an integer of 1 or greater. In some embodiments, each cellular receptor-binding moiety independently has the structure of–(RCN–(Xaa)y–RCC) or salt form thereof.

[0138] In some embodiments, an agent comprises one and no more than one binding moiety. In some embodiments, one or no more than one binding moiety is bound to a linker moiety. In some embodiments, a is 1. In some embodiments, a is 2 or more. In some embodiments, one and no more than one cellular receptor-binding moiety is bonded to a linker moiety. In some embodiments, b is 1. In some embodiments, two or more cellular receptor-binding moieties are bonded to a single linker moiety. In some embodiments, b is 2 or more. In some embodiments, an agent comprises one and no more than one cellular receptor-binding moiety. In some embodiments, c is 1. In some embodiments, b is 1 and c is 1. In some embodiments, a is 1, b is 1 and c is 1. In some embodiments, an agent comprises two or more IgM-binding moieties. In some embodiments, b is 2 or more and c is 1. In some embodiments, b is 2 or more and c is 2 or more. In some embodiments, b is 1, and c is 2 or more.

[0139] In some embodiments, c is 1-20, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, c is selected from the Markush group of size ranges, where c is 1-15, c is 1-10, c is 1-9, c is 1-8, c is 1-7, c is 1-6, c is 1-5, c is 1-4, c is 1-3, and c is 1-2. In some embodiments, c is a size selected from the Markush group of sizes consisting of 1, 2, 3, 4, 5, 6, 7, 8, and 9.

[0140] In some embodiments, each cellular receptor-binding moiety in an agent is the same. In some embodiments, each linker moiety connecting a cellular receptor-binding moiety to an antibody moiety is the same. In some embodiments, the TBT in agents is the same. In some embodiments, the –L–(TBT)bare the same.2330131-WO-PCT

[0141] In some embodiments, b is 1. In some embodiments, c is 1. In some embodiments, c is two or more. In some embodiments, c is 2. Persons having ordinary skill in the biomedical art know that several technologies can be used to conjugate antibody moieties with IgM-binding moieties, e.g., certain technologies used for preparing antibody-drug conjugates in accordance with this specification. In some embodiments, IgM-binding moieties are connected to antibody moieties through certain types of groups or amino acid residues. In some embodiments, IgM-binding moieties are connected to lysine residues optionally through linker moieties. In some embodiments, IgM-binding moieties are connected to cysteine residues optionally through linker moieties. In some embodiments, IgM-binding moieties are connected to unnatural amino acid residues optionally through linker moieties. In some embodiments, the invention provides technologies for selectively linking IgM-binding moieties to certain amino acid residues optionally through linker moieties. In some embodiments, provided technologies selectively connect IgM-binding moieties to certain types of amino acid residues, e.g., lysine residues, optionally through linker moieties. In some embodiments, provided technologies selectively connect IgM-binding moieties to sites of antibody moieties optionally through linker moieties. In some embodiments, provided technologies selectively connect IgM-binding moieties to certain types of amino acid residues at sites optionally through linker moieties. In some embodiments, IgM-binding moieties are connected to K246 and K248 of an IgGl heavy chain and amino acid residues corresponding thereto optionally through linker moieties. In some embodiments, IgM-binding moieties are connected to K251 and K253 of an IgG2 heavy chain and amino acid residues corresponding thereto optionally through linker moieties. In some embodiments, IgM-binding moieties are connected to K239 and K241 of a heavy chain and amino acid residues corresponding thereto optionally through linker moieties. In some embodiments, a cellular receptor-binding moiety is connected to a particular amino acid residue or site optionally through a linker. In some embodiments, each cellular receptor-binding moiety is independently connected to a particular amino acid residue or site optionally through a linker.

[0142] Persons having ordinary skill in the biomedical art know that an antibody agent may comprise more than one site, e.g., one on each of the more than one chain, e.g., one or each heavy chain. In some embodiments, an antibody moiety comprises two heavy chains, and one or both amino acid residues or amino acid residues corresponding thereto are each independently connected to a cellular receptor-binding moiety optionally through a linker. In some embodiments, one and no more than one is connected. In some embodiments, c is 1. In some embodiments, both are connected. In some embodiments, c is 2. In some embodiments, both IgM-binding moieties or both linker moieties (if any) are the same.2430131-WO-PCTTarget binding moiety.

[0143] In some embodiments, the IgM-binding moiety comprises a moiety selected from the Markush group consisting of one or more amino acid residues, a peptide moiety, a cyclic peptide moiety, a peptide comprising one or more natural amino acid residues, and a peptide comprising one or more unnatural natural amino acid residues.

[0144] In some embodiments, each binding moiety in an agent is of the same binding moiety or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, a binding moiety is or comprises Rc-(Xaa)z- or a salt form thereof, wherein each variable is as described in this specification.

[0146] In some embodiments, a protein-binding moiety is or comprises Rc-(Xaa)z- or a salt form thereof, wherein each variable is as described in this specification.

[0147] In some embodiments, -(Xaa)z- is or comprises a peptide unit.

[0148] In some embodiments, amino acid residues may form bridges, e.g., connections formed by side chains optionally through linker moieties, e.g., L); for example, as in many polypeptides, cysteine residues may form disulfide bridges.

[0149] In some embodiments, a peptide unit comprises an amino acid residue, e.g., at physiological pH about 7.4, positively charged amino acid residue, Xaap), e.g., a residue of an amino acid of formula LNK101 with a positively charged side chain. In some embodiments, a peptide unit comprises R. In some embodiments, at least one Xaa is R.

[0150] Several antibody-binding moieties, including universal antibody-binding moieties, can be used following the teachings of this specification. Certain antibody-binding moieties and technologies for identifying or assessing antibody-binding moieties are described in Intl. Pat. Publ. WO 2019 / 023501 and Inti. Pat. Publ. WO 2019 / 136442, each of which is incorporated in this specification in its entirety by reference. Persons having ordinary skill in the biomedical art know that additional technologies in the biomedical art may be suitable for identifying or assessing antibody-binding moieties in accordance with this specification. In some embodiments, an antibody-binding moiety comprises one or more amino acid residues, each independently natural or unnatural.

[0151] In some embodiments, a binding moiety, e.g., a universal antibody-binding moiety, is or comprises a peptide moiety, e.g., a moiety having the structure of Rc-(Xaa)z- or a salt form thereof, wherein each of Rc, z, and Xaa is independently as described in this specification. One or more Xaa may be independently an unnatural amino acid residue. Side chains of two or more amino acid residues may2530131-WO-PCTbe linked together to form bridges. Side chains of two cysteine residues may form a disulfide bridge comprising -S-S-.

[0152] In some embodiments, a peptide unit comprises a functional group in an amino acid residue that can react with a functional group of another amino acid residue. In some embodiments, a peptide unit comprises an amino acid residue with a side chain which comprises a functional group that can react with another functional group of the side chain of another amino acid residue to form a linkage. In some embodiments, one functional group of one amino acid residue is connected to a functional group of another amino acid residue to form a linkage (or bridge). Linkages are bonded to backbone atoms of peptide units and comprise no backbone atoms. In some embodiments, a peptide unit comprises a linkage formed by two side chains of non-neighboring amino acid residues. In some embodiments, a linkage is bonded to two backbone atoms of two non-neighboring amino acid residues. In some embodiments, both backbone atoms bonded to a linkage are carbon atoms.

[0153] Persons having ordinary skill in the biomedical art know that an amino acid residue may be replaced by another amino acid residue having similar properties, e.g., one XaaH, e.g., Val, Leu, etc., may be replaced with another XaaH, e.g., Leu, He, Ala, etc., one XaaAmay be replaced with another XaaA, one Xaapmay be replaced with another Xaap, one XaaNmay be replaced with another XaaN, one XaaLmay be replaced with another XaaL, etc.

[0154] In some embodiments, a moiety, e.g., a universal antibody-binding moiety, is or comprises an optionally substituted moiety as shown in the table provided in Intl. Pat. Publ. WO 2019 / 023501, pages 48-60, which table and patent publication are incorporated in this specification by reference.

[0155] In some embodiments, antibody-binding moieties, e.g., antibody-binding moieties, and useful technologies for developing or assessing these moieties are described in, e.g., Alves, Langmuir, 28, 9640–9648 (2012), Choe et al., Materials, 9, 994 (2016), Gupta et al., Nature Biomedical Engineering, 3, 917–929 (2019), Muguruma et al., ACS Omega, 4, 14390–14397 (2019), Yamada et al., Angewandte Chemie Int., Ed Engl.; 58(17), 5592-5597 (April 16, 2019), Kruljec et al., Bioconjugate Chem., 28(8): 2009-2030 (2017), e.g., Fabsorbent, triazines, etc.; Kruljec et al., Bioconjugate Chem., 29(8), 2763-2775 (2018), Inti. Pat. Publ. WO 2012 / 017021, etc., the binding moieties, e.g., antibody-binding moieties) of each of which is incorporated in this specification in its entirety by reference.

[0156] In some embodiments, an antibody-binding moiety, e.g., a protein-binding moiety, e.g., an antibody-binding moiety), is an affinity substance described in Inti. Pat. Publ. WO 2018 / 199337, the affinity substances of which is incorporated in this specification by reference.2630131-WO-PCT

[0157] In some embodiments, an antibody-binding moiety comprises an adapter protein agent, e.g., as described by Hui et al., Bioconjugate Chem., 26, 1456–1460 (2015). In some embodiments, when used in accordance with this specification, adapter proteins do not require reactive residues, e.g., BPA, to achieve one or more advantages.

[0158] In some embodiments, an antibody-binding moiety, e.g., an antibody-binding moiety, is or comprises a triazine moiety, e.g., one described in U. S. Pat. Publ. 2009 / 0286693. In some embodiments, an antibody-binding moiety, e.g., an antibody-binding moiety, is of such a structure that its corresponding compound is a compound described in U. S. Pat. Publ. 2009 / 0286693, the compounds of which are independently incorporated in this specification by reference. In some embodiments, an antibody-binding moiety, e.g., an antibody-binding moiety, is ABT. In some embodiments, ABT is of such a structure that H-ABT is a compound described in U. S. Pat. Publ. 2009 / 0286693, the compounds of which are independently incorporated in this specification by reference. In some embodiments, this compound can bind to an antibody. In some embodiments, this compound can bind to the Fc region of an antibody.

[0159] In some embodiments, an antibody-binding moiety, e.g., an antibody-binding moiety, is or comprises a triazine moiety, e.g., one described in Teng et al., J. Mol. Recognition, 12, 67–75 (1999). In some embodiments, an antibody-binding moiety, e.g., an antibody-binding moiety, is of such a structure that its corresponding compound is a compound described in Teng, the compounds of which are independently incorporated in this specification by reference. In some embodiments, an antibodybinding moiety, e.g., an antibody-binding moiety, is of such a structure that H-ABT is a compound described in Teng, the compounds of which are independently incorporated in this specification by reference. In some embodiments, this compound can bind to an antibody. In some embodiments, this compound can bind to the Fc region of an antibody.

[0160] In some embodiments, an antibody-binding moiety is a triazine moiety, e.g., H-ABT or another one described by Uttamchandani et al., J. Comb. Chem., 6(6), 862-8 (November-December 2004). the compounds of which are independently incorporated in this specification by reference. In some embodiments, this compound can bind to the Fc region of an antibody.

[0161] In some embodiments, an antibody-binding moiety binds to one or more binding sites of a protein selected from the Markush group of proteins consisting of protein A, protein G, protein L, protein Z, protein LG, protein LA, and protein AG. In some embodiments, an antibody-binding moiety is described in Choe, Durgannavar, & Chung, Materials, 9(12) (2016).2730131-WO-PCT

[0162] Other useful technologies are described in Mustafaoglu et al., Analyst, 141(24), 6571-6582 (November 28, 2016).

[0163] In some embodiments, the IgM antibody-binding moiety is selected from the Markush group consisting of the moieties listed in TABLE 5.30131-WO-PCT30131-WO-PCT

[0164] In some embodiments, the IgM antibody-binding moiety is selected from the Markush group consisting of the moieties listed in TABLE 6.30131-WO-PCT30131-WO-PCT30131-WO-PCT30131-WO-PCT30131-WO-PCT

[0165] In some embodiments, the IgM antibody-binding moiety is selected from the Markush group consisting of the moieties listed in TABLE 7.30131-WO-PCT

[0166] In some embodiments, the target-binding moiety that can bind to an IgM comprising one or more of the several autoimmune antibody-binding peptides and functional fragments thereof is selected from the Markush group consisting of SEQ ID NOS: 5-196. See International patent application PCT / US2024 / 051306 immunoglobulin peptides 1-192 (SEQ ID NOS: 443-634). See also Choe, Durgannavar, & Chung, Materials (Basel), 9(12), 994 (December 8, 2016).Linker moiety.

[0167] In some embodiments, provided compounds and agents may comprise one or more amino acid moieties, e.g., antibody-binding moieties, linker moieties, etc. Amino acid moieties can either be those of natural amino acids or unnatural amino acids. In some embodiments, an amino acid has the structure of the formula LNK101:NH(Ra1)-La1-C(Ra2)(Ra3)-La2-COOH,[LNK101] or a salt thereof, wherein:each of Ra1, Ra2, and Ra3is independently -La-R' or an amino acid side chain;each of La1and La2is independently La;each Lais independently a covalent bond, or an optionally substituted bivalent group selected from C1-C20 aliphatic or C1-C20 heteroaliphatic having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with -C(R')z-, -Cy-, -O-, -S-, -S-S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2--S(O)2N(R')-, -C(O)S-, or -C(O)O-;each -Cy- is independently an optionally substituted bivalent monocyclic, bicyclic, or polycyclic group wherein each monocyclic ring is independently selected from a C3-20 cycloaliphatic ring, a C6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-103630131-WO-PCTheteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon;each R' is independently -R, -C(O)R, -CO2R, or -SO2R;each R is independently -H, or an optionally substituted group selected from C1-30aliphatic, C1-30 heteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, C6-30 aryl, C6-30 arylaliphatic, C6-30 arylheteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, ortwo R groups are optionally and independently taken together to form a covalent bond, or: two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered, monocyclic, bicyclic, or polycyclic ring having, in addition to the atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; ortwo or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.In some embodiments, an amino acid residue, e.g., of an amino acid having the structure of formula LNK101, has the structure of -N(Ra1)-La1-C(Ra2)(Ra3)-La2-CO-. In some embodiments, each amino acid residue in a peptide independently has the structure of -N(Ra1)-La1-C(Ra2)(Ra3)-La2-CO-.

[0168] In some embodiments, the invention provides a derivative of an amino acid of formula LNK101 or a salt thereof. In some embodiments, a derivative is an ester. In some embodiments, the invention provides a composition of matter of formula NH(Ra1)-La1-C(Ra2)(Ra3)-La2-COORCTor salt thereof, wherein RCTis R' and each other variable is independently as described in this specification. In some embodiments, RCTis R. In some embodiments, RCTis optionally substituted aliphatic. In some embodiments, RCTis t-butyl.

[0169] In some embodiments, Lalis a covalent bond. In some embodiments, a composition of matter of formula LNK101 is of the structure NH(Ra1)-C(Ra2)(Ra3)-La2-COOH. In some embodiments, La2is -CH2SCH2-

[0170] In some embodiments, La2is a covalent bond. In some embodiments, a composition of matter of formula LNK101 is of the structure NH(Ra1)-La1-C(Ra2)(Ra3)-COOH. In some embodiments, an3730131-WO-PCTamino acid residue has the structure of -N(Ra1)-La1-C(Ra2)(Ra3)-CO-. In some embodiments, La1is -CH2CH2S-. In some embodiments, La1is -CH2CH2S-, wherein the CH2is bonded to NH(Ra1).

[0171] In some embodiments, Lalis a covalent bond, and La2is a covalent bond. In some embodiments, a composition of matter of formula LNK101 is of the structure NH(Ra1)-C(Ra2)(Ra3)-COOH. In some embodiments, a composition of matter of formula LNK101 is of the structureNH(Ra1)-CH(Ra2)-COOH. In some embodiments, a composition of matter of formula LNK101 has a structure selected from the Markush group of peptides consisting of NH(Ra1)-CH(Ra3)-COOH,NH2-CH(Ra2)-COOH, NH2-CH(Ra3)-COOH, -N(Ra1)-C(Ra2)(Ra3)-CO-, -N(Ra1)-CH(Ra2)-CO-, -N(Ra1)-CH(Ra3)-CO-, -NH-CH(Ra2)-CO-, and -NH-CH(Ra3)-CO-

[0172] In some embodiments, Lais a covalent bond. In some embodiments, Lais optionally substituted by C1-6bivalent aliphatic. In some embodiments, Lais optionally substituted for C1-6alkylene. In some embodiments, Lais -CH2-. In some embodiments, Lais -CH2CH2-. In some embodiments, Lais -CH2CH2CH2-.

[0173] In some embodiments, Lais bivalent optionally substituted C1-20 aliphatic, wherein one or more methylene units are independently replaced with -C(O)-, -N(R')-, -Cy-, or -O-. In some embodiments, Lais bivalent optionally substituted C1-20 aliphatic, wherein one or more methylene units are independently replaced with -C(O)N(R')-, -Cy-, and -O-. In some embodiments, Lais bivalent optionally substituted C1-20 aliphatic, wherein two or more methylene units are independently replaced with -C(O)N(R')-, and -Cy- in addition to other optional replacements. In some embodiments, -Cy- is optionally substituted. In some embodiments, -Cy- is optionally substituted with an electronwithdrawing group as described in this specification. In some embodiments, -Cy- is substituted with one or more -F. In some embodiments, -Cy- is optionally substituted 1,3-phenylene. In some embodiments, -Cy- is optionally substituted 1,4-phenylene.

[0174] In some embodiments, moieties are optionally connected through linker moieties. In some embodiments, a reactive group, e.g., RG, is connected to a cellular receptor-binding moiety, e.g., TBT, through a linker, e.g., LRM. In some embodiments, a moiety, e.g., LG, may also comprise one or more linkers, e.g., LLG1, LLG2, LLG3, LLG4, etc., to link several portions. In some embodiments, LLGis a linker moiety described in this specification. In some embodiments, LLG1is a linker moiety described in this specification. In some embodiments, LLG2is a linker moiety described in this specification. In some embodiments, LLG3is a linker moiety described in this specification. In some embodiments, LLG4is a linker moiety described in this specification. In some embodiments, LRMis a linker moiety described in this3830131-WO-PCTspecification. In some embodiments, LPMis L. In some embodiments, LPMis a linker moiety described in this specification. In some embodiments, LPMis L.

[0175] Linker moieties of several types or for several purposes, e.g., those used in antibody-drug conjugates, etc., may be used in accordance with this specification.

[0176] Linker moieties can be bivalent or polyvalent, depending on how they are used. In some embodiments, a linker moiety is bivalent. In some embodiments, a polyvalent linker connects more than two moieties.

[0177] In some embodiments, a linker moiety, e.g., Lz, e.g., LPM, LRM, LLG, LLG1, etc., is or comprises L.

[0178] In some embodiments, L is a covalent bond, or a bivalent or polyvalent optionally substituted, linear or branched C1-100 group comprising one or more aliphatic, aryl, heteroaliphatic having 1-20 heteroatoms, heteroaromatic having 1-20 heteroatoms, or any combinations thereof, wherein one or more methylene units of the group are optionally and independently replaced with C1-6alkylene, C1-6alkenylene, a bivalent C1-6heteroaliphatic group having 1-5 heteroatoms, —C≡C—, -Cy-, -C(R')2-, -O-, -S-, -S-S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -C(O)C(R')2N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, -C(O)O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, -P(S)(OR')-, -P(S)(SR')-, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')-, an amino acid residue, or -[(-O-C(R')2-C(R')2-)n]-, wherein n is 1-20. The linker optionally contains a cyclic group, Cy, defined below, and a reactive group, RG, as defined below. In some embodiments, each amino acid residue is independently a residue of an amino acid having the structure of formula LNK101 or a salt thereof. In some embodiments, each amino acid residue independently has the structure of -N(Ral)-Lal-C(Ra2)(Ra3)-La2-CO- or a salt form thereof.

[0179] In some embodiments, L is bivalent. In some embodiments, L is a covalent bond.

[0180] In some embodiments, L is a bivalent or optionally substituted linear or branched group, selected from C1-100 aliphatic and C1-100 heteroaliphatic having 1-50 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with C1-6alkylene, C1-6alkenylene, a bivalent C1-6heteroaliphatic group having 1-5 heteroatoms, C=C, -Cy-, -C(R')2-, -O-, -S-, -S-S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -C(O)C(R')2N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, -C(O)O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, -P(S)(OR')-, -P(S)(SR')-, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')-, an amino acid residue or -[(-O-C(R')2-C(R')2-)n]-. In some embodiments, L is a bivalent or optionally substituted linear or branched group selected from Ci-20aliphatic and Ci-20heteroaliphatic having 1-10 heteroatoms, wherein one or more methylene units of the group are optionally and independently3930131-WO-PCTreplaced with C1-6alkylene, C1-6alkenylene, a bivalent C1-6heteroaliphatic group having 1-5 heteroatoms, —C=C—, -Cy-, -C(R')2-, -O-, -S-, -S-S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -C(O)C(R')2N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, -C(O)O--P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, -P(S)(OR')-, -P(S)(SR')-, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')-, an amino acid residue or -[(-O-C(R')2-C(R')2-)n]-. In some embodiments, L is a bivalent or optionally substituted linear or branched group selected from Ci-20aliphatic, wherein one or more methylene units of the group are optionally and independently replaced with — C=C—, -Cy-, -C(R')2- -O-, -S-, -S-S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -C(O)C(R')2N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, -C(O)O--P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, -P(S)(OR')-, -P(S)(SR')-, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')-, an amino acid residue or -[(-O-C(R')2-C(R')2-)n]-. In some embodiments, L is a bivalent or optionally substituted, linear or branched Ci-20aliphatic wherein one or more methylene units of the group are optionally and independently replaced with —C≡C—, -Cy-, -C(R')2-, -O- -S-, -S-S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -C(O)C(R')2N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, -C(O)O-, an amino acid residue or - [(- O- C(R')2- C(R')2- )n]- • In some embodiments, L is a bivalent or optionally substituted linear or branched group Ci-100 aliphatic, wherein one or more methylene units of the group are optionally and independently replaced with — C=C —, -Cy-, -C(R')2-, -O-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -C(O)C(R')2N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, an amino acid residue or -[(-O-C(R')2-C(R')2-)n]-. In some embodiments, L is a bivalent or optionally substituted linear or branched group C1-50 aliphatic, wherein one or more methylene units of the group are optionally and independently replaced as described in this specification. In some embodiments, L is a bivalent or optionally substituted, linear, or branched group C1-40 aliphatic, wherein one or more methylene units of the group are optionally and independently replaced as described in this specification. In some embodiments, L is a bivalent or optionally substituted, linear, or branched group C1.20 aliphatic, wherein one or more methylene units of the group are optionally and independently replaced as described in this specification. In some embodiments, L is a bivalent or optionally substituted linear or branched group C1-10 aliphatic, wherein one or more methylene units of the group are optionally and independently replaced as described in this specification. In some embodiments, L is a bivalent or optionally substituted linear or branched group C1-100 alkylene, wherein one or more methylene units of the group are optionally and independently replaced as described in this specification. In some embodiments, L is a bivalent or optionally substituted linear or branched group C1-4030131-WO-PCTso alkylene, wherein one or more methylene units of the group are optionally and independently replaced as described in this specification. In some embodiments, L is a bivalent or optionally substituted linear or branched group C1-40 alkylene, wherein one or more methylene units of the group are optionally and independently replaced as described in this specification. In some embodiments, L is a bivalent or optionally substituted linear or branched group C1-20 alkylene, wherein one or more methylene units of the group are optionally and independently replaced as described in this specification. In some embodiments, L is a bivalent or optionally substituted linear or branched group C1-10 alkylene, wherein one or more methylene units of the group are optionally and independently replaced as described in this specification.

[0181] In some embodiments, a linker moiety, e.g., L, LPM, LRM, etc., comprises an acidic group, e.g., -S(O)2OH.

[0182] In some embodiments, L is or comprises -[(-O-C(R')2-C(R')2-)n]-. In some embodiments, L is or comprises -[(-O-CH2-CH2-)n]-. In some embodiments, L is -[(-CH2-CH2-O)6]-CH2-CH2-. In some embodiments, L is -[(-CH2-CH2-O)8]-CH2-CH2-. In some embodiments, -CH2-CH2-O- is bonded to an antibody-binding moiety at a -CH2-. In some embodiments, -CH2-CH2-O- is bonded to a cellular receptor-binding moiety at a -CH2-. In some embodiments, LPMis such L. In some embodiments, LRMis such L.

[0183] In some embodiments, a linker moiety comprises one or more -(CH2)n-O-, wherein each n is independently 1-20. In some embodiments, it is or comprises one or more -[(CH2)n-O]m-, wherein each n is independently 1-20, and m is 1-100. In some embodiments, it comprises two or more -[(CH2)n-O]m-, wherein each n is independently 1-20, and each m is 1-100. In some embodiments, it is or comprises one or more -(O)C-[(CH2)nO]m(CH2)nNH-, -[(CH2)nO]mNHC(O)[(CH2)nO]mNH-, -[(CH2)nO]m{NHC(O)[(CH2)nO]m)pNH— wherein each n is independently 1-20, and each m is independently 1-100, and where each p is independently 1 to 10. In some embodiments, n is selected from the Markush group of numbers consisting of 1-10, 1-5, and 2. In some embodiments, m is 1-50. In some embodiments, m is 1-40. In some embodiments, m is selected from the Markush group of numbers consisting of 1-30, 1-20, 1-10, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0184] In some embodiments, a linker moiety, or L, is or comprises -(CH2CH2O)n-, wherein each -CH2- is independently and optionally substituted, and n is 1-20. In some embodiments, a linker moiety, or L, is or comprises -(CH2)n-O-(CH2CH2O)n-(CH2)n-, wherein each n is independently 1-10, and each -CH2- is independently and optionally substituted.4130131-WO-PCT

[0185] In some embodiments, a linker moiety is trivalent or polyvalent. In some embodiments, a linker moiety is L, where L is trivalent or polyvalent. In some embodiments, L is trivalent. In some embodiments, L is -CH2-N(-CH2-)-C(O)-.

[0186] In some embodiments, a linker moiety, e.g., L, comprises one or more amino acid residues or analogues.

[0187] In some embodiments, a linker moiety, e.g., L, LRM, etc., is or comprises a reactive group as described in this specification. In some embodiments, an agent comprises an antibody-binding moiety and a cellular receptor-binding moiety linked through a linker comprising a reactive group. In some embodiments, a reactive group can react with a lysine residue of an antibody in an aqueous buffer. In some embodiments, a reactive group comprises -C(O)-O-. In some embodiments, a reactive group comprises -C(O)-O-, wherein -O- is bonded to an optionally substituted aryl group. In some embodiments, a reactive group comprises -C(O)-O-, wherein -O- is bonded to an aryl group substituted with one or more electron-withdrawing groups. In some embodiments, one or more of each electron-withdrawing group is independently selected from -NO2and -F. In some embodiments, an arylgroup has the structure of, wherein Rsis halogen, -NO2, -F, -L-R', -C(O)-L-R', -S(O)-L-R',- S(O)2- L- R', or -P(O)(-L-R')2. In some embodiments, an aryl group has the structurewherein each Rsis independently halogen, -NO2, -F, -L-R', -C(O)-L-R', -S(O)-L-R', -S(O)2-L-R', or- P(O)(— L- R')2. In some embodiments, an aryl group is. In some embodiments, an aryl groupsome embodiments, Cl is bound to the -O- of -C(O)-O-. In some embodiments, a cellular receptor-binding moiety is at the side of -C(O)- and an antibody-binding moiety is at the side of -O-.

[0188] In some embodiments, a linker moiety, e.g., LRM, comprises a reactive group, wherein upon contact with an antibody, the reactive group reacts with a group of the antibody and conjugates a cellular receptor-binding moiety, or a moiety comprising -(Xaa)y-, to the antibody optionally through a30131-WO-PCTlinker. In some embodiments, a reactive group is or compriseswherein the -C(O)- is connected to a cellular receptor-binding moiety or a moiety comprising -(Xaa)y-, optionally through alinker. In some embodiments, a reactive group is or comprises 0 J wherein the -C(O)- is connected to a cellular receptor-binding moiety, or a moiety comprising -(Xaa)y-, optionally through a linker and the other end of the reactive group is connected to an antibody-binding moiety.

[0189] In some embodiments, a linker moiety, e.g., L) is or comprises one or more, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more) polyethylene glycol units. In some embodiments, a linker moiety comprises -(CH2CH2O)n-, wherein n is described in this specification. In some embodiments, one or more methylene units of L are independently replaced with -(CH2CH2O)n-.

[0190] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some embodiments, n is 16. In some embodiments, n is 17. In some embodiments, n is 18. In some embodiments, n is 19. In some embodiments, n is 20.

[0191] In some embodiments, a linker moiety, e.g., L) is or comprises one or more, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more) amino acid residues. As used in this specification, "one or more" can be 1-100, 1-50, 1-40, 1-30, 1-20, 1-10, 1-5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 or more. In some embodiments, one or more methylene units of L are independently replaced with an amino acid residue. In some embodiments, one or more methylene units of L are independently replaced with an amino acid residue, wherein the amino acid residue is of an amino acid of formula LNK101 or a salt thereof. In some embodiments, one or more methylene units of L are independently replaced with an amino acid residue, wherein each amino acid residue independently has the structure of -N(Ral)-Lal-C(Ra2)(Ra3)-La2-CO- or a salt form thereof.

[0192] In some embodiments, a linker moiety comprises one or more moieties, e.g., amino, carbonyl, etc., that can be used for connection with other moieties. In some embodiments, a linker moiety comprises one or more -NR'-, wherein R' is described in this specification. In some embodiments, -NR'- improves solubility. In some embodiments, -NR'- serves as connection points to 4330131-WO-PCTanother moiety. In some embodiments, R' is -H. In some embodiments, one or more methylene units of L are independently replaced with -NR'-, wherein R' is as described in this specification.

[0193] In some embodiments, a linker moiety, e.g., L, comprises a -C(O)- group, which can be used for connections with a moiety. In some embodiments, one or more methylene units of L are independently replaced with -C(O)-.

[0194] In some embodiments, a linker moiety, e.g., L, comprises a -NR'- group, which can be used for connections with a moiety. In some embodiments, one or more methylene units of L are independently replaced with -N(R')-.

[0195] In some embodiments, a linker moiety, e.g., L, comprises a -C(O)NR'- group, which can be used for connections with a moiety. In some embodiments, one or more methylene units of L are independently replaced with -C(O)N(R')-.

[0196] In some embodiments, a linker moiety, e.g., L, comprises a -C(R')2- group. In some embodiments, one or more methylene units of L are independently replaced with -C(R')2-. In some embodiments, -C(R')2- is -CHR'-. In some embodiments, R' is -(CH2)2C(O)NH(CH2)11COOH. In some embodiments, R' is -(CH2)2COOH. In some embodiments, R' is -COOH.

[0197] In some embodiments, a linker moiety is or comprises one or more ring moieties, e.g., one or more methylene units of L are replaced with -Cy-. In some embodiments, a linker moiety, e.g., L, comprises an aryl ring. In some embodiments, a linker moiety, e.g., L, comprises a heteroaryl ring. In some embodiments, a linker moiety, e.g., L, comprises an aliphatic ring. In some embodiments, a linker moiety, e.g., L, comprises a heterocyclyl ring. In some embodiments, a linker moiety, e.g., L, comprises a polycyclic ring. In some embodiments, a ring in a linker moiety, e.g., L, is 3-20 membered. In some embodiments, a ring is 5-membered. In some embodiments, a ring is 6-membered. In some embodiments, a ring in a linker is the product of a cycloaddition reaction, e.g., click chemistry, and variants thereof used to link different moieties together.N=N

[0198] In some embodiments, a linker moiety, e.g., L, is or comprisesIn some N=Nembodiments, a methylene unit of L is replaced withIn some embodiments, a methylene unit of L is replaced with -Cy-. In some embodiments, -Cy- is.

[0199] In some embodiments, a linker moiety, e.g., L) is or comprises -CO)y-. In some embodiments, L is or comprises -[(CH2)nO]mCy[(CH2)nO]mNH, or L is -[(CH2)nO]mCy[(CH2)nO]mNHC(O)[(CH2)nO]mNH-, or L is4430131-WO-PCT-[(CH2)nO]mCy[(CH2)nO]m{NHC(O)[(CH2)nO]m}pNH-, where n, m, and p are independently chosen at each occurrence from 1-20, from 1-12, or 2-10. In some embodiments, each n is 2, and m is independently chosen at each occurrence from an integer from 2-10. In some embodiments, m is N=Nindependently chosen from an integer from 2-6, and Cy is. In some embodiments, a-KT Y, N methylene unit of L is replaced with -Cy-. In some embodiments, -Cy- Is ' — '. In someembodiments, -Cy- isIn some embodiments,

[0200] In some embodiments, LRMis a covalent bond. In some embodiments, LRMis not a covalent bond. In some embodiments, LRMis or comprises -(CH2CH2O)n-. In some embodiments, LRMis or comprises -(CH2)n-O-(CH2CH2O)n-(CH2)n-, wherein each n is independently as described in this specification, and each -CH2- is independently optionally substituted. In some embodiments, LRMis -(CH2)n-O-(CH2CH2O)n-(CH2)n-, wherein each n is independently as described in this specification, and each — CH2— is independently optionally substituted. In some embodiments, LRMis-(CH2)2-O-(CH2CH2O)n-(CH2)2-, wherein n is as described in this specification, and each -CH2- is independently optionally substituted. In some embodiments, LRMis -(CH2)2-O-(CH2CH2O)n-(CH2)2-, wherein n is as described in this specification.

[0201] In some embodiments, LPMis a covalent bond. In some embodiments, LPMis not a covalent bond. In some embodiments, LPMis or comprises -(CH2CH2O)n-. In some embodiments, LPMis or comprises -(CH2)n-O-(CH2CH2O)n-(CH2)n-, wherein each n is independently as described in this specification, and each -CH2- is independently optionally substituted. In some embodiments, LPMis -(CH2)n-O-(CH2CH2O)n-(CH2)n-, wherein each n is independently as described in this specification, and each — CH2— is independently optionally substituted. In some embodiments, LPMis-(CH2)2-O-(CH2CH2O)n-(CH2)2-, wherein n is as described in this specification, and each -CH2- is independently optionally substituted. In some embodiments, LPMis -(CH2)2-O-(CH2CH2O)n-(CH2)2-, wherein n is as described in this specification.

[0202] In some embodiments, LPM, e.g., in a product of a first and a second agent, is or comprises a reaction product moiety formed by a first and second reactive moiety.4530131-WO-PCT

[0203] In some embodiments, a linker moiety, e.g., LPMin a product of a first and a second agent, is N=Nor comprises. In some embodiments, a methylene unit of a linker moiety, e.g., a linker moiety that can be L, e.g., LRMor LPM, is replaced with -Cy-. In some embodiments, -Cy- is optionally N=N N=Nsubstituted. In some embodiments, -Cy- is. In some embodiments L is -[(CH2)nO]mCH2Cy[(CH2)nO]m- or In some embodiments,. In someembodiments,Cellular receptor-binding moiety.

[0204] According to embodiments of the present invention, several receptor-binding moieties are described in Inti. Pat. Publ. WO2019 / 199621A1, WO 2019 / 199634, published October 17, 2019, WO 2021 / 072246, published April 15, 2021, and WO 2021 / 072246, published April 15, 2021, each of which is incorporated in this specification in its entirety by reference.

[0205] In an embodiment, the cellular receptor-binding moiety may include an asialoglycoprotein receptor (ASGPR) binding group connected through an amine group to the linker moiety.

[0206] The amine group may be a primary alkyl amine group or a secondary alkyl amine group, each of which is optionally substituted on the amine group with a C1-C3 alkyl group.

[0207] The cellular receptor-binding moiety may include an ASGPR binding group according to the chemical structure disclosed in Inti. Pat. Publ. WO 2019 / 199621.4630131-WO-PCT

[0208] The cellular receptor-binding moiety may have the following structure:where RAis a C1-C3 alkyl group optionally substituted with 1-5 halo groups (preferably RAis a methyl or ethyl group optionally substituted with from 1-3 fluoro groups);ZAis -(CH2)IM, -O-(CH2)IM, S-(CH2)IM, NRM-(CH2)IM, C(O)-(CH2)IM- a PEG group containing from 1 to 8 preferably 1-4 ethylene glycol residues or a -C(O)(CH2)IMNRMgroup (preferably a PEG containing group comprising from 1 to 8 ethylene glycol, preferably 2-4 ethylene glycol residues) where IM and RM are the same as above; andZBis absent, (CH2)IM, C(O)-(CH2)IM- or C(O)-(CH2)IM-NRM, where IM and RMare the same as above.

[0209] In an embodiment, RAmay be a methyl or ethyl group optionally substituted with one to three fluoro groups.

[0210] In an embodiment, ZA is a PEG group containing 1 to 4 ethylene glycol residues.

[0211] In an embodiment, the methyl or ethyl group may be substituted with from 1-3 fluoro groups.

[0212] In an embodiment, the ASGPR binding group may be N-acetyl-D-galactosamine.

[0213] In an embodiment, the cellular receptor-binding moiety may be a low-density lipoprotein receptor-related protein 1 (LRP1), a low-density lipoprotein receptor (LDLR), a FcyRI binding group, a FcRN binding group, a transferrin receptor-binding group, or a macrophage scavenger receptor-binding group.4730131-WO-PCT

[0214] In some embodiments, the cellular-binding moiety is selected from the Markush group consisting of the moieties listed in TABLE 8.30131-WO-PCT

[0215] In an embodiment, the composition of matter may have the structure of Formula (I):VHH-[CONl]-Cys-S-[maleimide]-[LINKER]-[CON2]-[ASGPR](I)

[0216] In another embodiment, the composition of matter may have the structure of Formula (II):FcµR-[CON1]-Cys-S-[maleimide]-[LINKER]-[CON2]-[ASGPR](II)

[0217] In Formulas (I) and (II), the target binding moieties, as they are defined above, are VHH and FcpR. [CONI] is a connecting moiety, which may be a single chemical bond or a peptide moiety comprising a sequence of amino acids. In an embodiment, the amino acids included in the peptide moiety may be selected from the group consisting of G, E, L, P, Q, S, and T. In another embodiment, the4930131-WO-PCTpeptide moiety may be G4S-His6-G4S. In another embodiment, the peptide moiety may be G4S. In another embodiment, the peptide moiety may be G3E.

[0218] In Formulas (I) and (II), [maleimide] is a maleimide moiety which may be a cyclic maleimide moiety or ring-opened (hydrolyzed) maleimide moiety. [LINKER] may be a single chemical bond or a linking moiety. [CON2] may be a single chemical bond or a linking moiety. The linking moiety included in [LINKER] and [CON2] may independently be a moiety selected from the group consisting of:wherein,X2are independently CH2, O, S, NR4, C(O), S(O), S(O)2, S(O)2O, OS(O)2, or OS(O)2O;X3are independently O, S, NR4, wherein R4is H or a C1-C3 alkyl; andk and n are independently 1 to 25.

[0219] In Formulas (I) and (II), [ASGPR] is an asialoglycoprotein binding moiety, which may be monodentate, bidentate, or tridentate. In an embodiment, [ASGPR] may include one, two, or three GalNAc moieties.

[0220] In an embodiment, the composition of matter obtained through MATE™ conjugation may have the structure of Formula (III):VHH-[CON1]-[IgG1Fc]-NH-[LINKER]-[CON2]-[ASGPR](HI)

[0221] In another embodiment, the composition of matter obtained through MATE™ conjugation may have the structure of Formula (IV):FcµR-[CON1]-[IgG1Fc]-NH-[LINKER]-[CON2]-[ASGPR](IV)

[0222] In Formulas (III) and (IV), target binding moieties VHH and FcpR, connecting moieties [CONI] and [CON2], linking moiety [LINKER], and asialoglycoprotein binding moiety [ASGPR] may be the same as in Formulas (I) and (II) above.30131-WO-PCT

[0223] In Formulas (III) and (IV), [IgGlFc] is an IgGl fragment crystallizable region which may optionally include one or more amino acid mutations. In an embodiment, the amino acid mutations may be L234A / L235A. In another embodiment, the amino acid mutations may be L234A / L235A / P329A. In another embodiment, the amino acid mutations may be L234A / L235A / P329G.

[0224] In an embodiment, the composition of matter may have the structure of Formula (IV):VHH-[CON1]-[LPETG]-[LINKER]-[CON2]-[ASGPR](V)

[0225] In another embodiment, the composition of matter may have the structure of Formula (IV):FcµR-[CON1]-[LPETG]-[LINKER]-[CON2]-[ASGPR](VI)

[0226] In Formulas (V) and (VI), target binding moieties VHH and FcpR, connecting moieties [CONI] and [CON2], linking moiety [LINKER], and asialoglycoprotein binding moiety [ASGPR] may be the same as in Formulas (I), (II), (III), and (IV) above.

[0227] In some embodiments, the composition of matter has the structure of:Formula (VII),wherein,each is a target binding moiety;eachmeans for connecting and5130131-WO-PCTeach is a peptide moiety having SEQ ID NO: 396, wherein themoieties are linked together via two disulfide bridges >as shown in Formula (II), wherein one disulfide bridge links cysteine residues located in position 11 ofSEQ ID NO: 396 of each moiety, and wherein the other disulfide bridge linkscysteine residues located in position 14 of SEQ ID NO: 396 of each moietyeachis a means for connecting, whereineachis connected to via a side chain amino group of a lysineresidue of to formeachis an asialoglycoprotein receptor (" ASGPR") binding moiety comprising an N-acetyl- D-galactosamine (" GalNAc") group having Formula (II):Formula (II)

[0228] The composition of matter having the structure Formula (VII) is a dimeric degrader obtained through MATE™ conjugation.5230131-WO-PCT

[0229] In another embodiment, eachmay be VHH or FcpR.

[0230] In another embodiment, ( ) is a single bond or a peptide moiety. The peptide moiety may include an amino acid selected from the group consisting of glycine (G), glutamate (E), leucine (L), proline (P), glutamine (Q), serine (S), and threonine (T).

[0231] In another embodiment, each O may be G4S.

[0232] In another embodiment, eachcomprises a moiety selected from the Markush group consisting of:wherein,X2are independently CH2, O, S, NR4, C(O), S(O), S(O)2, S(O)2O, OS(O)2, or OS(O)2O;X3are independently O, S, NR4, wherein R4is H or a C1-C3 alkyl; andk and n are independently 1 to 25.5330131-WO-PCT

[0233] In another embodiment, eachfurther comprises a moiety selected from the group consisting of:wherein,X2are independently CH2, O, S, NR4, C(O), S(O), S(O)2, S(O)2O, OS(O)2, or OS(O)2O;X3are independently O, S, NR4, wherein R4is H or a C1-C3 alkyl;k and n are independently 1 to 25.

[0234] In another embodiment, eachcomprises one or more-(O)C-[(CH2)nO]m(CH2)nNH-, -[(CH2)nO]m(CH2)nNHC(O)[(CH2)nO]m-, and -[(CH2)nO]m(CH2)n{NHC(O)[(CH2)nO]m}p(CH2)nC(O)NH-, wherein each m and n are independently 1 to 10.

[0235] In another embodiment, eachcomprises one or more -[(CH2)n-O]m-, wherein each m and n are independently 1 to 10.

[0236] In another embodiment, eachcomprises -(CH2)n-O-(CH2CH2O)n-(CH2)n-, wherein each n is independently 1 to 10.5430131-WO-PCT

[0238] (HI):wherein,ZBis absent, -(CH2)IM-, -C(=O)-(CH2)IM-, or -C(=O)-(CH2)IM-NRM-;RMis H or C1-C3alkyl; andeach occurrence of IM is independently 1, 2, or 3.5530131-WO-PCTFormula (V)

[0240] In another embodiment, the lysine residue of is located in position 31 or position 33 of SEQ ID NO: 396.30131-WO-PCT

[0241] In another embodiment, the cysteine residues in positions 46 and 106 of SEQ ID NO: 396 are connected to form a disulfide bridge, and wherein the cysteine residues in positions 152 and 210 of SEQ ID NO: 396 are connected to form a disulfide bridge.

[0242] In a specific embodiment, the composition of matter is AGN7560 or AGN7561.( A )

[0243] In an embodiment, may be an IgM binding moiety described above. In another ( Aembodiment, may be the IgM binding moiety including a sequence having 80% or greater sequence identity with SEQ ID NO: 4 (ABT0101). For example, the sequence identity with SEQ ID NO: 4 may be 80% or greater, 85% or greater, 90% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater.

[0000] Connecting moiety serves as a spacer structure connecting moietiesand ( C ). A spacer is a structure that is located between different structural modules and can spatially separate the structural modules. The definition of spacer is not limited by whether it has a certain function or whether it can be cleaved or degraded in vivo. Examples of spacers include but are not limited to amino acids and non-amino acid structures, wherein non-amino acid structures can be, but are not limited to, amino acid derivatives or analogues. In an embodiment a spacer structure may include a spacer sequence. As used herein, "spacer sequence" refers to an amino acid sequence serving as a spacer, and examples thereof include but are not limited to a single amino acid, a sequence containing a plurality of amino acids, for example, a sequence containing two amino acids such as GA, etc., or, for example, GGGGS (SEQ ID NO: 397) (G4S), GGGGSGGGGS (SEQ ID NO: 398) (G4S 2x), GGGGSGGGGSGGGGS (SEQ ID NO: 399) (G4S 3x), etc.30131-WO-PCT

[0245] In Formula (I),may be a single chemical bond or a polypeptide that provides (7)separation between the IgM binding moiety and Fc polypeptide moiety( C ) ®. In an embodiment,Jmay be a peptide connecting moiety comprising an amino acid selected from the group consisting of G, E, L, P, Q, S, and T.

[0246] In an embodiment,may include a (G4S)4linker. For example,may include a G4S®polypeptide having sequence GGGGS (SEQ ID NO: 397). In another example, ' may include a 2XG4S®polypeptide having sequence GGGGSGGGGS (SEQ ID NO: 398). In another example, may include a® 3XG4S polypeptide having sequence GGGGSGGGGSGGGGS (SEQ ID NO: 399). In another example,x' may include a G4S 4x polypeptide having sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 400). Inanother example, ® — may include a G4S 5x polypeptide having sequence GGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 401).

[0247] In an embodiment, ® — may include a G4S polypeptide and further include one or more ofthe amino acids selected from the group consisting of E, P, K, and A. For example, ®v— * may be a polypeptide having the sequence GGGGSEPKSA (SEQ ID NO: 402).

[0248] Methods of connecting or fusing the IgM-binding moietyand Fc polypeptide moiety ( c )are known in the biomedical art. Either one or both moieties may have a recognition sequence Gnof a ligase acceptor substrate, which facilitates enzyme-catalyzed coupling of a compound of formula (I) with the targeting molecule under the catalysis of the ligase. The targeting molecule optionally modified and comprises the corresponding recognition sequence of a ligase5830131-WO-PCT® ® (. c. )acceptor substrate. In an embodiment,, —, and may be linked together to constitute a part of a continuous recombinant protein sequence.

[0249] In an embodiment, the ligase may be a transpeptidase. In an embodiment, the ligase may be selected from the group consisting of a natural transpeptidase, an unnatural transpeptidase, variants thereof, and the combination thereof. Unnatural transpeptidase enzymes can be, but are not limited to, those obtained by engineering of natural transpeptidase. In an embodiment, the ligase may be selected from the group consisting of a natural Sortase, an unnatural Sortase, and the combination thereof. The species of natural Sortase include Sortase A, Sortase B, Sortase C, Sortase D, Sortase L. plantarum, etc. (detailed description can be found in U. S. Pat. Publ. 2011 / 0321183, which is incorporated herein by reference). The type of ligase corresponds to the ligase recognition sequence and is thereby used to achieve specific conjugation between different molecules or structural fragments.

[0250] In some embodiments, the ligase may be a Sortase selected from Sortase A, Sortase B, Sortase C, Sortase D and Sortase L. plantarum. In these embodiments, the recognition sequence of the ligase acceptor substrate may be selected from the group consisting of oligomeric glycine, oligomeric alanine, and a mixture of oligomeric glycine / alanine having a degree of polymerization of 3-10. In a particular embodiment, the recognition sequence of the ligase acceptor substrate may be Gn, wherein G is glycine (Gly), and n is an integer of 2 to 10.

[0251] In another embodiment, the ligase may be Sortase A from Staphylococcus aureus.Accordingly, the ligase recognition sequence may be a typical recognition sequence of the enzyme as LPXTG (SEQ ID NO: 403). In yet another particular embodiment, the recognition sequence of the ligase donor substrate may be LPXTGJ (SEQ ID NO: 404), and the recognition sequence of the ligase acceptor substrate may be Gn, wherein X can be any single amino acid that is natural or unnatural; J may be absent or may be an amino acid fragment comprising 1-10 amino acids, optionally labeled. In an embodiment, J may be absent. In yet another embodiment, J may be an amino acid fragment comprising 1-10 amino acids, wherein each amino acid may be independently any natural or unnatural amino acid. In another embodiment, J may be Gm, wherein m may be an integer of 1 to 10. In yet another embodiment, the recognition sequence of the ligase donor substrate may be LPETG (SEQ ID NO: 405). In another particular embodiment, the recognition sequence of the ligase donor substrate may be LPETGG (SEQ ID NO: 406).

[0252] In an embodiment, the ligase may be Sortase B from Staphylococcus aureus, and the corresponding donor substrate recognition sequence may be NPQTN (SEQ ID NO: 407). In another5930131-WO-PCTembodiment, the ligase may be Sortase B from Bacillus anthracis, and the corresponding donor substrate recognition sequence may be NPKTG (SEQ ID NO: 408).

[0253] In yet another embodiment, the ligase may be Sortase A from Streptococcus pyogenes, and the corresponding donor substrate recognition sequence may be LPXTGJ (SEQ ID NO: 404), wherein J may be as defined above. In another embodiment, the ligase may be Sortase subfamily 5 from Streptomyces coelicolor, and the corresponding donor substrate recognition sequence may be LAXTG (SEQ ID NO: 409).

[0254] In yet another embodiment, the ligase may be Sortase A from Lactobacillus plantarum, and the corresponding donor substrate recognition sequence may be LPQTSEQ (SEQ ID NO: 410).

[0255] The ligase recognition sequence can also be other totally new recognition sequence for transpeptidase optimized by manual screening.( C JPolypeptide Moiety( C )

[0256] In an embodiment, the polypeptide moiety may be a Fc fragment generated from the heavy chain constant region of an immunoglobulin, an Fc monomer, an Fc dimer, or ( C ~)fragments thereof (e.g., synthetic peptides). For example, may be an Fc-monomer. In some embodiments, the Fc fragment may be conjugated to a single variable domain on a heavy chain (VHH) antibody, a nanobody, a domain, or a fragment thereof, to form an VHH antigen fusion. In some embodiments, the Fc polypeptide may be conjugated to an antigen to form an Fc-antigen fusion. In various embodiments, the Fc fragment may be conjugated to the IgM binding moietythrough the linking polypeptide.(.. )

[0257] In an embodiment, the polypeptide moiety may have SEQ ID NO:( C )396. In another embodiment, the polypeptide moiety may have a sequence having 80% or greater sequence identity with SEQ ID NO: 396. For example, the sequence identity with SEQ ID NO: 396 may be 80% or greater, 85% or greater, 90% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater.30131-WO-PCT

[0258] Various linkers described in the art may be used as the linking groupsin Formula (I) according to embodiments of the present invention.

[0259] In an embodiment, each linking groupin Formula (I) may include any of the linkers [LINKERS] and [CON] disclosed in International Patent Publication WO 2019 / 199634, which is incorporated herein in its entirety by reference.

[0260] In another embodiment, each linking groupin Formula (I) may include any of the linkers [LinkerA], [LinkerB], [LinkerC], and [LinkerD] disclosed in International Patent Publication WO 2021 / 155317, which is incorporated herein in its entirety by reference.

[0261] In another embodiment, each linking groupin Formula (I) may include any of the linkers L disclosed in International Patent Publication WO 2024155750, which is incorporated herein in its entirety by reference.

[0262] In an embodiment, eachin Formula (I) may include one or more-(O)C-[(CH2)nO]m(CH2)nNH- -[(CH2)nO]m(CH2)nNHC(O)[(CH2)nO]m- and -[(CH2)nO]m(CH2)n{NHC(O)[(CH2)nO]m}p(CH2)nC(O)NH-, wherein each m and n are independently 1 to 10.

[0263] In another embodiment, eachin Formula (I) may include one or more - [(CH2)n- O]m-, wherein each m and n are independently 1 to 10.

[0264] In another embodiment, eachin Formula (I) may include-(CH2)n-O-(CH2CH2O)n-(CH2)n-, wherein each n is independently 1 to 10.30131-WO-PCT

[0265] In an embodiment, eachin Formula (I) may include a moiety selected from the group consisting of:wherein,X2are independently CH2, O, S, NR4, C(O), S(O), S(O)2, S(O)2O, OS(O)2, or OS(O)2O;X3are independently O, S, NR4, wherein R4is H or a C1-C3 alkyl; andk and n are independently 1 to 25.

[0266] Various ASGPR binding moieties described in the art may be used as the ASGPR bindingmoietiesin Formula (I) according to embodiments of the present invention.

[0267] In an embodiment, each ASGPR binding moietyin Formula (I) may include any of the moieties [CRBM] and [ASGPRBM] disclosed in International Patent Publication WO 2019 / 199634, which is incorporated herein in its entirety by reference.

[0268] In another embodiment, each ASGPR binding moietyin Formula (I) may include any of the galactose and mannose ASGPR binding moieties disclosed in International Patent Publication WO 2021 / 155317, which is incorporated herein in its entirety by reference.

[0269] In another embodiment, each ASGPR binding moietyin Formula (I) may include any of the lysosomal targeting moieties X disclosed in International Patent Publication WO 2024 / 155750, which is incorporated herein in its entirety by reference.6230131-WO-PCT

[0270] in Formula (I) may include a group having by Formula (Ila):

[0271] In an embodiment, each ASGPR binding moietymay further include a moiety selected from the group consisting of:wherein,X2are independently CH2, O, S, NR4, C(O), S(O), S(O)2, S(O)2O, OS(O)2, or OS(O)2O;X3are independently O, S, NR4, wherein R4is H or a C1-C3 alkyl;k and n are independently 1 to 25.6330131-WO-PCT

[0272] Formula (III):wherein,ZBis absent, -(CH2)IM-, -C(=O)-(CH2)IM-, or -C(=O)-(CH2)IM-NRM-;RMis H or C1-C3alkyl; andeach occurrence of IM is independently 1, 2, or 3.6430131-WO-PCTFormula (V)6530131-WO-PCTMATE™

[0274] As used herein, the term " MATE™" refers to Multimodal Antibody Therapy Enhancer. This next-generation antibody conjugation technology enables site-directed pairing with therapeutic monoclonal antibodies (mAbs), or therapeutic immunoglobulin (IG) pooled from donors. Persons having ordinary skill in the biomedical art can use MATE™ materials and methods as guidance to predictable results when making and using the invention.

[0275] This agent may be referred to as a MATE™ agent or MATE™. The MATE™ agents are described, for example, in Inti. Pat. Publ. WO 2021 / 102052 (Kleo Pharmaceuticals, Inc.), the content of which is incorporated in this specification in its entirety by reference. In some embodiments, an agent comprises an antibody moiety, a cellular receptor-binding moiety, and a linker moiety linking an antibody moiety and a cellular receptor-binding moiety.

[0276] In some embodiments, the invention provides agents, each independently comprising an antibody-binding moiety that binds to an antibody agent, a reactive group, a cellular receptor-binding moiety, and optionally one or more linker moieties linking these groups / moieties. In some embodiments, these agents are useful as reaction partners, e.g., first agents for conjugating moieties of interest, e.g., IgM-binding moieties, reactive groups, e.g., second reactive groups to agents comprising antibody moieties, e.g., second agents. In some embodiments, the invention provides agents for conjugating moieties of interest to antibody moieties in several agents or antibody agents, e.g., monoclonal antibody agents, polyclonal antibody agents, antibody agents of I VIG preparations, etc. In some embodiments, provided agents each comprise a cellular receptor-binding moiety, a reactive group, an antibody-binding moiety, and optionally one or more linker moieties (linkers) linking these moieties. In some embodiments, an antibody-binding moiety is part of a leaving group that is released after contacting this agent, e.g., a first agent, with an antibody moiety, e.g., of a second agent, and reacting a reactive group of this agent, e.g., a first reactive group of a first agent, with a reactive group of an antibody moiety, e.g., a second reactive group of a second agent, such as -NH2of a Lys residue of an antibody protein.6630131-WO-PCT

[0277] In some embodiments, provided technologies can provide improved conjugation efficiency, high selectivity, or fewer steps (in some cases, single steps) to conjugation product agents. In some embodiments, a provided agent, e.g., a first agent, is a composition of matter of formula AGN301 or a salt thereof:LG-RG-LRM-TBT,[AGN301] or a salt thereof, wherein:LG is a group comprising an antibody-binding moiety;RG is a reactive group;LRM is a linker; andTBT is a cellular receptor-binding moiety.

[0278] In some embodiments, IgM-binding moieties may be conjugated to antibody moieties optionally through linker moieties using technologies described in U. S. Pat. Publ. 2020 / 0190165 (Yamada et al.).

[0279] In some embodiments, where a particular protecting group (PG), leaving group (LG), or transformation condition is depicted, persons having ordinary skill in the biomedical art know that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. These groups and transformations are described in Greene's Protecting Groups in Organic Synthesis, Wuts, editor (John Wiley & Sons, 2014), the entirety of which is incorporated in this specification by reference.

[0280] In some embodiments, an oxygen-protecting group includes carbonyl and hydroxylprotecting groups, etc. Hydroxyl-protecting groups and amino-protecting groups are well known in the biomedical art and include those described in Greene's Protecting Groups in Organic Synthesis, Wuts, editor (John Wiley & Sons, 2014).

[0281] Persons having ordinary skill in the biomedical art know that provided agents may contain one or more stereocenters and may be present as a racemic or diastereomeric mixture. They know that there are many methods known in the biomedical art for the separation of isomers to obtain stereoenriched or stereopure isomers of those compounds, including but not limited to HPLC, chiral HPLC, fractional crystallization of diastereomeric salts, kinetic enzymatic resolution, e.g., by fungal-derived, bacterial- derived, or animal-derived lipases or esterases), and formation of covalent diastereomeric derivatives using an enantioenriched reagent.

[0282] Persons having ordinary skill in the biomedical art know that several functional groups present in compounds of this specification, such as aliphatic groups, alcohols, carboxylic acids, esters,6730131-WO-PCTamides, aldehydes, halogens, and nitriles, can be interconverted by techniques well known in the biomedical art including, but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. See Smith & March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thedition (John Wiley & Sons, 2001), which is incorporated in this specification by reference. These interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing compounds of this specification are described below in the Exemplification.

[0283] As known by persons having ordinary skill in the biomedical art, reaction partners are generally contacted with each other under conditions and for a time sufficient for producing the desired results, e.g., formation of product agents and compositions thereof to desired extents. Many reaction conditions / reaction times may be assessed and used if they are suitable for desired purposes in accordance with this specification.

[0284] In some embodiments, the invention provides products of provided processes, which have low levels of damage to antibody moieties compared to processes comprising steps performed for antibody-binding moiety removal but not for substantial conjugation of moieties of interest, e.g., IgM-binding moieties. In some embodiments, provided product agent compositions have high homogeneity, e.g., regarding the number of cellular receptor-binding moiety per antibody moiety or positions of amino acid residues in antibody moieties conjugated to moieties of interest) compared to reference product compositions, e.g., those from technologies without using antibody-binding moieties or using extra step(s) for antibody-binding moiety removal, e.g., not using reaction partners described in this specification which comprise a reactive group located between an antibody-binding moiety and a cellular receptor-binding moiety.

[0285] In some embodiments, the invention provides a product agent, which is an agent comprising an antibody moiety, a cellular receptor-binding moiety, and optionally a linker moiety linking an antibody-binding moiety and a cellular receptor-binding moiety. In some embodiments, the invention provides compositions of such agents.6830131-WO-PCTPlurality of agents.

[0286] In some embodiments, the invention provides a composition comprising a plurality of agents, wherein each agent independently comprises:an antibody moiety,a cellular receptor-binding moiety, andoptionally a linker moiety linking an antibody-binding moiety and a cellular receptor-binding moiety.

[0287] In some embodiments, product agents are MATE™ agents. In some embodiments, an antibody agent moiety comprises an Fc region. In some embodiments, an antibody moiety is connected to a cellular receptor-binding moiety through an amino group, optionally through a linker. In some embodiments, it is through a lysine residue wherein the amino group of the side chain is connected to a cellular receptor-binding moiety optionally through a linker, e.g., forming -NH-C(O)- as part of an amide group, a carbamate group, etc.

[0288] In some embodiments, selected locations of antibody moieties are used for conjugation. In some embodiments, K246 or K248 of an antibody agent (EU numbering or corresponding residues) are conjugation locations. In some embodiments, a conjugation location is K246 of the heavy chain (unless otherwise specified, locations in this specification include corresponding residues in, e.g., modified sequence, e.g., longer, shorter, rearranged, etc., sequences. In some embodiments, a location is K248 of the heavy chain. In some embodiments, a location is K288 or K290 of heavy chain. In some embodiments, a location is K288 of the heavy chain. In some embodiments, a location is K290 of heavy chain. In some embodiments, a location is K317. In some embodiments, an antibody moiety is a moiety of an IgGl antibody or a fragment thereof. In some embodiments, an antibody moiety is a moiety of an lgG2 antibody or a fragment thereof. In some embodiments, an antibody moiety is a moiety of an antibody or a fragment thereof. In some embodiments, a composition comprises a plurality of MATE™ agents, wherein antibody moieties of the plurality of MATE™ agents are independently an antibody moiety of an IgGl, lgG2, or lgG4 antibody, or a fragment thereof.

[0289] In some embodiments, antibody heavy chains are selectively conjugated / labeled over light chains.6930131-WO-PCT

[0290] In some embodiments, the invention provides a composition comprising a plurality of agents, each of which independently comprises:an antibody moiety,a cellular receptor-binding moiety, andoptionally a linker moiety linking the antibody moiety and the cellular receptor-binding moiety; wherein antibody moieties of agents of the plurality comprise a common amino acid sequence, and agents of the plurality share a common cellular receptor-binding moiety independently of at least one common amino acid residue of the common amino acid sequence; andwherein about l%-100% of all agents that comprise an antibody moiety that comprises the common amino acid sequence and the cellular receptor-binding moiety are agents of the plurality.

[0291] In some embodiments, the invention provides a composition comprising a plurality of agents, each of which independently comprises:an antibody moiety,a cellular receptor-binding moiety, andoptionally a linker moiety linking an antibody moiety and a cellular receptor-binding moiety; wherein agents of the plurality share the same or substantially the same antibody moiety and a cellular receptor-binding moiety at least one common location; andwherein about l%-100% of all agents that comprise the antibody moiety and the cellular receptor-binding moiety are agents of the plurality.Reactive Group

[0292] In some embodiments, provided agents, compounds, e.g., those useful as reaction partners such as first agents, comprise reactive groups, e.g., RG. In some embodiments, reactive groups are located between antibody-binding moieties and moieties of interest. Reactive groups are optionally and independently linked to antibody-binding moieties and moieties of interest via linkers. In some embodiments, RG is a reaction group, as described in this specification.

[0293] In some embodiments, reactive groups, when used in agents that comprise no antibodybinding moieties, react slowly and provide a low level of, in some embodiments, substantially no conjugation of moieties of interest with target agents. As shown in this specification, a combination of reactive groups with antibody-binding moieties in the same agents, e.g., as in compounds of formula AGN301 or salts thereof, can promote reactions between reactive groups and target agents, enhance reaction efficiency, reduce side reactions, or improve reaction selectivity, e.g., in terms of target sites wherein conjugation of moieties of interest with target agents occurs.7030131-WO-PCT

[0294] Reactive groups in agents can react with several groups in target agents. In some embodiments, reactive groups in agents selectively react with amino groups of target agents, e.g., -NH2groups on side chains of lysine residues of proteins. In some embodiments, reactive groups when used in agents, e.g., those of formula AGN301 or salts thereof, selectively react with sites of target agents, e.g., as shown in examples in this specification, one or more of K246, K248, K288, K290, K317, etc. for IgGl, one or more of K251, K253, etc. for lgG2, and one or more of K239, K241 for lgG4. In some embodiments, a site is K246 or K248 of an antibody heavy chain. In some embodiments, sites are K246 or K248 of an antibody heavy chain. In some embodiments, a site is K246 of an antibody heavy chain. In some embodiments, a site is K248 of an antibody heavy chain. In some embodiments, a site is K288 or K290 of an antibody heavy chain. In some embodiments, a site is K288 of an antibody heavy chain. In some embodiments, a site is K290 of an antibody heavy chain. In some embodiments, a site is K317. In some embodiments, a site is K414 of an antibody heavy chain. In some embodiments, a site is K185 of an antibody light chain. In some embodiments, a site is K187 of an antibody light chain. In some embodiments, sites are K251 or K253 of an IgG2 heavy chain. In some embodiments, a site is K251 of an IgG2 heavy chain. In some embodiments, a site is K253 of an IgG2 heavy chain. In some embodiments, sites are K239 or K241 of an antibody heavy chain. In some embodiments, a site is K239 of an antibody heavy chain. In some embodiments, a site is K241 of an antibody heavy chain. In some embodiments, conjugation selectively occurs at one or more heavy chain sites over light chain sites. In some embodiments, for technologies without antibody-binding moieties, conjugation occurs at light chain sites more than heavy chain sites.

[0295] In some embodiments, a reactive group, e.g., RG, is or comprises an ester group. In some embodiments, a reactive group, e.g., RG, is or comprises an electrophilic group, e.g., a Michael acceptor.

[0296] In some embodiments, a reactive group, e.g., RG, is or comprises — LRG1— LRG2—, wherein each of LRG1and LRG2is independently L. In some embodiments, a reactive group, e.g., RG, is or comprises -LLG4-LRG1-LRG2-, wherein each variable is as described in this specification. In some embodiments, a reactive group, e.g., RG, is or comprises -LLG3-LLG4-LRG1-LRG2-, wherein each variable is as described in this specification. In some embodiments, a reactive group, e.g., RG, is or comprises-LLG2-LLG3-LLG4-LRG1-LRG2-, wherein each variable is as described in this specification. In some embodiments, a reactive group, e.g., RG, is or comprises -LLG4-LRG2-, wherein each variable is as described in this specification. In some embodiments, a reactive group, e.g., RG, is or comprises -LLG3-LLG4-LRG2-, wherein each variable is as described in this specification. In some embodiments, a7130131-WO-PCTreactive group, e.g., RG, is or comprises -LLG2-LLG3-LLG4-LRG2-, wherein each variable is as described in this specification.

[0297] In some embodiments, LLG4is -O-. In some embodiments, LLG4is -N(R)-. In some embodiments, LLG4is -NH-.

[0298] In some embodiments, LLG3is or comprises an optionally substituted aryl ring. In some embodiments, LLG3is or comprises a phenyl ring. In some embodiments, an aryl or phenyl ring is substituted. In some embodiments, a substituent is an electron-withdrawing group as described in this specification, e.g., -NO2, -F, etc.

[0299] In some embodiments, LRG1is a covalent bond. In some embodiments, LRG1is not a covalent bond. In some embodiments, LRG1is -S(O)2-.

[0300] In some embodiments, LRG2is -C(O)-. In some embodiments, a reactive group comprises LLG4-C(O), wherein each variable is described in this specification. In some embodiments, a reactive group comprises -LLG3-LLG4-C(O)-, wherein each variable is as described in this specification. In some embodiments, a reactive group comprises -LLG2-LLG3-LLG4-C(O)-, wherein each variable is as described in this specification.

[0301] In some embodiments, LRG2is -LRG3-C(=CRRG1RRG2)-CRRG3RRG4-, wherein each of RRG1, RRG2, RRG3and RRG4is independently -L-R', and LRG3is -C(O)-, -C(O)O-, -C(O)N(R')-, -S(O)-, -S(O)2-, -P(O)(OR')-, -P(O)(SR')-, or -P(O)(N(R')2)-. In some embodiments, each of RRG1, RRG2, RRG3, and RRG4is independently R'. In some embodiments, one or more of RRG1, RRG2, RRG3and RRG4is independently -H. In some embodiments, LRG3is -C(O)-. In some embodiments, LRG3is -C(O)O-. In some embodiments, -O-, -N(R')-, etc. of LRG3is bonded to LPM.

[0302] In some embodiments, RRG1is -H. In some embodiments, RRG3is -H.

[0303] In some embodiments, LRG2is optionally substituted -LRG3-C(=CHRRG2)-CHRRG4-, wherein each variable is as described in this specification.

[0304] In some embodiments, RRG2and RRG4are taken together with their intervening atoms to form an optionally substituted ring as described in this specification. In some embodiments, a formed ring is an optionally substituted 3-10 membered monocyclic or bicyclic ring having 0-5 heteroatoms. In some embodiments, a formed ring is an optionally substituted 3-10-membered cycloaliphatic ring. In some embodiments, a formed ring is selected from the Markush group consisting of optionally substituted cycloaliphatic rings consisting of a 3-8 membered cycloaliphatic ring, a 5-8 membered cycloaliphatic ring., a 5-membered cycloaliphatic ring, a 6-membered cycloaliphatic ring, and a 7-membered cycloaliphatic ring. In some embodiments, a formed ring is substituted. In some7230131-WO-PCTembodiments, a formed ring is not substituted. In some embodiments, a formed ring contains no additional unsaturation besides the double bond in C(=CHRRG2) or C(=CRRG1RRG2).

[0305] In some embodiments, -C(=CHRRG2)-CHRRG4or -C(=CRRG1RRG2)-CRRG3RRG4is optionally

[0307] In some embodiments, -LLG4-LRG2- is -N(-)-C(O)-, wherein N is a ring atom of an optionally substituted heteroaryl ring. In some embodiments, -LLG4-LRG2- is -N(-)-C(O)-, wherein N is a ring atom of LLG4, which is or comprises an optionally substituted heteroaryl ring. In some embodiments, -LLG4-LRG2- is -N(-)-C(O)-O-, wherein N is a ring atom of LLG4, which is or comprises an optionally substituted heteroaryl ring.

[0308] In some embodiments, LRG2is optionally substituted -CH2-C(O)-, wherein -CH2- is bonded to an electron-withdrawing group comprising or connected to an antibody-binding moiety. In some embodiments, LRG2is optionally substituted -CH2- bonded to an electron-withdrawing group comprising or connected to an antibody-binding moiety. In some embodiments, LRG1is an electron-withdrawing group. In some embodiments, LRG1is selected from the Markush group consisting of -C(O)-, -S(O)-, -S(O)2-, -P(O(OR)-, -P(O(SR)-, -P(O(N(R)2)-, -OP(O(OR)-, -OP(O(SR)-, and -OP(O(N(R)2)-.

[0309] In some embodiments, LRG2is optionally substituted -CH2-C(O)-, wherein -CH2- is bonded to a leaving group comprising or connected to an antibody-binding moiety. In some embodiments, LRG2is optionally substituted -CH2- bonded to a leaving group comprising or connected to an antibody-binding30131-WO-PCTmoiety. In some embodiments, LRG1is selected from the Markush group consisting of -O-C(O)-, -OS(O)2-, -OP(O(OR)-, -OP(O(SR)-, and -OP(O(N(R)2)-.

[0310] In some embodiments, a reactive group reacts with an amino group of a target agent. In some embodiments, an amino group is -NH2of the side chain of a lysine residue.

[0311] In some embodiments, a target agent is a protein agent. In some embodiments, a target agent is an antibody agent. In some embodiments, a reactive group reacts with an amino acid residue of this protein or antibody agent. In some embodiments, an amino acid residue is a lysine residue. In some embodiments, a reactive group reacts with -NH2of the side chain of a lysine residue. In some embodiments, a reactive group is or comprises -C(O)-O- reacts with -NH2, e.g., of the side chain of a lysine residue) and forms an amide group -C(O)-O- with the -NH2.

[0312] In some embodiments, reactive groups, e.g., a first reactive group, a second reactive group, etc., are located at terminal locations. In some embodiments, the first agents comprise the first reactive groups linked to IgM-binding moieties optionally through linker moieties, and they do not contain antibody-binding moieties.

[0313] In some embodiments, the invention provides methods for preparing a composition comprising a plurality of agents, wherein each agent independently comprises:an antibody moiety,a cellular receptor-binding moiety, andoptionally a linker moiety linking an antibody moiety and a cellular receptor-binding moiety; which method comprises:contacting a plurality of agents, each independently comprising a reactive group with a plurality of antibody agents.

[0314] In some embodiments, an agent comprising a reactive group comprises an antibody-binding moiety, a cellular receptor-binding moiety, and optionally a linker. In some embodiments, agents comprising a reactive group share the same cellular receptor-binding moiety. In some embodiments, agents comprising a reactive group share the same structure. In some embodiments, antibody molecules are of such structures, properties, or activities to provide antibody moieties in agents described in this specification. In some embodiments, a plurality of antibody molecules comprises two or more IgG subclasses. In some embodiments, a plurality of antibody molecules comprises IgGl. In some embodiments, a plurality of antibody molecules comprises lgG2. In some embodiments, a plurality of antibody molecules comprises lgG4. In some embodiments, a plurality of antibody molecules comprises IgGl and lgG2. In some embodiments, a plurality of antibody molecules comprises IgGl, lgG2,7430131-WO-PCTand lgG4. In some embodiments, a plurality of antibody molecules comprises IgGl, lgG2, lgG3 and lgG4. In some embodiments, a plurality of antibody molecules is I VIG antibody molecules.•, Jv

[0315] In some embodiments, provided agents comprise a reactive group, e.g., OIn some embodiments, -C(O)- is connected to a cellular receptor-binding moiety or a moiety comprising -(Xaa)y-, optionally through a linker, and the other end is connected to an antibody-binding moiety.osome embodiments, 0 J reacts with an amino group of another moiety, e.g., an antibody moiety, forming an amide group with the moiety and releasing a moiety comprising an antibody-binding moiety. In some embodiments, an amino group is -NH2of a lysine side chain. In some embodiments, — C(O)— is connected to a cellular receptor-binding moiety or a moiety comprising -(Xaa)y-, optionally through a linker, and the other end is connected to R' or an optional substituent. In some embodiments, provided agents comprise optionally substituted ffi. Such reactive groups may be useful for conjugation with detection, diagnosis, or therapeutic agents. Persons having ordinary skill in the biomedical art know that many agents and technologies, e.g., click chemistry, reactions based on functional groups such as amino groups, e.g., amide formation), hydroxyl groups, carboxyl groups, etc. can be used for conjugation in accordance with this specification.

[0316] In some embodiments, antibody-binding moieties bind to Fc regions of antibodies. In some embodiments, reactions occur at residues at Fc regions. In some embodiments, IgM-binding moieties are conjugated to residues of Fc regions, optionally through linker moieties. In some embodiments, a residue is a Lys residue. In some embodiments, an antibody is or comprises IgGl. In some embodiments, an antibody is or comprises lgG2. In some embodiments, an antibody is or comprises lgG4. In some embodiments, an antibody composition used in a method comprises IgGl and lgG2. In some embodiments, an antibody composition used in a method comprises IgGl, lgG2, and lgG4. In some embodiments, an antibody composition used in a method comprises IgGl, lgG2, lgG3, and lgG4.

[0317] In some embodiments, a product is or comprises IgGl. In some embodiments, a product is or comprises lgG2. In some embodiments, a product is or comprises lgG4. In some embodiments, a product composition comprises IgGl and lgG2. In some embodiments, a product composition comprises IgGl, lgG2, and lgG4. In some embodiments, a product composition comprises IgGl, lgG2, lgG3, and lgG4.7530131-WO-PCT

[0318] In some embodiments, provided agents comprising antibody moieties provide one or more or substantially all antibody immune activities, e.g., recruiting one or more types of immune cells or providing short-term and long-term immune activities. In some embodiments, provided agents comprising antibody moieties do not significantly reduce one or more or substantially all relevant antibody immune activities. In some embodiments, provided agents comprising antibody moieties improve one or more or substantially all relevant antibody immune activities, e.g., compared to antibody moieties by themselves. In some embodiments, provided agents provide comparable or better stability than antibody moieties by themselves, e.g., residence time in blood. In some embodiments, antibody moieties in provided agents can bind to the FcRy of immune cells, e.g., several FcRy of immune effector cells for desired immune activities, typically at comparable or better levels. In some embodiments, antibody moieties in provided agents have comparable Fab / antigen binding capabilities. In some embodiments, antibody moieties in provided agents have comparable Fab / antigen binding capabilities. In some embodiments, antibody moieties in provided agents provide FcRn binding. In some embodiments, antibody moieties in provided agents provide FcRn binding, e.g., for antibody recycling or prolonged half-life. In some embodiments, provided technologies are useful for modifying blood-derived IgG products as provided technologies are suitable for and can use all IgG subclasses.

[0319] In some embodiments, a provided method comprises one of the steps described below. Insome embodiments, JA 0 / J reacts with an amino group of a lysine side chain to form an amide bond with an antibody molecule and release it.Second agent.

[0320] In another embodiment, the invention provides a composition including the agent and at least one additional agent comprising a moiety capable of binding to the antibody that forms the antibody moiety of the first compound.

[0321] In some embodiments, a first composition comprises a first agent described in this specification. In some embodiments, second agents independently comprise second reactive groups. In some embodiments, a second composition comprises a plurality of agents as described in this specification, wherein each cellular receptor-binding moiety is independently a reactive group as described in this specification. In some embodiments, a second composition is an antibody composition, wherein antibodies in the composition are not chemically modified. In some embodiments, a second7630131-WO-PCTcomposition is an IVIG preparation. In some embodiments, a product composition comprises a plurality of agents as described in this specification, wherein each cellular receptor-binding moiety is independently a cellular receptor-binding moiety as described in this specification.

[0322] In some embodiments, a cellular receptor-binding moiety in a product agent is a cellular receptor-binding moiety in a first agent. In some embodiments, an antibody moiety in a product agent is an antibody moiety in a second agent. In some embodiments, a second agent is an antibody agent, e.g., a monoclonal antibody, an antibody in a polyclonal antibody, an antibody in an I VIG preparation, etc. In some embodiments, a second reactive group is a function group of an amino acid residue, e.g., -NH2 of Lys, -SH of Cys, etc. In some embodiments, a second reactive group is -NH2 of a Lys residue, e.g., of a residue selected from K246 and K248 of IgGl heavy chain amino acid residues corresponding thereto, K251 and K253 of an IgG2 heavy chain and amino acid residues corresponding thereto, and K239 and K241 of a heavy chain and amino acid residues corresponding thereto. In some embodiments, the invention provides selective reactions at amino acid residues of antibody moieties.

[0323] In some embodiments, a second reactive group is installed to an antibody moiety optionally through a linker. In some embodiments, a second reactive group is installed to an antibody moiety through a linker. In some embodiments, a second reactive group is selectively linked to certain location(s) of an antibody moiety, e.g., certain location(s) selected from K246 and K248 of IgGl heavy chain amino acid residues corresponding thereto, K251 and K253 of an IgG2 heavy chain and amino acid residues corresponding thereto, and K239 and K241 of a heavy chain and amino acid residues corresponding thereto. In some embodiments, the invention provides selective reactions at amino acid residues of antibody moieties.Pharmaceutically acceptable excipients.

[0324] Formulations suitable for parenteral administration, such as by intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, and subcutaneous routes, include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. In the practice of this invention, compositions can be administered by intravenous infusion, orally, topically, intraperitoneally, intravesically, or intrathecally. Parenteral, oral, and intravenous are the preferred administration7730131-WO-PCTmethods. The formulations of compounds can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials.

[0325] Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include these components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicities such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.Methods of identifying a patient needing treatment. Methods of measuring the removal of IgM from a subject or patient.

[0326] The selection of patients who can benefit from the administration of the IgM bifunctional degrader and the therapeutic progression of patients to whom the IgM bifunctional degrader should be administered can be assayed by methods known in the biomedical art. MGUS is usually detected by chance when the patient has a blood test for another condition or as part of standard screening. The secreted antibody is found during standard laboratory blood or urine tests, e.g., in a protein electrophoresis assay. Patients may be diagnosed with MGUS if they fulfill four criteria: (1) a monoclonal paraprotein band less than 30 g / L (< 3g / d L); (2) plasma cells less than 10% on bone marrow examination; (3) no evidence of bone lesions, anemia, hypercalcemia, or chronic kidney disease related to the paraprotein, and (4) No evidence of another B-cell proliferative disorder. International Myeloma Working Group, British J. Haematol., 121(5), 749-757 (2003).

[0327] Diagnostic testing for IgM MGUS. Monoclonal gammopathy of unknown significance (MGUS) is a non-cancerous condition where the subject or patient makes an abnormal monoclonal protein or paraprotein. IgM MGUS subjects or patients have an increased risk of developing other conditions such as low-grade lymphomas. The risk of progression among patients with IgM MGUS is around 2% per year in the first ten years after diagnosis and 1% per year thereafter. IgM MGUS patients should be monitored over the time, often repeated once a year. This monitoring should include quantification of the M-protein on serum electrophoresis and immunoglobulin levels; full blood counts; assays of renal and liver function; assays of bone profile; and lactate dehydrogenase (LDH) testing. A7830131-WO-PCTbone marrow test is a relatively quick routine procedure where liquid bone marrow, and a very small core of bone is removed from the back of your pelvic bone using local anesthetic.

[0328] Diagnostic workup for cold agglutinin disease. Laboratory findings are consistent with hemolysis (and may, therefore, include reticulocytosis, elevated lactate dehydrogenase, unconjugated hyperbilirubinemia and decreased haptoglobin), the monospecific direct antiglobulin test is strongly positive for C3d and there is a cold agglutinin titer of >1:64 at 4°C. Blood samples should be handled warm until separation to prevent agglutination. Khwaja et al., Haematologica, 107(9), 2037-2050 (June 30, 2022).

[0329] Diagnostic workup for cryoglobulinemia. Symptoms do not correlate with the cryocrit and depend instead on the temperature at which precipitation occurs. Harel et al., British J. Haematol. 168(5), 671-678 (2015). Accurate detection of cryoglobulins requires samples to be taken into prewarmed tubes which are not allowed to cool below 37°C until the serum is separated, as the cryoglobulin may precipitate and not be detected. Similarly, a false-negative M-protein result may result from the same process. Kolopp-Sarda, Nombel, & Miossec, Arthritis Rheumatol., 71(11), 1904-1912 (2019). Care must be taken with preanalytical variables; repeat testing of M-protein and cryoglobulins is indicated if the clinical suspicion is high. Increased plasma viscosity in the absence of a high IgM should trigger clinicians to consider cryoglobulinemia. A tissue biopsy may be indicated to identify renal or nerve involvement and distinguish it from other causes. Intravascular precipitation of IgM triggered by exposure to cold results in thrombotic obstruction and ischemia in small vessels as evidenced on biopsy in type I cryoglobulinemia. Leukocytoclastic vasculitis may be evident in type II cryoglobulinemia. See Khwaja et al., Haematologica, 107(9), 2037-2050 (June 30, 2022).

[0330] Diagnostic workup for IgM-associated AL amyloidosis. The Mayo group has suggested two types of clonal dyscrasia, based on morphology; lymphoid predominant (lymphoplasmacytic lymphoma) or plasma cell predominant (pure plasma cell neoplasm). Sidana et al., Leukemia, 34(5), 1373-1382 (2020). Patients with the pure plasma cell neoplasm type appear to have poorer outcomes.

[0331] Diagnostic workup for IgM-related neuropathy. Most patients with IgM-related neuropathy (>90%) have symptoms of the underlying neurological disorder at diagnosis. Patients should be tested for anti-MAG antibodies, but only high-titer antibodies are clinically relevant in the presence of a characteristic clinical picture in anti-MAG neuropathy. D'Sa et al., British J. Haematol., 176(5), 728-742 (2017). A reduction in anti-MAG titers and levels of IgM M-protein with therapy appeared to correlate with improvement in neuropathy in a retrospective analysis of fifty studies. Hänggi et al., Neurol.Neuroimmunol. Neuroinflamm., 9(1), e1109 (2022). Progressive demyelination may result in secondary7930131-WO-PCTaxonal loss which affects the likelihood of neural recovery. Comprehensive consensus guidelines provide further details. D'Sa et al., British J. Haematol., 176(5), 728-742 (2017).

[0332] Diagnostic workup for Schnitzler syndrome. There is no single diagnostic test for Schnitzler syndrome. The diagnosis is made based on clinical characteristics. Differential diagnoses for the rash and fever include adult-onset Still disease, systemic lupus erythematosus, acquired Cl esterase deficiency, cryopyrinopathies, and cryoglobulinemia (cold-induced urticaria). Skin biopsy reveals a neutrophilic urticarial dermatosis without features of vasculitis.Methods of testing patients having an IgM disorder.The state-of-the-art methods of testing patients having an IgM disorder can also be used to test subjects or patients to whom a bifunctional degrader of the invention has been or is being administered, to assay the subject's or patient's therapeutic progress. Comprehensive consensus guidelines provide further details. D'Sa et al., British J. Haematol., 176(5), 728-742 (2017).

[0333] Cryocrit.

[0334] Direct antiglobulin test (DAT). See also the antibody tests described above.

[0335] Erythropoietin (EPO).

[0336] Histological assessment includes targeting affecting organ, consider abdominal fat biopsy. Exclude other acquired and hereditary amyloidoses. Organ assessment includes comprehensive evaluation of organs including cardiac, renal, neurological, gastrointestinal and soft tissue involvement.

[0337] Lactate dehydrogenase (LDH).

[0338] Magnetic resonance imaging (MRI) of the neuraxis and evaluation of large volumes of cerebrospinal fluid may be required if central nervous system involvement is suspected. A nerve biopsy may be needed if the diagnosis remains elusive despite systematic investigation. Nerve biopsy is performed after consultation with an expert neurologist in selected cases only.

[0339] Nerve conduction studies, electromyography (NCS / EMG). The peripheral neuropathy associated with IgM MGUS usually presents as a distal, symmetric, and slowly progressive sensorimotor neuropathy with predominantly demyelinating features in the nerve conduction studies.

[0340] Positron emission tomography (PET).

[0341] Serum protein electrophoresis (SPEP). See also the antibody tests described above.

[0342] Urine protein creatinine ratio (uPCR).

[0343] Multidimensional flow cytometry (MFC).

[0344] Gene expression profiling (GEP).8030131-WO-PCT

[0345] Next-generation sequencing (NGS).Methods of treatment.

[0346] How to administer. The best mode of administration depends on where treatment is taking place, whether a hospital or outpatient. In one embodiment, the method of administration is by subcutaneous administration to a patient or subject of 50 mg / ml of the composition of matter (agent).Material generation of recombinant ligand constructs. Fc mutation strategies to reduce FcyR and c1q binding.

[0347] In some embodiments, an antibody-binding moiety is a moiety, e.g., a small molecule, peptide, nucleic acid, etc., that can selectively bind to IgG and provide or stimulate ADCC or ADCP. In some embodiments, peptide display technologies, e.g., phase display, non-cellular display, etc., can identify antibody-binding moieties. In some embodiments, an antibody-binding moiety is a moiety, e.g., small molecule moiety, peptide moiety, nucleic acid moiety, etc., that can bind to IgG and optionally can compete with known antibody binders, e.g., protein A, protein G, protein L, etc.

[0348] Persons having ordinary skill in the biomedical art can mutate an antibody, an antibody variant, or an antigen-binding fragment thereof in the Fc region to insert a LALA mutation using biomedical art-recognized methods first described by the Winter group in the 1990s. LALA = L234A / L235A.

[0349] Persons having ordinary skill in the biomedical art can mutate an antibody, an antibody variant, or an antigen-binding fragment thereof in the Fc region to insert a LALA mutation using biomedical-art recognized methods first described by the Winter group in the 1990s, then inserted P mutations, such as by the biomedical-art recognized methods introduced by Roche team in 2016, such as the technology for adding P329G and P329G combined with LALA. LALA / PA = L234A / L235A / P329A. LALA / PG = L234A / L235A / P329G. See Tilman et al., Protein Engineering, Design and Selection, Volume 29, Issue 10, pages 457-466 (October 2016), which shows that LALA abolishes c1q binding. P329A alone was tested. P329A abolishes c1q binding and reduces FcgR binding. They show that P329G / LALA further reduces FcyR binding beyond LALA alone.

[0350] Persons having ordinary skill in the biomedical art can mutate an antibody, an antibody variant, or an antigen-binding fragment thereof in other regions. N297A / Q removes the natural N-linked glycosylation site in the hinge region.8130131-WO-PCTMaterial generation of recombinant ligand constructs. Fc mutation strategies to enhance FcRn binding to prolong exposure.

[0351] There are many publicly available approaches and mutation sets to increase the binding of an Fc to FcRn. See TABLE 9. Strohl, Current Opinion in Biotechnology, 20(6), 685-691 (2009) provided an older summary.

[0352] For an example of introducing a YTE region in a protein (M252Y / S254T / T256E), see Acqua et al., The Journal of Immunology 169(9), 5171-5180 (2002). For a recent example combining LALA and YTE, see Cobb et al., bioRxiv, 2021-09 (2021). Additional references with details of engineering are also available. For an example of introducing an LS region in a protein (M428L / N434S), see Zalevsky et al., Nature Biotechnology, 28(2), 157-159 (2010).Material generation of conjugated recombinant ligand constructs.

[0353] GN3 sortase reagent. Persons having ordinary skill in the biomedical art have access to commercially available protocols for sortase conjugation using the ASPGR binder for the C-terminal sortase tag (LPETGG) for conjugation (GN3 / linker).

[0354] GN3-maleimide reagent (maleimide-GN3 / linker), with a C-terminal Cys for conjugation.Methods of assessing the chemical structure and function of the agent.

[0355] HDX-MS measures the exposure of hydrogen molecules on the surface of a protein or protein complex. The first step causes exposed hydrogen molecules to be readily exchanged with30131-WO-PCTdeuterium. Hydrogen molecules buried within the structure, for example, at the binding site of an antibody-antigen complex, are not exchanged as readily.

[0356] Comparing the deuterium uptake between proteins in their free and complex states via mass spectrometry provides valuable information about the binding regions.

[0357] Protein sequencing. In one protein sequencing method, eight digestions are prepared using five different enzymes (pepsin, Lys C, trypsin, chymotrypsin, Asp N). The digestions for the sample are processed with disulfide reduction, cysteine blocking, and then enzyme digestion. Digestions were analyzed by LC-MS / MS using a Thermo-Fisher Orbitrap fusion™ mass spectrometer. Peptides are characterized from LC-MS / MS data using de novo peptide sequencing and assembled into antibody sequences.Methods for testing recombinant ligand constructs.

[0358] Many technologies are available for identifying, assessing, or characterizing antibodybinding moieties, including protein-binding moieties, e.g., antibody-binding moieties such as universal antibody-binding moieties, or their use in provided technologies, e.g., those described in Intl. Pat. Publ. WO 2019 / 023501, the technologies of which are incorporated in this specification by reference.

[0359] Persons having ordinary skill in the biomedical art know that antibody-binding moieties described in this specification target antibodies with several properties and activities, e.g., antibodies recognizing different antigens, having optional modifications, etc. In some embodiments, these antibodies include antibodies administered to a subject, e.g., for therapeutic purposes. In some embodiments, antibody-binding moieties described in this specification may bind antibodies toward different antigens and are useful for conjugating moieties of interest with several antibodies.

[0360] In some embodiments, an antibody-binding moiety comprises a meditope agent moiety. A meditope agent is described in, e.g., U. S. Pat. Publ. 2019 / 0111149.

[0361] In some embodiments, an antibody-binding moiety, e.g., an antibody-binding moiety, can bind to human IgG. In some embodiments, an antibody-binding moiety, e.g., an antibody-binding moiety, can bind to an antibody selected from the Markush group of antibodies consisting of rabbit IgG, IgGl, lgG2, lgG3, and lgG4. In some embodiments, an antibody-binding moiety, e.g., an antibody-binding moiety, binds to IgGl, lgG2, and lgG4.

[0362] Biophysical / biochemical potency assay to measure IgM engagement. A biomolecule coupled to the surface of the sensor chip as a ligand. As the analyte is flowed in solution over an immobilized ligand, binding to the sensor chip surface induces a change in refractive index proportional to bound8330131-WO-PCTmass. The assay can be done using a Biacore instrument, which has a high sensitivity and low-medium throughput. A ligand variant fragment is dosed 1 nM to 1 μM and characterized by single cycle kinetics.

[0363] Cellular in vitro activity: ASGPR-dependent uptake assay. A HEK293 fluorescence cell-based assay was used to assess IgM uptake by cells in vitro. This on-mechanism endocytosis assay measures the accumulation in HEK293 cells.

[0364] Measurement of off-target bindings in an in-house C-type lectin panel. The signal is boosted in the HEK293 versus HepG2 cells when measuring signal accumulation, not degradation. Western assays can measure the degradation in HEK cells and other cell lines.

[0365] Biochemical / biophysical in vitro activity: Ternary complex by TR-FRET. FRET assays assess ternary complex in solution.Methods of making agents

[0366] Agents of this specification may be prepared or isolated by synthetic or semi-synthetic methods or recombinant methods in accordance with this specification. In some embodiments, polypeptide agents, e.g., cellular receptor-binding moiety peptide agents, may be prepared using biological expression systems. In some embodiments, provided agents are prepared synthetically. In some embodiments, provided agents are prepared using certain technologies described in Int. Patent Publ. WO 2019 / 023501, which is incorporated in this specification in its entirety by reference.

[0367] Several technologies, such as those for preparing antibody-drug conjugates, may be used in preparing MATE™ agents. In some embodiments, the invention provides technologies for selective conjugation of IgM-binding moieties at amino acid residue sites.

[0368] In some embodiments, the invention provides a method of synthesis, comprising the steps of (1) contacting a first agent comprising a cellular receptor-binding moiety linked to a first reactive group optionally through a first linker with a second agent comprising an antibody moiety linked to a second reactive group optionally through a second linker, wherein the first reactive group reacts with a second reactive group, and (2) forming a product agent comprising a cellular receptor-binding moiety and an antibody-binding moiety optionally through a linker.

[0369] In some embodiments, the invention provides a method of synthesis comprising the steps of (1) contacting a first composition comprising a plurality of first agents, each independently comprising a cellular receptor-binding moiety linked to a first reactive group optionally through a first linker moiety, with a second composition comprising a plurality of second agents, each independently comprising an antibody moiety optionally linked to a second reactive group, optionally through a second linker moiety,8430131-WO-PCT(2) wherein a product composition comprising a plurality of product agents, each independently comprising a cellular receptor-binding moiety and an antibody-binding moiety optionally through a linker, is formed.Statistical analyses.

[0370] Normal distribution quantitative variables can be expressed as means and SDs and compared by an independent-sample t-test. The inventors used median and interquartile ranges for non-normally distributed variables and analyzed them with the Mann-Whitney U test. Categorical data was summarized by percentages. A two-sided p-value <0.05 was considered statistically significant. All statistical tests were performed using SPSS version 16.0.EXAMPLES

[0371] The invention is further illustrated by non-limiting examples.EXAMPLE 1Exemplary compositions of matterStructures and functions of some conjugated degraders (agents, MoDE™)30131-WO-PCT30131-WO-PCT30131-WO-PCT30131-WO-PCTEXAMPLE 2Exemplary IgM-related diseases or conditions30131-WO-PCT30131-WO-PCT30131-WO-PCT

[0372] Treatment with IgM degrader can be complementary to the previous standard-of-care, and potentially eligible for coadministration.Diagnosis of Waldenstrom macroglobulinaemia.

[0373] See International Prognostic Scoring System for Waldenstrom Macroglobulinaemia (ISSWM). An overview of the clinical presentations associated with IgM monoclonal gammopathy of clinical significance.

[0374] For diagnosis of Schnitzler's syndrome, see Girard et al., Frontiers in Oncology (2022).

[0375] RF factor is understood in the biomedical art to be a biomarker for several autoimmune diseases. RF factor is understood in the biomedical art to be pathogenic in rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome.9230131-WO-PCT

[0376] CNS symptoms include blurring or loss of vision, headache, ataxia, dementia, and stroke. Other Neurologic symptoms are weakness, neuropathy, low back pain, motor deficits, and parasthesias.

[0377] At presentation, the most common presenting features include weakness, fatigue, weight loss, and chronic oozing of blood from the nose or gums. During disease course, symptoms related to infiltration of hematopoietic or other tissues are anemia, enlarged lymph nodes, spleen, and liver. Symptoms related to the IgM monoclonal protein are blood hyperviscosity and peripheral neuropathy.

[0378] Diagnosis is based on bone marrow biopsy, serum IgM presence, and clinical symptoms. See Garcia-Sanz et al., British J. Haematol. (2001).

[0379] Blood tests: Elevated circulating IgM in serum of any size.

[0380] Bone marrow biopsy. >10% sample demonstrates infiltration lymphoplasmacytic lymphoma

[0381] Genetic testing: MYD88 L265P gene mutation has been identified in patientsPrevious standard-of-care for Waldenström macroglobulinaemia

[0382] Rituximab is associated with increase in IgM levels (IgM flare) which can cause hyperviscosity symptoms, worsen neuropathy, cryoglobulinemia, and cold agglutinin disease. Treatment modifications can reduce the risk of IgM flare. Plasmapheresis is a first-line therapy for hyperviscosity syndrome and may be used before anti-CD20 monoclonal antibody administration to prevent flare in patients with high IgM levels (typically >4000 mg / dL). Plasmapheresis before administration can prevent flares in patients with high IgM levels (typically >4000 mg / dL).

[0383] BTK inhibitors include ibrutinib, acalabrutinib, and zanubrutinib. A BTK inhibitor is an appropriate alternative for older patients and for others who are not eligible for or do not want systemic chemotherapy.

[0384] BDR = bortezomib, dexamethasone, rituximab.

[0385] BR= bendamustine rituximab.

[0386] DRC = dexamethasone rituximab, cyclophosphamide.

[0387] IR = ibrutinib plus rituximab.Diagnosis of MGUS

[0388] Monoclonal gammopathy of unknown significance (MGUS) is defined by a <10% plasma cell (or lymphoplasmacytic cell) bone marrow (BM) infiltrate with paraproteinaemia quantified at less than 30g / l. Patients have no symptoms or organ damage. IgM MGUS is characterized by progression to Waldenstrom macroglobulinaemia (WM) or light chain amyloidosis (ALA).9330131-WO-PCT

[0389] Patients with monoclonal gammopathy of undetermined significance of the IgM class (IgM MGUS) are at increased risk for WM, DLBCL, and mucosa-associated lymphoid tissue (MALT) lymphoma, as well as chronic lymphocytic leukemia.Previous standard-of-care for MGUS

[0390] The previous standard-of-care was watch and wait. See Yu et al., Cancer Research (2018), Alcoceba Int. J. Mol. Sci. (2022), and Dimopoulos et al. (American Society of Hematology), IWWM-7 consensus. Blood, 124:1404 (2014).EXAMPLE 3Surface plasmon resonance

[0391] Goal: Binding assay to assess and characterize potential IgM ligands to incorporate into molecules for ASGPR-mediated degradation.

[0392] Method: Surface plasmon resonance.

[0393] Biochemical / biophysical in vitro activity: Binding confirmation by surface plasmon resonance (SPR). The binding ability of the IgM-binding moiety can be measured by surface plasmon resonance (Biacore™ and IBIS-MX96 systems). IgM (ligand) is immobilized to a CM5 chip via amine coupling. IgM ligands (analytes) are dosed from 1 nM to 1 μM and characterized by single-cycle kinetics. First run, single cycle kinetics, steady-state KD(nM): 22. Second run, single cycle kinetics, steady-state KD(nM): 24. Persons having ordinary skill can assay commercial antibodies that bind to human Fc as a control. The theoretical Rmax indicates active surface (data quality control metric and indicator of possible immobilization method).Assay methods for kinetics

[0394] Single cycle kinetics (SCK) is a kinetics analysis that consists of sequential injections of increasing concentrations of the analyte over the ligand, without dissociation or regeneration between each sample concentration. The last (highest) analyte concentration is then followed by a single, long dissociation phase.

[0395] Multi-cycle kinetics (MCK) is a kinetic analysis that is performed with alternating cycles of analyte injections and surface regeneration.9430131-WO-PCT30131-WO-PCTpH scout for IgM SPR assays. Determining optimal pH forSPR ligand.

[0396] Assay details.

[0397] Ligand-. Human IgM (myeloma) (009-0107).

[0398] VHH analyte. Titrated by halves from 1000 nM to 0.9765625 nM.

[0399] 10 mM sodium acetate buffers: pH 5.5 (sample 5), pH 5 (sample 6), pH 4.5 (sample 7), and pH 4 (sample 8)

[0400] Conclusions: pH 5 looks good and is closest to what is physiologically relevant, proceeding with this buffer condition for IgM immobilization.9630131-WO-PCTEXAMPLE 4Binding Kinetics of compounds

[0401] Binding kinetics ofAGN7560 (repeat). The kinetics were performed with 180s association, 900s dissociation time and at two different temperatures 25°C and 30°C. Dose tested 20 nM to 0.02 nM (6-point, 4-fold dilution series)

[0402] Binding check of compound AGN7600 and AGN7562. This compound exhibits very weak binding with myeloma IgM.30131-WO-PCTEXAMPLE 5Ternary complex detection using TR-FRET observed with VHH and FcuRAssay setup

[0403] IgM- Alexa Fluor® 647 ChromPure™ Human IgM (myeloma), whole molecule #009-600-012 (C-term fluorophore) - 12.5 nM.

[0404] N-Avi-ASGPRl (148-291) construct 8 (ASGPRl-8)9.59 mg / mL (2023.06.21) - 25 nM.

[0405] Degrader. 3.3 pM- 100 pM.

[0406] Europium. Streptavidin-Eu cryptate (610SAKLB) - 2.5 nM.

[0407] Envision 2105- PerkinElmer 1050241.

[0408] Buffer: 25 mM Hepes pH 7.5, 150 mM NaCI, 5 mM CaCI2, 0.01% Tween-20, 1 mM DTT.

[0409] VHH EC50.

[0410] Fit to a four-parameter logistic curve (sigmoidal).Y = Bottom + (Top - Bottom) / (10HillSlope x (LogEC50) = 1

[0411] X: log of dose or concentration.

[0412] Y: Response, increasing as X increases.

[0413] Top and bottom: Plateaus in same units as Y. If you have subtracted off a baseline, consider constraining Bottom to zero.

[0414] logECso: same log units as X.

[0415] HillSlope: Slope factor or Hill slope, unitless.30131-WO-PCTResults: FcuR ternary complex detected with TR-FRET

[0416] Ternary complex formation observed.

[0417] Dose-dependent response seen with IgM FRET signal and ABT7519.

[0418] IgM 647 (009-600-012). FNHS labeled fluorophore. IgM from myeloma, pentamer (+)-chain).

[0419] FcpR binds proximal to C-terminus of IgM (Cu4 domain).

[0420] See Nyamboya, Sutton, & Calvert, Biochim Biophys Acta Proteins Proteom., 1868(1), 140266 (January 2020).30131-WO-PCT

[0421] Peptides were tested for binding with IgM mu chain and myeloma IgM. Eight unique peptides were tested for binding: ABT6851, ABT6852, ABT6853, ABT6855, ABT6856, ABT6857, ABT7020, and ABT7021. At immobilization level: ~3000 RU, no binding observed with all eight peptides. At immobilization level: ~6000 RU, no binding observed with all eight peptides.EXAMPLE 6ELISA analysis with monomeric IgM

[0422] Anti-IgM VHH exhibited binding to the native IgM Fc.

[0423] Peptides showed binding to IgM AA 1-453.

[0424] No binding was observed with the native IgM Fc.EXAMPLE 7MSD Protocol10030131-WO-PCT

[0425] Coating: (1) Prepare capture peptide / protein in PBS. (2) Dispense 50 mL into the bottom corner of each well. (3) Seal the plate and incubate overnight at 4°C without shaking.

[0426] Blocking: (1) Wash plate 3X with 150 mL Wash Buffer. (2) Add 150 ml / well of Blocker A. (3) Seal the plate and incubate for one hour with shaking (700 rpm) at room temperature.

[0427] Test antibody: (1) Wash plate 3X with 150 mL Wash Buffer. (2) Add 25 mL of test antibodies in Diluent 100. (3) Incubate for one hour with shaking.

[0428] Detection: (1) Wash plate 3X with 150 mL Wash Buffer. (2) Add 25 μL sulfo detection antibody in Diluent 100. (3) Shake at room temperature for one hour. (4) Wash 3X with 150 mL Wash Buffer (5) Add 150 mL of Gold Read Buffer A using the reverse pipetting technique. (6) Read immediately on Meso Sector S 600MM.EXAMPLE 8Internalization of IgM with VHH-based degraders

[0429] Procedure. (1) Seed HEK293T cells. (2) After sixteen hours, remove the media, then add media with labeled IgM. (3) Titrate in the degrader (ASGPR-HEK293T, 0.5 μg / μl IgM). (4) At about every four hours for the next twenty-four hours, image the cells using IncuCyte machine. (5) Quantify fluorescent signal within cells.

[0430] Results showed robust internalization of IgM, but not the negative controls.

[0431] Results: AGN7560 > ABT7561 » ABT7557 > ABT7558 ~ ABT7559.30131-WO-PCTEXAMPLE 9Rheumatoid Factor Assay

[0432] Rheumatoid Factor (RF) is a class of Ig that can bind the Fc portion of IgG. Among the different RF isotypes, IgM-RF is the most clinically used to estimate disease prognosis in rheumatoid arthritis. See Nicolo et al., Front. Immunol., 13, 1016263 (October 21, 2022).

[0433] Two approaches to obtain RF-IgM results: (1) Purify RF-IgM + IgG complex from plasma. Purify RF-IgM with IgM column followed by HPLC (bypass IgG column). (2) Incubate recombinant RF-IgM (RF61) with IgG.10230131-WO-PCTEXAMPLE 10IgM expression in vitro30131-WO-PCTEXAMPLE 11IgM ELISA protocol:

[0434] (1) Coating: Add 100 μl of samples: peptide / VHH (PC / NC) prepared in coating buffer to each well and cover.

[0435] (2) Incubate plate at 2 to 8°C overnight.

[0436] (3) Next day, bring all the reagents and coated plated to room temperature.

[0437] Blocking reagent used - IX DPBS + 0.05% Tween 20 + 5% skim milk

[0438] Sample diluent for primary and secondary - IX DPBS + 0.05% Tween 20 + 0.2% skim milk

[0439] (4) Dump the well contents. Wash the plate 3x using washing buffer, 300 pl / well. Blot and gently tap over absorbent paper to remove residual liquid.

[0440] (5) Add 200 pl / well of blocking buffer. Cover the plate and incubate at 37°C for two hours.

[0441] (6) Dump the well contents. Wash the plate 3x using washing buffer, 300 pl / well. Blot and gently tap over absorbent paper to remove residual liquid.

[0442] (7) Add 100 pl of samples prepared in sample diluent to the respective wells.

[0443] (8) Cover and incubate the plate at room temperature on a plate shaker set at 300 rpm for an hour.

[0444] (9) Dump the well contents. Wash the plate 4x using washing buffer, 300 pl / well. Blot and gently tap over absorbent paper to remove residual liquid.

[0445] (10) Add 100 pl / well of anti-IgM horse radish peroxidase conjugate diluted 1:6000 fold in sample diluent.

[0446] (11) Cover and incubate the plate at room temperature on a plate shaker set at 300 rpm for an hour.

[0447] (12) Dump the well contents. Wash the plate 4x using washing buffer, 300 pl / well. Blot and gently tap over absorbent paper to remove residual liquid.

[0448] (13) Add 100 pl / well of TMB substrate.

[0449] (14) Cover and incubate the plate at room temperature in dark for ~thirty minutes until reaction mixture in PC wells turns blue).

[0450] (15) Add 100 pl / well of stop solution (IN sulfuric acid).

[0451] (14) Read the absorbance in plate reader at 450-650nm wavelength.10430131-WO-PCT30131-WO-PCTEXAMPLE 12Testing of IgM Bifunctional Degraders

[0452] ABT7518 (125 amino acids, 13.6 kDa) (VHH) (SEQ ID NO: 212).

[0453] ABT7519 (113 amino acids, 12.5 kDa) (FcμR) (SEQ ID NO: 357).EXAMPLE 13Further IgM bifunctional degraders30131-WO-PCT107 30131-WO-PCT108 30131-WO-PCT30131-WO-PCT30131-WO-PCT30131-WO-PCTEXAMPLE 14Conjugation Process Protocol (AGN7557 (ABT7229-TBT6506)).Conjugation Protocol.

[0454] 1. Nanobody

[0455] 2. pH Adjustment. 20 mM histidine-acetate, 150 mM NaCI, pH 5.5 storage buffer adjusted by 10% 1M Tris pH 7.5.

[0456] 3. Reduction. TCEP / nanobody molar ratio: 1.5; DTPA added to 4 mM. Incubate at 22°C incubation for seventeen hours.

[0457] 4. Conjugation. Drug / nanobody molar ratio: 3. Incubate at 22°C for one hour.

[0458] 5. Purification. Buffer: phosphate-buffered saline pH 7.4. The reactions were purified by Amicon (8X10 k, 15 mL, 40 DV).

[0459] 6. Filtration using a 0.22 pm filter.

[0460] 7. Quality Control testing. NanoDrop spectrophotometry, size exclusion chromatography(SEC-HPLC), hydrophobic interaction chromatography (HIC-HPLC), and liquid chromatography / mass spectroscopy, endotoxin testing, and free drug testing were performed on the samples.

[0461] Size exclusion chromatography, hydrophobic interaction chromatography, and liquid chromatography / mass spectroscopy were performed on the samples

[0462] 8. Aliquoting and freezing.11230131-WO-PCT30131-WO-PCT114 30131-WO-PCTEXAMPLE 15Conjugation Process Protocol (AGN7558 (ABT7231-TBT6506)).Chromatography

[0463] Column: Luna Omega 1.6 μm Polar C18 100A.

[0464] Mobile Phase: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile.

[0465] 100.

[0466] Where:

[0467] BAR : drug to antibody ratio.

[0468] concentration of free drug in anti-drug conjugate (pM).

[0469] concentration of protein in 0.4 mg / mL anti-drug conjugate (pM).

[0470] 11530131-WO-PCTEXAMPLE 16Conjugation Process Protocol (AGN7559 (ABT7232-TBT6506)).>30131-WO-PCTChromatography

[0471] Column: Luna Omega 1.6 μm Polar C18 100A.

[0472] Mobile Phase: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile.

[0473] 100.

[0474] Where:

[0475] DAR: drug to antibody ratio.

[0476] concentration of free drug in anti-drug conjugate (pM).

[0477] concentration of protein in 0.4 mg / mL anti-drug conjugate (pM).

[0478] 30131-WO-PCT

[0479] Note: Hydrolysis of AGN7559 produces AGN17420.EXAMPLE 17Conjugation Process Protocol (AGN7562 (ABT7323-TBT6544)).

[0480] Antibody.

[0481] Concentration adjustment. No concentration adjustment.

[0482] Conjugation. Reagent / antibody molar ratio: 8; Sortase / antibody molar ratio: 0.01.

[0483] Analysis. 4°C incubation until get targeting BAR value.Purification by Amicon. Amicon Ultra (10 kDa, 15 mL). Buffer: Phosphate-buffered saline pH 7.4, 5% DMSO for 50 DV follow by buffer exchange to phosphate-buffered saline, pH 7.4 for 10 DV.

[0484] Filtration using a 0.22 pm filter.

[0485] Quality Control testing. NanoDrop spectrophotometry, size exclusion chromatography(SEC- HPLC), hydrophobic interaction chromatography (HIC-HPLC), and liquid chromatography / mass spectroscopy, endotoxin testing, and free drug testing were performed on the samples.

[0486] Aliquoting and freezing.11830131-WO-PCT30131-WO-PCTÄKTA™ profile (high-performance liquid chromatography by Cytiva) for AGN7562 (ABT7323-TBT6544)

[0487] Column: HiTrap excel, 1 mL

[0488] Equilibration buffer: 20 mM PB, 500 mM NaCI, 10 mM imidazole, pH 7.4

[0489] Elution buffer: 0.2 M NaOH

[0490] Flow rate: 1 mL / min

[0491] The conjugate and monoclonal antibody were flowed through during the loading process.

[0492] The sortase was eluted by 0.2M NaOH.

[0493] Pooled flow through together and performed buffer exchange to phosphate-buffered saline pH 7.4, 5% DMSO for 50 DV follow by buffer exchange to phosphate-buffered saline pH 7.4, 2 mM EDTA for 10 DV.

[0494] The free drug residual is semi-quantitated by LC-MS. (1) Prepare standard drug concentration (1.0%, 2.0%, 5.0%). (2) Precipitate the anti-drug conjugate with solvent I, final concentration as 0.4 mg / mL; remove the supernatant for LC-MS analysis.30131-WO-PCT

[0496] Where:

[0497] BAR : drug to antibody ratio.

[0498] Cfreedrug: concentration of free drug in anti-drug conjugate (pM)

[0499] Cprotein: concentration of protein in 0.4 mg / mL anti-drug conjugate (pM)

[0500] AKTA profile for AGN7562 (ABT7323-TBT6544)

[0501] Column: HiTrap excel, 5 mL

[0502] Equilibration buffer: 20 mM PB, 500 mM NaCI, 10 mM imidazole, pH 7.4

[0503] Elution buffer: 0.2 M NaOH

[0504] Flow rate: 5 mL / min

[0505] The conjugate and mAb were flowed through during the loading process.

[0506] The unconjugated protein and sortase were eluted by 0.2M NaOH.

[0507] Pooled flow through together and performed buffer exchange to phosphate-buffered saline, pH 7.4, 5% DMSO for 50 DV follow by buffer exchange to phosphate-buffered saline, pH 7.4, 2 mM EDTA for 10 DV.

[0508] Size exclusion chromatography, hydrophobic interaction chromatography, and liquid chromatography / mass spectroscopy were performed on the samples.

[0509] BAR = (1×AbundanceBAR1+ 2 × AbundanceBAR2+ ••• + n × AbundanceBARn) / (AbundanceBAR0+ ••• + AbundanceBARn).12130131-WO-PCT

[0510] Free Drug Assay for AGN7562 (ABT7323-TBT6544). The free drug residual is semiquantitated by LC-MS. (1) Prepare standard drug concentration (1.0%, 2.0%, 5.0%). (2) Precipitate the anti-drug conjugate with solvent I, final concentration as 0.4 mg / mL; remove the supernatant for LC-MS analysis. The free drug residual of AGN7562 (ABT7323-TBT6544) is <1.0%.

[0511]

[0512] Where:

[0513] BAR : drug to antibody ratio.12230131-WO-PCT

[0514] Cfreedrug: Concentration of free drug in anti-drug conjugate (pM).

[0515] Cprotein: Concentration of protein in 0.4 mg / mL anti-drug conjugate (pM).

[0516] Cprotein = 0.4 / MWproteinBulk Conjugation Process Protocol (AGN7562 (ABT7323-TBT6544))

[0517] Antibody.

[0518] Concentration adjustment. No concentration adjustment.

[0519] Conjugation. Reagent / antibody molar ratio: 8. Sortase / antibody molar ratio: 0.01.

[0520] Analysis. 4°C incubation until get targeting BAR value..

[0521] Purification by Amicon. Amicon Ultra (10 kDa, 15 mL). Buffer: Phosphate-buffered saline, pH 7.4, 5% DMSO for 50 DV follow by buffer exchange to phosphate-buffered saline, pH 7.4, 2 mM EDTA for 10 DV.

[0522] Filtration using a 0.22 pm filter.

[0523] Quality Control testing. NanoDrop spectrophotometry, size exclusion chromatography(SEC- HPLC), hydrophobic interaction chromatography (HIC-HPLC), and liquid chromatography / mass spectroscopy, endotoxin testing, and free drug testing were performed on the samples.

[0524] Aliquoting and freezing.12330131-WO-PCT30131-WO-PCTResidual uABT(Cpd2378) standard curve

[0525] Column: Luna Omega 1.6 pm Polar C18100A.

[0526] Mobile phase: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile.

[0527] % mol / mol — CResidual leaving group) / (Cprotein) * 100%.AKTA profile for AGN7562 (ABT7323-TBT6544)

[0528] Column: HiTrap excel, 5 mL

[0529] Equilibration buffer: 20 mM PB, 500 mM NaCI, 10 mM imidazole, pH 7.4

[0530] Elution buffer: 0.2 M NaOH

[0531] Flow rate: 5 mL / min

[0532] The conjugate and monoclonal antibody were flowed through during the loading process.

[0533] The unconjugated protein and sortase were eluted by 0. 2M NaOH.

[0534] Pooled flow through together and performed buffer exchange to phosphate-buffered saline, pH 7.4, 5% DMSO for 50 DV follow by buffer exchange to phosphate-buffered saline, pH 7.4, 2 mM EDTA for 10 DV.

[0535] Size exclusion chromatography, hydrophobic interaction chromatography, and liquid chromatography / mass spectroscopy were performed on the samples.

[0536] BAR = (1×AbundanceBAR1+ 2 × AbundanceBAR2+ ••• + n × AbundanceBARn) / (AbundanceBAR0+ ••• + AbundanceBARn)

[0537] Free Drug Assay for AGN7562 (ABT7323-TBT6544). The free drug residual is semiquantitated by LC-MS. (1) Prepare standard drug concentration (1.0%, 2.0%, 5.0%). (2) Precipitate the antibody-drug conjugate with solvent I, final concentration as 0.4 mg / mL; remove the supernatant for LC-MS analysis.

[0538] The free drug residual of AGN7562 (ABT7323-TBT6544) is <1.0%.30131-WO-PCT

[0539] % mol / mol= Cfree drug / (Cfree drug+BAR × Cprotein) ×100

[0540] Where:

[0541] BAR : drug to antibody ratio

[0542] Cfreedrug: concentration of free drug in anti-drug conjugate (pM)

[0543] Cprotein: concentration of protein in 0.4 mg / mL anti-drug conjugate (pM)

[0544] Cprotein = 0.4 / MWprotein

[0545] Size exclusion chromatography and liquid chromatography / mass spectroscopy were performed on the samples.EXAMPLE 18Conjugation Process Protocol (AGN7561 (ABT7322-TBT3070)).

[0546] Antibody.

[0547] Concentration adjustment. Buffer exchange to conjugation buffer. Adjust the concentration to 10 mg / mL.

[0548] Conjugation. Reagent / antibody molar ratio: 4.0.

[0549] Analysis. 25°C incubation until get targeting BAR value..

[0550] Purification by UFDF. TFF ultrafiltration (30 kDa, 0.11 m2). Buffer: phosphate-buffered saline, pH 7.4, 10% DMSO for 50 DV, followed by phosphate-buffered saline, pH 7.4 for 10 DV.

[0551] Purification byAmicon. Concentrate to 7-9mg / mL by Amicon (30 kDa).

[0552] Filtration using a 0.22 pm filter.

[0553] Quality Control testing. NanoDrop spectrophotometry, size exclusion chromatography(SEC- HPLC), hydrophobic interaction chromatography (HIC-HPLC), and liquid chromatography / mass spectroscopy, endotoxin testing, and free drug testing were performed on the samples.

[0554] Aliquoting and freezing.12630131-WO-PCTConstruction of a residual uABT (Cpd2378) standard curve

[0555] Column: Luna Omega 1.6 pm Polar C18100A

[0556] Mobile Phase: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile

[0557] 12730131-WO-PCTConstruction of residual reagent (TBT3070) standard curve

[0558] Column: Luna Omega 1.6 pm Polar C18100A

[0559] Mobile Phase: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile

[0560] % mol / mol— (Cfree Payload) / (Cfree Payload + DAR X Cprotein) * 100%Residual payload (cpd1777) standard curve.

[0561] Column: Luna Omega 1.6 pm Polar C18100A.

[0562] Mobile Phase: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile.

[0563] % mol / mol— (Cfree Payload) / (Cfree Payload + DAR X Cprotein) * 100%.12830131-WO-PCTConjugation Process Protocol

[0564] Antibody.

[0565] Concentration adjustment. Buffer exchange to conjugation buffer. Adjust the concentration to 10 mg / mL.

[0566] Conjugation. Reagent / antibody molar ratio: 4.0.

[0567] Analysis. 25°C incubation until get targeting BAR value.

[0568] Purification by UFDF. TFF ultrafiltration (30 kDa, 0.11 m2). Buffer: phosphate-buffered saline, pH 7.4, 10% DMSO for 50 DV, followed by phosphate-buffered saline, pH 7.4 for 10 DV.

[0569] Purification byAmicon. Concentrate to 7-9 mg / mL by Amicon (30 kDa).

[0570] Filtration using a 0.22 pm filter.

[0571] Quality Control testing. NanoDrop spectrophotometry, size exclusion chromatography(SEC- HPLC), hydrophobic interaction chromatography (HIC-HPLC), and liquid chromatography / mass spectroscopy, endotoxin testing, and free drug testing were performed on the samples.

[0572] Aliquoting and freezing.30131-WO-PCTResidual reagent (TBT3070) standard curve

[0573] Column: Luna Omega 1.6 |im Polar C18100A.130 30131-WO-PCT

[0574] Mobile phase: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile.

[0575] % mol / mol— (Cfree Payload) / (Cfree Payload + DAR X Cprotein) * 100%.Residual payload (cpd1777) standard curve

[0576] Column: Luna Omega 1.6 |im Polar C18100A.

[0577] Mobile phase: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile.

[0578] % mol / mol— (Cfree Payload) / (Cfree Payload + DAR X Cprotein) * 100%.EXAMPLE 19Conjugation Process Protocol (AGN7560 (ABT7233-TBT3070)).

[0579] Antibody.

[0580] Concentration adjustment. No concentration adjustment.

[0581] Conjugation. Reagent / Ab. molar ratio: 8. Sortase / antibody molar ratio: 0.01.

[0582] Analysis. 4°C incubation until get targeting BAR value.13130131-WO-PCTPurification by Amicon. Amicon Ultra (10 kDa, 15 mL). Buffer: Phosphate-buffered saline, pH 7.4, 5% DMSO for 50 DV follow by buffer exchange to phosphate-buffered saline, pH 7.4, 2mM EDTA for 10 DV.

[0583] Filtration using a 0.22 pm filter.

[0584] Quality Control testing. NanoDrop spectrophotometry, size exclusion chromatography(SEC-HPLC), hydrophobic interaction chromatography (HIC-HPLC), and liquid chromatography / mass spectroscopy, endotoxin testing, and free drug testing were performed on the samples.

[0585] Aliquoting and freezing.Residual reagent (TBT3070) standard curve

[0586] Column: Luna Omega 1.6 |im Polar C18100A

[0587] Mobile phase: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile

[0588] % mol / mol— (Cfree Payload) / (Cfree Payload + DAR X Cprotein) * 100%30131-WO-PCTConstruction of residual payload (cpd1777) standard curve

[0589] Column: Luna Omega 1.6 pm Polar C18100A

[0590] Mobile phase: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile

[0591] % mol / mol— (Cfree Payload) / (Cfree Payload + DAR X Cprotein) * 100%

[0592] Size exclusion chromatography, hydrophobic interaction chromatography, and liquid chromatography / mass spectroscopy were performed on the samples.

[0593] BAR = (lxAbundanceBARi + 2 x AbundanceBAR2+ ••• + n x AbundanceBARn) / (AbundanceBARo + ••• + AbundanceBARn)Construction of residual uABT (Cpd2378) standard curve

[0594] Column: Luna Omega 1.6 pm Polar C18100A.

[0595] Mobile phase: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile.

[0596] % mol / mol — CResidual leaving group) / (Cprotein) * 100%.EXAMPLE 20Conjugation Process Protocol (AGN7600 (ABT7316-TBT6506)).

[0597] Antibody.

[0598] Concentration adjustment. Buffer exchange to conjugation buffer. Adjust the concentration to 4.45 mg / mL.

[0599] Reduction. TCEP / Ab. ratio: 1.5.

[0600] Centrifugation. 7,000 ref for ten minutes (16,000 ref for minutes at pilot_2).

[0601] Conjugation. Reagent / antibody ratio: 3 and incubate at 22°C for one hour.13330131-WO-PCT

[0602] Purification by Amicon. Buffer exchange to phosphate-buffered saline, pH 7.4, by Amicon for 30 DV.

[0603] Purification by ÄKTA. Column: Superdex 200, 16 / 600 mm. Elution buffer: Phosphate-buffered saline, pH 7.4.

[0604] Filtration using a 0.22 pm filter.

[0605] Quality Control testing. NanoDrop spectrophotometry, size exclusion chromatography(SEC- HPLC), hydrophobic interaction chromatography (HIC-HPLC), and liquid chromatography / mass spectroscopy, endotoxin testing, and free drug testing were performed on the samples.

[0606] Aliquoting and freezing.30131-WO-PCTConstruction of a residual reagent (TBT6506) standard curve

[0607] Column: Luna Omega 1.6 pm Polar C18100A.

[0608] Mobile Phase: A: 0.1% TFA in H2O; B: 0.1% TFA in CAN.

[0609] mol / mol — (Cfree Reagent) / ( Cfree Reagent " I" BAR ^Cprotein) 100%.30131-WO-PCTEXAMPLE 21Pharmacodynamic assays

[0610] Several bifunctional degraders, including AGN7559 and AGN7560 were tested in pharmacodynamic assays. The bifunctional degraders and human IgM were administered intravenously or subcutaneously to NOD SCID mice (n=3 per timepoint.) Blood was collected in K3-EDTA tubes at 0 minutes, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, and 8 hours. Plasma was isolated. Results are shown in FIG. 6, FIG. 7, FIG. 8, and FIG. 9.EXAMPLE 22Catalytic IgM degrader recycling constructs

[0611] The inventors produced a catalytic version of it using FcRn binding domains. As a proof-of-concept, the inventors made a VHH fusion to an affibody that had been engineered with pH dependent binding and could allow for degrader recycling.

[0612] The inventors used versions of PT-0137 to make the constructs. The sequence can be VDAKYAKEQDAAAHEIRWLPNLTFDQRVAFIHKLADDPSQSSELLSEAKKLNDSQAPK (SEQ ID. NO: 412). See TABLE 79 and TABLE 81 below. See also, U. S. Pat. No. 9,975,943, SEQ ID NO: 707 therein.30131-WO-PCT

[0613] Additional guidance useful making recycling constructs with pH-dependent binding to FcRn can be found in Seijsing et al., Applied Biological Sciences, 111 (48), 17110-17115 (November 18, 2014).EQUIVALENTS

[0614] Persons having ordinary skill in the biomedical art will recognize or be able to determine using no more than routine experimentation many equivalents to the specific procedures described in this specification. These equivalents are within the scope of this invention and are covered by the following claims. For example, pharmaceutically acceptable salts other than those specifically disclosed in the description and Examples in this specification can be employed. Furthermore, it is intended that specific items within lists of items, or subset groups of items within larger groups of items, can be combined with other specific items, subset groups of items, or larger groups of items whether there is a specific disclosure in this specification identifying such a combination.REFERENCES

[0615] Persons having ordinary skill in the biomedical art can use these patents, patent applications, and scientific references as guidance to predictable results when making and using the invention.Patent literature

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[0729] Throughout this specification, several publications are referenced by author name and date or by patent or patent publication number. The disclosures of these publications are incorporated in their entireties by reference into this specification to describe the state of the art more fully as known to persons having ordinary skill in the biomedical art as of the date of the invention described and claimed in this specification. However, the citation of a reference in this specification should not be construed as an acknowledgment that this reference is prior art to the present invention.

[0730] All patents and publications cited throughout this specification are incorporated by reference to disclose and describe the materials and methods that might be used with the technologies14530131-WO-PCTdescribed in this specification. The publications discussed are provided only for their disclosure before the filing date. They should not be construed as an admission that the inventors may not antedate this disclosure under prior invention or for any other reason. If there is an apparent discrepancy between a prior patent or publication and the description provided in this specification, the specification (including any definitions) and claims shall control. All statements about the date or contents of these documents are based on the information available to the applicants. These statements are no admission to the correctness of the dates or contents of these documents. The publication dates in this specification may differ from the actual publication dates. If there is an apparent discrepancy between a publication date in this specification and the actual publication date supplied by the publisher, the actual publication date shall control.14630131-WO-PCTSEQUENCE LISTINGSequence Number ( ID): 1Length: 330Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 330> mol type, protein> organism, Homo sapienssResidues:ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPBPVTVS WNSGALTSGV HTFPAVLQSS 60 GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 120 PSVFLFPPKP KDTLMISRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 180 STYRVVSVLT VLHQDWINGK EYKCRVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 240 LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 300 QQGNVFSCSV MHEATHNHYT QKSLSLSPGK 330Sequence Number ( ID): 2Length: 326Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 326> mol type, protein> organism, Homo sapienssResidues:ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPBPVTVS WNSGALTSGV HTFPAVLQSS 60 GLYSLSSWT VPSSNFGTQT YTCNVDHKPS NTKVDKTVER KCCVECPPCP APPVAGPSVF 120 LFPPKPKDTL MISRTPEVTC VWDVSHEDP EVQFNWYVDG VEVHNAKTKP REBQFNSTFR 180 WSVLTVLHQ DWLNGKEYKC KVSNKGLPAP IEKTISKTKG OPREPQVYTL PPSREEMTKN 240 QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPMLDSD GSFFLYSKLT VDKSRWQQGN 300 VFSCSVMHEA THNHYTQKSL SLSPGK 326Sequence Number ( ID): 3Length: 327Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 327> mol type, protein14730131-WO-PCT> organism, Homo sapienssResidues:ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPBPVTVS WNSGALTSGV HTFPAVLQSS 60 GLYSLSSWT VPSSSLGTKT YTCNVDHKPS NTKVDKRVES KTGPPCPSCP APEFLGGPSV 120 FLFPPKPKDT LMISRTPEVT CVWDVSQED PEVQFNWYVD GVEVHNAKTK PREEQ FNSTY 180 RVVSVLTVLH QDWINGKEYK CKVSNKGLPS SIEKTISKAK GOPREPQVYT LPPSQEEMTK 240 NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSRL TVDKSRWQEG 300 NVFSCSVMHE ATHNHYTQKS LSLSLGK 327Sequence Number ( ID): 4Length: 131Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 131> mol type, protein> organism, synthetic construct- REGION, 26.. 32> note, CDR1- REGION, 52.. 57> note, CDR2- REGION, 99.. 114> note, CDR3Residues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSSACPGC A 131Sequence Number ( ID): 5Length: 24Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 24> mol type, protein> organism, Homo sapienssResidues:ADYEKHKVYA CEVTHQGLSS PVTK14830131-WO-PCTSequence Number (ID): 6Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:ALPAPIE 7Sequence Number (ID): 7Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:APIEKTI 7Sequence Number (ID): 8Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:APSVTLF 7Sequence Number ( ID): 9Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienss14930131-WO-PCTResidues:ASTRESGSequence Number (ID): 10Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:ATLVCLI 7Sequence Number (ID): 11Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:AWFAYWG 7Sequence Number (ID): 12Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:AWHQQQP 7Sequence Number ( ID): 13Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 715030131-WO-PCT> mol type, protein> organism, Homo sapienssResidues:AYWGQGTSequence Number (ID): 14Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:CKVSNKA 7Sequence Number (ID): 15Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:CSFSGFS 7Sequence Number (ID): 16Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:CSVMHEA 7Sequence Number ( ID): 17Length: 7Molecule Type: AA15130131-WO-PCTFeatures Location / Qualifiers:- source, 1..7> mol type, protein> organism, Homo sapienssResidues:CSVMHEGSequence Number (ID): 18Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:DELTKNQ 7Sequence Number (ID): 19Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:DGAWFAY 7Sequence Number ( ID): 20Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:DGKEYKC 715230131-WO-PCTSequence Number (ID): 21Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:DGSFFLY 7Sequence Number (ID): 22Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:DKSRWQE 7Sequence Number (ID): 23Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:DLAVYFC 7Sequence Number ( ID): 24Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienss15330131-WO-PCTResidues:DSDGSFFSequence Number (ID): 25Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:DVSHEDP 7Sequence Number (ID): 26Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:EDLAVYF 7Sequence Number (ID): 27Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:EGLHNHY 7Sequence Number ( ID): 28Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 715430131-WO-PCT> mol type, protein> organism, Homo sapienssResidues:EGNVFSCSequence Number (ID): 29Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:EKTISKA 7Sequence Number (ID): 30Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:EPQVYTL 7Sequence Number (ID): 31Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:ERGLRYL 7Sequence Number ( ID): 32Length: 7Molecule Type: AA15530131-WO-PCTFeatures Location / Qualifiers:- source, 1..7> mol type, protein> organism, Homo sapienssResidues:ERILTISSequence Number (ID): 33Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:ESGVPDR 7Sequence Number (ID): 34Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:EWLAHIW 7Sequence Number ( ID): 35Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:EYKCKVS 715630131-WO-PCTSequence Number (ID): 36Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:FAYWGQG 7Sequence Number (ID): 37Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:FFLYSKL 7Sequence Number (ID): 38Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:FLFPPKP 7Sequence Number ( ID): 39Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienss15730131-WO-PCTResidues:FLYSKLTSequence Number (ID): 40Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:FNWYVDG 7Sequence Number (ID): 41Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:FPPKPKD 7Sequence Number (ID): 42Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:FSGFSLT 7Sequence Number ( ID): 43Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 715830131-WO-PCT> mol type, protein> organism, Homo sapienssResidues:GASVKVTSequence Number (ID): 44Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:GAVTVAW 7Sequence Number (ID): 45Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:GAWFAYW 7Sequence Number (ID): 46Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:GFSLTTY 7Sequence Number ( ID): 47Length: 7Molecule Type: AA15930131-WO-PCTFeatures Location / Qualifiers:- source, 1..7> mol type, protein> organism, Homo sapienssResidues:GIGVGWISequence Number (ID): 48Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:GKEYKCK 7Sequence Number (ID): 49Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:GKGLEWL 7Sequence Number ( ID): 50Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:GLEWLAH 716030131-WO-PCTSequence Number (ID): 51Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:GLHNHYT 7Sequence Number (ID): 52Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:GNVFSCS 7Sequence Number (ID): 53Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:GPSVFLF 7Sequence Number ( ID): 54Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienss30131-WO-PCTResidues:GQPREPQ 7Sequence Number (ID): 55Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:GQSPKLL 7Sequence Number (ID): 56Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:GSFFLYS 7Sequence Number (ID): 57Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:GSGSGTD 7Sequence Number ( ID): 58Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 716230131-WO-PCT> mol type, protein> organism, Homo sapienssResidues:GSGTDFTSequence Number (ID): 59Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:GSHTRGD 7Sequence Number (ID): 60Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:GVGWIRQ 7Sequence Number (ID): 61Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:GVPDRFT 7Sequence Number ( ID): 62Length: 7Molecule Type: AA16330131-WO-PCTFeatures Location / Qualifiers:- source, 1..7> mol type, protein> organism, Homo sapienssResidues:GVQVHNASequence Number (ID): 63Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:HEGLHNH 7Sequence Number (ID): 64Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:HQNWLDG 7Sequence Number ( ID): 65Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:IEKTISK 716430131-WO-PCTSequence Number (ID): 66Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:IGVGWIR 7Sequence Number (ID): 67Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:ISKAKGQ 7Sequence Number (ID): 68Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:KALPAPI 7Sequence Number ( ID): 69Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, Homo sapienss30131-WO-PCTResidues:KATLVCLISD FYPGAV 16Sequence Number (ID): 70Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:KCKVSNK 7Sequence Number (ID): 71Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:KEYKCKV 7Sequence Number (ID): 72Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:KFNWYVD 7Sequence Number ( ID): 73Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 716630131-WO-PCT> mol type, protein> organism, Homo sapienssResidues:KGLEWLASequence Number (ID): 74Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:KLLIYWA 7Sequence Number (ID): 75Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:KNQVSLT 7Sequence Number (ID): 76Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:KNYLAWY 7Sequence Number ( ID): 77Length: 7Molecule Type: AA16730131-WO-PCTFeatures Location / Qualifiers:- source, 1..7> mol type, protein> organism, Homo sapienssResidues:KSLSLSPSequence Number (ID): 78Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:KSRWQEG 7Sequence Number (ID): 79Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:KTISKAK 7Sequence Number ( ID): 80Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:KTKPREQ 716830131-WO-PCTSequence Number (ID): 81Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:KVSNKAL 7Sequence Number (ID): 82Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:LDGKEYK 7Sequence Number (ID): 83Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:LDSDGSF 7Sequence Number ( ID): 84Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienss16930131-WO-PCTResidues:LEWLAHISequence Number (ID): 85Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:LFPPKPK 7Sequence Number (ID): 86Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:LHNHYTQ 7Sequence Number (ID): 87Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:LHQNWLD 7Sequence Number ( ID): 88Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 717030131-WO-PCT> mol type, protein> organism, Homo sapienssResidues:LIYWASTSequence Number (ID): 89Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:LLIYWAS 7Sequence Number (ID): 90Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:LMKINSD 7Sequence Number (ID): 91Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:LPAPIEK 7Sequence Number ( ID): 92Length: 7Molecule Type: AA17130131-WO-PCTFeatures Location / Qualifiers:- source, 1..7> mol type, protein> organism, Homo sapienssResidues:LTCSFSGSequence Number (ID): 93Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:LTKNQVS 7Sequence Number (ID): 94Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:LTVLHQN 7Sequence Number ( ID): 95Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:MHEALHN 717230131-WO-PCTSequence Number (ID): 96Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:MHEGLHN 7Sequence Number (ID): 97Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:NAKTKPR 7Sequence Number (ID): 98Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:NQVSLTC 7Sequence Number ( ID): 99Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienss17330131-WO-PCTResidues:NSTYRVV 7Sequence Number (ID): 100Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:NVFSCSV 7Sequence Number (ID): 101Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:NWLDGKE 7Sequence Number (ID): 102Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:NWYVDGV 7Sequence Number ( ID): 103Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 717430131-WO-PCT> mol type, protein> organism, Homo sapienssResidues:NYKTTPPSequence Number (ID): 104Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:NYLAWYQ 7Sequence Number (ID): 105Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:PAPIEKT 7Sequence Number (ID): 106Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:PDRFSGS 7Sequence Number ( ID): 107Length: 7Molecule Type: AA17530131-WO-PCTFeatures Location / Qualifiers:- source, 1..7> mol type, protein> organism, Homo sapienssResidues:PGQSPKLSequence Number (ID): 108Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:PIEKTIS 7Sequence Number (ID): 109Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:PKLLIYW 7Sequence Number ( ID): 110Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:PPSRDEL 717630131-WO-PCTSequence Number (ID): 111Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:PPSREEM 7Sequence Number (ID): 112Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:PQVYTLP 7Sequence Number (ID): 113Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:PREPQVY 7Sequence Number ( ID): 114Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienss17730131-WO-PCTResidues:PSRDELTSequence Number (ID): 115Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:PSREEMT 7Sequence Number (ID): 116Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:PSVFLFP 7Sequence Number (ID): 117Length: 20Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 20> mol type, protein> organism, Homo sapienssResidues:PVPSTPPTPS PSTPPTPSPS 20Sequence Number ( ID): 118Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 717830131-WO-PCT> mol type, protein> organism, Homo sapienssResidues:QKSLSLSSequence Number (ID): 119Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:QNWLDGK 7Sequence Number (ID): 120Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:QPREPQV 7Sequence Number (ID): 121Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:QSPKLLI 7Sequence Number ( ID): 122Length: 7Molecule Type: AA17930131-WO-PCTFeatures Location / Qualifiers:- source, 1..7> mol type, protein> organism, Homo sapienssResidues:QSVLYSSSequence Number (ID): 123Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:QVSLTCLSequence Number (ID): 124Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:QVYTLPPSequence Number ( ID): 125Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:QYNSTYR18030131-WO-PCTSequence Number (ID): 126Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:REPQVYT 7Sequence Number (ID): 127Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:RESGVPD 7Sequence Number (ID): 128Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:RGYDSYA 7Sequence Number ( ID): 129Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienss30131-WO-PCTResidues:RVVSVLTSequence Number (ID): 130Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:RWQEGNV 7Sequence Number (ID): 131Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:SCSVMHE 7Sequence Number (ID): 132Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:SDGSFFL 7Sequence Number ( ID): 133Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 718230131-WO-PCT> mol type, protein> organism, Homo sapienssResidues:SFFLYSKSequence Number (ID): 134Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:SFSGFSL 7Sequence Number (ID): 135Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:SGFSLTT 7Sequence Number (ID): 136Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, Homo sapienssResidues:SGLQAEDEAD YYCSSY 16Sequence Number ( ID): 137Length: 7Molecule Type: AA18330131-WO-PCTFeatures Location / Qualifiers:- source, 1..7> mol type, protein> organism, Homo sapienssResidues:SGSGTDFSequence Number (ID): 138Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:SGVPDRF 7Sequence Number (ID): 139Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:SLSLSPG 7Sequence Number ( ID): 140Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:SLTCLVK 718430131-WO-PCTSequence Number (ID): 141Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:SNKALPA 7Sequence Number (ID): 142Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:SPKLLIY 7Sequence Number (ID): 143Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:SQSVLYS 7Sequence Number ( ID): 144Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienss18530131-WO-PCTResidues:SREEMTKSequence Number (ID): 145Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:SRWQEGN 7Sequence Number (ID): 146Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:SSQSVLY 7Sequence Number (ID): 147Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:STRESGV 7Sequence Number ( ID): 148Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 718630131-WO-PCT> mol type, protein> organism, Homo sapienssResidues:SVFLFPPSequence Number (ID): 149Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:SVLTVLH 7Sequence Number (ID): 150Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:SVMHEAL 7Sequence Number (ID): 151Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:SVMHEGL 7Sequence Number ( ID): 152Length: 7Molecule Type: AA18730131-WO-PCTFeatures Location / Qualifiers:- source, 1..7> mol type, protein> organism, Homo sapienssResidues:SYLSLTPSequence Number (ID): 153Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:SYSCQVT 7Sequence Number (ID): 154Length: 13Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 13> mol type, protein> organism, Homo sapienssResidues:TCPPCPAPEL LGG 13Sequence Number ( ID): 155Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:TCSFSGF 718830131-WO-PCTSequence Number (ID): 156Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:TEDLAVY 7Sequence Number (ID): 157Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:TGSGSGT 7Sequence Number (ID): 158Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, Homo sapienssResidues:TGTSSDVGGY NYVSWY 16Sequence Number ( ID): 159Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienss18930131-WO-PCTResidues:TISKAKGSequence Number (ID): 160Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:TKNQVSL 7Sequence Number (ID): 161Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:TLPPSRE 7Sequence Number (ID): 162Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:TRESGVP 7Sequence Number ( ID): 163Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 719030131-WO-PCT> mol type, protein> organism, Homo sapienssResidues:TVLHQNWSequence Number (ID): 164Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:TYRVVSV 7Sequence Number (ID): 165Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:TYYCARM 7Sequence Number (ID): 166Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:VDGVQVH 7Sequence Number ( ID): 167Length: 7Molecule Type: AA19130131-WO-PCTFeatures Location / Qualifiers:- source, 1..7> mol type, protein> organism, Homo sapienssResidues:VFLFPPKSequence Number (ID): 168Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:VFSCSVM 7Sequence Number (ID): 169Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:VHNAKTK 7Sequence Number ( ID): 170Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:VKFNWYV 719230131-WO-PCTSequence Number (ID): 171Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:VLHQNWL 7Sequence Number (ID): 172Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:VLTVLHQ 7Sequence Number (ID): 173Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:VMHEALH 7Sequence Number ( ID): 174Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienss19330131-WO-PCTResidues:VMHEGLH 7Sequence Number (ID): 175Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:VPDRFTG 7Sequence Number (ID): 176Length: 19Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 19> mol type, protein> organism, Homo sapienssResidues:VPSTPPTPSP STPPTPSPS 19Sequence Number (ID): 177Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:VSLTCLV 7Sequence Number ( ID): 178Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 719430131-WO-PCT> mol type, protein> organism, Homo sapienssResidues:VSNKALPSequence Number (ID): 179Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:VSVLTVL 7Sequence Number (ID): 180Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:VVSVLTV 7Sequence Number (ID): 181Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:VYTLPPS 7Sequence Number ( ID): 182Length: 7Molecule Type: AA19530131-WO-PCTFeatures Location / Qualifiers:- source, 1..7> mol type, protein> organism, Homo sapienssResidues:WASTRESSequence Number (ID): 183Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:WFAYWGQ 7Sequence Number (ID): 184Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:WLAHIWW 7Sequence Number ( ID): 185Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:WLDGKEY 719630131-WO-PCTSequence Number (ID): 186Length: 6Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 6> mol type, protein> organism, Homo sapienssResidues:WQEGNV 6Sequence Number (ID): 187Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:WYVDGVQ 7Sequence Number (ID): 188Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:YAASSYL 7Sequence Number ( ID): 189Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienss19730131-WO-PCTResidues:YCQTWGSSequence Number (ID): 190Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:YDSYAIA 7Sequence Number (ID): 191Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:YKCKVSN 7Sequence Number (ID): 192Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:YLAWYQQ 7Sequence Number ( ID): 193Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 719830131-WO-PCT> mol type, protein> organism, Homo sapienssResidues:YNSTYRVSequence Number (ID): 194Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:YRVVSVL 7Sequence Number (ID): 195Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:YVDGVQV 7Sequence Number (ID): 196Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, Homo sapienssResidues:YWASTRE 7Sequence Number ( ID): 197Length: 142Molecule Type: AA19930131-WO-PCTFeatures Location / Qualifiers:- source, 1.. 142> mol type, protein> organism, synthetic construct- SITE, 142> note, Terminal cysteine- REGION, 126..130> note, GGGGS spacer- REGION, 131.. 136> note, His tag- REGION, 137.. 141> note, GGGGS linkerResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSSGGGS HHHHHHHGGGG SC 142Sequence Number ( ID): 198Length: 143Molecule Type: AAFeatures Location / Qualifiers:- source, 1..143> mol type, protein> organism, synthetic construct- SITE, 143> note, Terminal cysteine- REGION, 132.. 137> note, ACPGCA hinge- REGION, 138..142> note, His tag- REGION, 138..142> note, GGGGS spacerResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSSACPGC AHHHHHHGGG GSC 14330131-WO-PCTSequence Number (ID): 199Length: 131Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 131> mol type, protein> organism, synthetic construct- SITE, 131> note, Terminal cysteine- REGION, 126..130> note, GGGGS spacerResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSSGGGGS C 131Sequence Number ( ID): 200Length: 131Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 131> mol type, protein> organism, synthetic construct- REGION, 126.. 129> note, GGGE spacerResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSSGGGEC S 131Sequence Number ( ID): 201Length: 362Molecule Type: AAFeatures Location / Qualifiers:- source, 1..362> mol type, protein> organism, synthetic construct- VARIANT, 253.. 25420130131-WO-PCT> note, LALA sequence- VARIANT, 329> note, PA sequenceResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSSGGGGS EPKSADKTHT CPPCPAPEAA GGPSVFLFPP KPKDTLMISR TPEVTCVVD 180 VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ YNSTYRWSV LTVLHQDWLN GKEYKCKVSN 240 KALAAPIEKT ISKAKGQPRE PQVYTLPPSR DELTKNQVSL TCLVKGFYPS DIAVEWESNG 300 QPENNYKTTP PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP 360 GK 362Sequence Number ( ID): 202Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic constructResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number ( ID): 203Length: 124Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 124> mol type, protein> organism, synthetic construct- REGION, 1.. 15> note, Unstructured terminal.- REGION, 108.. 112> note, GGGGS spacer- REGION, 113.. 118> note, His6 tag- REGION, 119.. 12320230131-WO-PCT> note, GGGGS spacerResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSGGG GSHHHHHHGG 120 GGSC 124Sequence Number ( ID): 204Length: 104Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 104> mol type, protein> organism, synthetic construct- REGION, 93.. 98> note, His6 tag- REGION, 99.. 103> note, GGGGS spacerResidues:VTIKCPLPEM HVRIYLCREM AGSGTCGTVV STTNFIKAEY KGRVTLKQYP RKNLFLVEVT 60 QLTESDSGVY ACGAGMNTDR GKTQKVTGGG GSHHHHHHGG GGSC 104Sequence Number ( ID): 205Length: 119Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 119> mol type, protein> organism, synthetic construct- REGION, 1.. 15> note, Unstructured terminal- REGION, 108.. 113> note, His6 tag- REGION, 114.. 118> note, GGGGS spacerResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHHGGGGSC 11930131-WO-PCTSequence Number ( ID): 206Length: 104Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 104> mol type, protein> organism, synthetic constructResidues:VTIKCPLPEM HVRIYLCREM AGSGTCGTVV STTNFIKAEY KGRVTLKQYP RKNLFLVEVT 60 QLTESDSGVY ACGAGMNTDR GKTQKVTLNV HSHHHHHHGG GGSC 104Sequence Number ( ID): 207Length: 119Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 119> mol type, protein> organism, synthetic construct- REGION, 1.. 15> note, Unstructured terminal- REGION, 114.. 117> note, GGGE spacer- REGION, 108.. 113> note, His6 tagResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHHGGGECS 119Sequence Number ( ID): 208Length: 104Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 104> mol type, protein> organism, synthetic constructResidues:VTIKCPLPEM HVRIYLCREM AGSGTCGTVV STTNFIKAEY KGRVTLKQYP RKNLFLVEVT 60 QLTESDSGVY ACGAGMNTDR GKTQKVTLNV HSHHHHHHGG GECS 10420430131-WO-PCTSequence Number ( ID): 209Length: 343Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 343> mol type, protein> organism, synthetic construct- REGION, 1.. 15> note, Unstructured terminal- VARIANT, 253..254> note, LALA sequence- VARIANT, 329> note, PA sequence- REGION, 108.. Il l> note, GGGS spacerResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSGGG SEPKSADKTH 120 TCPPCPAPEA AGGPSVFLFP PKPKDTLMIS RTPEVTCVW DVSHEDPEVK FNWYVDGVEV 180 HNAKTKPREE QYNSTYRWS VLTVLHQDWL NGKEYKCKVS NKALAAPIEK TISKAKGQPR 240 EPQVYTLPPS RDELTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF 300 FLYSKLTVDK SRWQQGNVFS CSVMHEALHN HYTQKSLSLS PGK 343Sequence Number ( ID): 210Length: 124Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 124> mol type, protein> organism, synthetic construct- REGION, 1.. 15> note, Unstructured terminiResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSGGG GSLPETGGHH 120 HHHH 12420530131-WO-PCTSequence Number ( ID): 211Length: 104Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 104> mol type, protein> organism, synthetic constructResidues:VTIKCPLPEM HVRIYLCREM AGSGTCGTVV STTNFIKAEY KGRVTLKQYP RKNLFLVEVT 60 QLTESDSGVY ACGAGMNTDR GKTQKVTGGG GSLPETGGHH HHHH 104Sequence Number ( ID): 212Length: 131Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 131> mol type, protein> organism, synthetic construct- REGION, 128.. 131> note, ACPGCA C-terminal sequenceResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSSACPGC A 131Sequence Number ( ID): 213Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic constructResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 214Length: 12520630131-WO-PCTMolecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 99> note, A to H- REGION, 99..114> note, CDR3 is HYRGSDHYTGRRNYNYResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAHY RGSDHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number ( ID): 215Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 100> note, Y to H- REGION, 99.. 114> note, CDR3 is AHRGSDHYTGRRNYNYResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAH RGSDHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number ( ID): 216Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1..125> mol type, protein> organism, synthetic construct- VARIANT, 10120730131-WO-PCT> note, R to H- REGION, 99..114> note, CDR3 is AYHGSDHYTGRRNYNYResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY HGSDHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number (ID): 217Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 102> note, G to H- REGION, 99..114> note, CDR3 is AYRHSDHYTGRRNYNYResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RHSDHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number ( ID): 218Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1..125> mol type, protein> organism, synthetic construct- VARIANT, 103> note, S to H- REGION, 99.. 114> note, CDR3 is AYRGHDHYTGRRNYNY30131-WO-PCTResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGHDHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number (ID): 219Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 104> note, D to H- REGION, 99..114> note, CDR3 is AYRGSHHYTGRRNYNYResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSHHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number ( ID): 220Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 106> note, Y to H- REGION, 99.. 114> note, CDR3 is AYRGSDHHTGRRNYNYResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHHTGRR NYNYWGQGTQ 120 VTVSS 12520930131-WO-PCTSequence Number (ID): 221Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 107> note, T to H- REGION, 99..114> note, CDR3 is AYRGSDHYHGRRNYNYResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYHGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number ( ID): 222Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 108> note, G to H- REGION, 99.. 114> note, CDR3 is AYRGSDHYTHRRNYNYResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTHRR NYNYWGQGTQ 120 VTVSS 125Sequence Number ( ID): 223Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1..125> mol type, protein21030131-WO-PCT> organism, synthetic construct- VARIANT, 109> note, R to H- REGION, 99..114> note, CDR3 is AYRGSDHYTGHRNYNYResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGHR NYNYWGQGTQ 120 VTVSSSequence Number (ID): 224Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 110> note, R to H- REGION, 99.. 114> note, CDR3 is AYRGSDHYTGRHNYNYResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRH NYNYWGQGTQ 120 VTVSS 125Sequence Number ( ID): 225Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1..125> mol type, protein> organism, synthetic construct- VARIANT, 111> note, N to H- REGION, 99.. 114> note, CDR3 is AYRGSDHYTGRRHYNY21130131-WO-PCTResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR HYNYWGQGTQ 120 VTVSS 125Sequence Number (ID): 226Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 112> note, Y to H- REGION, 99..114> note, CDR3 is AYRGSDHYTGRRNHNYResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NHNYWGQGTQ 120 VTVSS 125Sequence Number ( ID): 227Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 113> note, N to H- REGION, 99.. 114> note, CDR3 is AYRGSDHYTGRRNYHYResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYHYWGQGTQ 120 VTVSS 12521230131-WO-PCTSequence Number (ID): 228Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 114> note, Y to H- REGION, 99..114> note, CDR3 is AYRGSDHYTGRRNYNHResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNHWGQGTQ 120 VTVSS 125Sequence Number ( ID): 229Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 53> note, G to H- REGION, 52.. 58> note, CDR2 is SHSGSSResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISHSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number ( ID): 230Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1..125> mol type, protein21330131-WO-PCT> organism, synthetic construct- VARIANT, 55> note, G to H- REGION, 52.. 58> note, CDR2 is SGSHSSResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSHSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number (ID): 231Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 52> note, S to H- REGION, 52.. 58> note, CDR2 is HGSGSSResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA IHGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number ( ID): 232Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1..125> mol type, protein> organism, synthetic construct- VARIANT, 54> note, S to H- REGION, 52.. 58> note, CDR2 is SGHGSS30131-WO-PCTResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGHGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number (ID): 233Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 56> note, S to H- REGION, 52.. 58> note, CDR2 is SGSGHSResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGHSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number ( ID): 234Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 57> note, S to H- REGION, 52.. 58> note, CDR2 is SGSGSHResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSHTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSS 12521530131-WO-PCTSequence Number ( ID): 235Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 26> note, G to H- REGION, 26.. 32> note, CDR1 is HRTFSNYResidues:QVQLQDSGGG LVQAGGSLRL SCAASHRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number ( ID): 236Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 27> note, R to H- REGION, 26.. 32> note, CDR1 is GHTFSNYResidues:QVQLQDSGGG LVQAGGSLRL SCAASGHTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number ( ID): 237Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein21630131-WO-PCT> organism, synthetic construct- VARIANT, 28> note, T to H- REGION, 26..32> note, CDR1 is GRHFSNYResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRHFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number (ID): 238Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 29> note, F to H- REGION, 26.. 32> note, CDR1 is GRTHSNYResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTHS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number ( ID): 239Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1..125> mol type, protein> organism, synthetic construct- VARIANT, 30> note, S to H- REGION, 26..32> note, CDR1 is GRTFHNY21730131-WO-PCTResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFH NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number (ID): 240Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 31> note, N to H- REGION, 26..32> note, CDR1 is GRTFSHYResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS HYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSS 125Sequence Number ( ID): 241Length: 125Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 125> mol type, protein> organism, synthetic construct- VARIANT, 32> note, Y to H- REGION, 26.. 32> note, CDR1 is GRTFSNHResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NHNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSS 12521830131-WO-PCTSequence Number (ID): 242Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 23> note, P to H- REGION, 23..28> note, HEMHVRResidues:RILPEVKVEG ELGGSVTIKC PLHEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 243Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 42> note, E to HResidues:RILPEVKVEG ELGGSVTIKC PLPHMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 244Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1..113> mol type, protein> organism, synthetic construct- VARIANT, 25> note, M to H21930131-WO-PCTResidues:RILPEVKVEG ELGGSVTIKC PLPEHHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 245Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 26> note, H to AResidues:RILPEVKVEG ELGGSVTIKC PLPEMAVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 246Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 27> note, V to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHHRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 247Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 2822030131-WO-PCT> note, R to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVHIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 248Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 42> note, G to H- REGION, 42.. 53> note, HTWSTTNFIKAResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CHTWSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 249Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 43> note, T to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGHWSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 250Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 11322130131-WO-PCT> mol type, protein> organism, synthetic construct- VARIANT, 44> note, V to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTHVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 251Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 45> note, V to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVHSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 252Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 46> note, S to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTWHTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 253Length: 113Molecule Type: AAFeatures Location / Qualifiers:22230131-WO-PCT- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 47> note, T to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTWSHTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 254Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 48> note, T to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTWSTHNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 255Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 49> note, N to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTWSTTHF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 256Length: 113Molecule Type: AA22330131-WO-PCTFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 50> note, F to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTWSTTNH IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 257Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 51> note, I to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTWSTTNF HKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 258Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 52> note, K to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTWSTTNF IHAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 259Length: 11322430131-WO-PCTMolecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 53> note, A to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTWSTTNF IKHEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 260Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 89> note, A to H- REGION, 89.. 98> note, HGMNTDRGKTResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGHG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 261Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 90> note, G to H- REGION, 89.. 98> note, AHMNTDRGKT30131-WO-PCTResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAH MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 262Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 91> note, M to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG HNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 263Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 92> note, N to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MHTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 264Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 9322630131-WO-PCT> note, T to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNHDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 265Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 94> note, D to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTHRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 266Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 95> note, R to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDHGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 267Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct22730131-WO-PCT- VARIANT, 96> note, G to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRHKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 268Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 97> note, K to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGHTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 269Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 98> note, T to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKHQK VTLNVHSHHH HHH 113Sequence Number ( ID): 270Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein22830131-WO-PCT> organism, synthetic construct- VARIANT, 40> note, T to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGH CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 271Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic construct- VARIANT, 56> note, K to HResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTWSTTNF IKAEYHGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 272Length: 159Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 159> mol type, protein> organism, synthetic constructResidues:MKNHLLFWGV LAVFIKAVHV KAQEDERIVL VDNKCKCARI TSRIIRSSED PNEDIVERNI 60 RIIVPLNNRE NISDPTSPLR TRFVYHLSDL CKKCDPTEVE LDNQIVTATQ SNICDEDSAT 120 ETCYTYDRNK CYTAWPLVY GGETKMVETA LTPDACYPD 159Sequence Number ( ID): 273Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein22930131-WO-PCT> organism, synthetic constructResidues:SWISSRDWT 9Sequence Number (ID): 274Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic constructResidues:SWISSKDWT 9Sequence Number (ID): 275Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic constructResidues:YDWIPSSAW 9Sequence Number (ID): 276Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic constructResidues:QKWISSADW 9Sequence Number ( ID): 277Length: 10Molecule Type: AAFeatures Location / Qualifiers:23030131-WO-PCT- source, 1.. 10> mol type, protein> organism, synthetic construct- MOD_RES, 10> note, K is PEG4-biotin-modifiedResidues:YDWIPSSAWK 10Sequence Number (ID): 278Length: 10Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 10> mol type, protein> organism, synthetic constructResidues:YDWIPSSAWT 10Sequence Number ( ID): 279Length: 10Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 10> mol type, protein> organism, synthetic constructResidues:YSWISSRDWT 10Sequence Number ( ID): 280Length: 10Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 10> mol type, protein> organism, synthetic construct- MOD_RES, 1> note, K is PEG4-biotin-modified23130131-WO-PCTResidues:KYDWIPSSAWSequence Number (ID): 281Length: 13Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 13> mol type, protein> organism, synthetic construct- MOD_RES, 1> note, K is PEG4-biotin-modifiedResidues:KNGNNVNGNR NNN 13Sequence Number (ID): 282Length: 13Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 13> mol type, protein> organism, synthetic construct- MOD_RES, 13> note, K is PEG4-biotin-modifiedResidues:NGNNVNGNRN NNK 13Sequence Number ( ID): 283Length: 12Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 12> mol type, protein> organism, synthetic constructResidues:NGNNVNGNRN NN 1223230131-WO-PCTSequence Number (ID): 284Length: 20Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 20> mol type, protein> organism, synthetic constructResidues:TNFIKAEYKG RVTLKQYPRK 20Sequence Number (ID): 285Length: 12Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 12> mol type, protein> organism, synthetic constructResidues:LMKNMDPLND NV 12Sequence Number (ID): 286Length: 12Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 12> mol type, protein> organism, synthetic constructResidues:SYNNNNHVSN RN 12Sequence Number ( ID): 287Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic construct30131-WO-PCTResidues:TWISSNDWT 9Sequence Number (ID): 288Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic constructResidues:KGWISANDW 9Sequence Number (ID): 289Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic constructResidues:QKWISSAWD 9Sequence Number (ID): 290Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic constructResidues:DWIPQASWE 9Sequence Number ( ID): 291Length: 12Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 1223430131-WO-PCT> mol type, protein> organism, synthetic constructResidues:YNNNNGNYTY RNSequence Number (ID): 292Length: 12Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 12> mol type, protein> organism, synthetic constructResidues:ANTRNGATNN NM 12Sequence Number (ID): 293Length: 12Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 12> mol type, protein> organism, synthetic constructResidues:WNNNGRNACN AN 12Sequence Number (ID): 294Length: 12Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 12> mol type, protein> organism, synthetic constructResidues:HNSTSNGCND NV 12Sequence Number ( ID): 295Length: 12Molecule Type: AA23530131-WO-PCTFeatures Location / Qualifiers:- source, 1.. 12> mol type, protein> organism, synthetic constructResidues:NSNSRYNSNS NN 12Sequence Number (ID): 296Length: 12Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 12> mol type, protein> organism, synthetic constructResidues:KRNNHNNHNR SN 12Sequence Number (ID): 297Length: 12Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 12> mol type, protein> organism, synthetic constructResidues:LMKNMDPLND NI 12Sequence Number ( ID): 298Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic constructResidues:DWIDQMYDW 930131-WO-PCTSequence Number (ID): 299Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic constructResidues:AGAIWQKDWSequence Number (ID): 300Length: 8Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 8> mol type, protein> organism, synthetic constructResidues:AGIWQKDWSequence Number (ID): 301Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic constructResidues:EAILSGDWA 9Sequence Number ( ID): 302Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic construct23730131-WO-PCTResidues:EAVYSKDWL 9Sequence Number (ID): 303Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic constructResidues:FYGVTGVDW 9Sequence Number (ID): 304Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic constructResidues:NRVVWQKDW 9Sequence Number (ID): 305Length: 8Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 8> mol type, protein> organism, synthetic constructResidues:NKWISQDW 8Sequence Number ( ID): 306Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 923830131-WO-PCT> mol type, protein> organism, synthetic constructResidues:NTVIWSNDW 9Sequence Number (ID): 307Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic constructResidues:LSWISGEDW 9Sequence Number (ID): 308Length: 11Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 11> mol type, protein> organism, synthetic constructResidues:ASGRTFSNYN M 11Sequence Number (ID): 309Length: 13Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 13> mol type, protein> organism, synthetic constructResidues:AASGRTFSNY NMG 13Sequence Number ( ID): 310Length: 12Molecule Type: AA23930131-WO-PCTFeatures Location / Qualifiers:- source, 1.. 12> mol type, protein> organism, synthetic constructResidues:AAISGSGSST DY 12Sequence Number (ID): 311Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic constructResidues:PSWISQVDW 9Sequence Number (ID): 312Length: 10Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 10> mol type, protein> organism, synthetic construct- MOD_RES, 1> note, K is PEG4-biotin-modifiedResidues:KNTVIWSNDW 10Sequence Number ( ID): 313Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic construct- MOD_RES, 1> note, K is PEG4-biotin-modified30131-WO-PCTResidues:KNKWISQDW 9Sequence Number (ID): 314Length: 6Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 6> mol type, protein> organism, synthetic constructResidues:SGSGSS 6Sequence Number (ID): 315Length: 13Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 13> mol type, protein> organism, synthetic construct- MOD_RES, 1> note, K is PEG4-biotin-modifiedResidues:KLMKNMDPLN DNI 13Sequence Number ( ID): 316Length: 13Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 13> mol type, protein> organism, synthetic construct- MOD_RES, 1> note, K is PEG4-biotin-modifiedResidues:KCDSSCDSVG NCN 1324130131-WO-PCTSequence Number (ID): 317Length: 13Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 13> mol type, protein> organism, synthetic construct- MOD_RES, 1> note, K is PEG4-biotin-modifiedResidues:KDVANHNNSN HGN 13Sequence Number (ID): 318Length: 10Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 10> mol type, protein> organism, synthetic construct- MOD_RES, 1> note, K is PEG4-biotin-modifiedResidues:KFYGVTGVDW 10Sequence Number ( ID): 319Length: 10Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 10> mol type, protein> organism, synthetic construct- MOD_RES, 1> note, K is PEG4-biotin-modifiedResidues:KLSWISGEDW 10Sequence Number ( ID): 320Length: 1624230131-WO-PCTMolecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, synthetic constructResidues:RTWSTTNFI KMNTDR 16Sequence Number (ID): 321Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, synthetic constructResidues:RMNTDRTWS TTNFIK 16Sequence Number (ID): 322Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, synthetic constructResidues:TVVSTTNFIK MNTDRR 16Sequence Number ( ID): 323Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, synthetic constructResidues:MNTDRRTWS TTNFIK 1624330131-WO-PCTSequence Number (ID): 324Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, synthetic constructResidues:MNTDRTWST TNFIKR 16Sequence Number (ID): 325Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, synthetic constructResidues:TWSTTNFIK RMNTDR 16Sequence Number (ID): 326Length: 21Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 21> mol type, protein> organism, synthetic construct- MOD_RES, 1> note, K is PEG4-biotin-modifiedResidues:KTNFIKAEYK GRVTLKQYPR K 21Sequence Number ( ID): 327Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein24430131-WO-PCT> organism, synthetic construct- MOD_RES, 1> note, Oxi-threonineResidues:TWSTTNFIK RMNTDR 16Sequence Number (ID): 328Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, synthetic construct- SITE, 1> note, N-terminal acetylationResidues:RTWSTTNFI KMNTDR 16Sequence Number ( ID): 329Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, synthetic construct- SITE, 1> note, N-terminal acetylationResidues:RMNTDRTWS TTNFIK 16Sequence Number ( ID): 330Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, synthetic construct- SITE, 124530131-WO-PCT> note, N-terminal acetylationResidues:TWSTTNFIK RMNTDR 16Sequence Number (ID): 331Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, synthetic construct- SITE, 1> note, N-terminal acetylationResidues:MNTDRTWST TNFIKR 16Sequence Number (ID): 332Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic constructResidues:AMMEDSDSD 9Sequence Number ( ID): 333Length: 10Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 10> mol type, protein> organism, synthetic constructResidues:SGMDFWLWPL 10Sequence Number ( ID): 334Length: 824630131-WO-PCTMolecule Type: AAFeatures Location / Qualifiers:- source, 1.. 8> mol type, protein> organism, synthetic constructResidues:TLNVHSEY 8Sequence Number (ID): 335Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, synthetic constructResidues:RTWSTTNFI KMNTDY 16Sequence Number (ID): 336Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, synthetic constructResidues:RMNTDRTWS TTNFIF 16Sequence Number ( ID): 337Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, synthetic constructResidues:RMNTDRTWS TTNFIY 1624730131-WO-PCTSequence Number (ID): 338Length: 12Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 12> mol type, protein> organism, synthetic constructResidues:NGNNVNGNRN NY 12Sequence Number (ID): 339Length: 22Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 22> mol type, protein> organism, synthetic constructResidues:TTNFIKAEYK GRVTLKQYPR KN 22Sequence Number (ID): 340Length: 24Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 24> mol type, protein> organism, synthetic constructResidues:STTNFIKAEY KGRVTLKQYP RKNL 24Sequence Number ( ID): 341Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, synthetic construct30131-WO-PCTResidues:RTVVSTTNFI KMNTDF 16Sequence Number (ID): 342Length: 13Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 13> mol type, protein> organism, synthetic construct- MOD_RES, 13> note, K is PEG4-biotin-modifiedResidues:CDSSCDSVGN CNK 13Sequence Number (ID): 343Length: 21Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 21> mol type, protein> organism, synthetic construct- MOD_RES, 21> note, K is PEG4-click-GN3-modif ledResidues:KRPYQKLTVR GKYEAKIFNT K 21Sequence Number ( ID): 344Length: 21Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 21> mol type, protein> organism, synthetic construct- MOD_RES, 21> note, K is PEG4-biotin-modifiedResidues:TNFIKAEYKG RVTLKQYPRK K 2124930131-WO-PCTSequence Number (ID): 345Length: 13Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 13> mol type, protein> organism, synthetic construct- MOD_RES, 13> note, K is PEG4-biotin-modifiedResidues:DVANHNNSNH GNK 13Sequence Number (ID): 346Length: 10Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 10> mol type, protein> organism, synthetic construct- MOD_RES, 10> note, K is PEG4-biotin-modifiedResidues:TWISSNDWTK 10Sequence Number ( ID): 347Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic constructResidues:AGAIWQRDW 9Sequence Number ( ID): 348Length: 12Molecule Type: AA25030131-WO-PCTFeatures Location / Qualifiers:- source, 1.. 12> mol type, protein> organism, synthetic constructResidues:CDSSCDSVGN CN 12Sequence Number (ID): 349Length: 12Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 12> mol type, protein> organism, synthetic constructResidues:DVANHNNSNH GN 12Sequence Number (ID): 350Length: 11Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 11> mol type, protein> organism, synthetic constructResidues:APARSPSPST Q 11Sequence Number ( ID): 351Length: 17Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 17> mol type, protein> organism, synthetic constructResidues:TMMASHYKQH CPPTPEY 1730131-WO-PCTSequence Number (ID): 352Length: 18Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 18> mol type, protein> organism, synthetic construct- MOD_RES, 1> note, K is PEG4-biotin-modifiedResidues:KTMMASHYKQ HCPPTPEY 18Sequence Number (ID): 353Length: 18Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 18> mol type, protein> organism, synthetic construct- MOD_RES, 18> note, K is PEG4-biotin-modifiedResidues:TMMASHYKQH CPPTPEYK 18Sequence Number ( ID): 354Length: 7Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 7> mol type, protein> organism, synthetic construct- REGION, 1.. 7> note, VHH CDR1Residues:GRTFSNY 7Sequence Number ( ID): 355Length: 14225230131-WO-PCTMolecule Type: AAFeatures Location / Qualifiers:- source, 1.. 142> mol type, protein> organism, synthetic constructResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSSGGGGS LPETGGHHHH HH 142Sequence Number (ID): 356Length: 152Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 152> mol type, protein> organism, synthetic constructResidues:QVQLQDSGGG LVQAGGSLRL SCAASGRTFS NYNMGWFRQA PGKEREFVAA ISGSGSSTDY 60 ADSVKGRFTV SRDNAKNTVH LQMNSLKPED TAVYYCAAAY RGSDHYTGRR NYNYWGQGTQ 120 VTVSSGGGGS GGGGSGGGGS LPETGGHHHH HH 152Sequence Number (ID): 357Length: 113Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 113> mol type, protein> organism, synthetic constructResidues:RILPEVKVEG ELGGSVTIKC PLPEMHVRIY LCREMAGSGT CGTVVSTTNF IKAEYKGRVT 60 LKQYPRKNLF LVEVTQLTES DSGVYACGAG MNTDRGKTQK VTLNVHSHHH HHH 113Sequence Number ( ID): 358Length: 118Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 11825330131-WO-PCT> mol type, protein> organism, synthetic constructResidues:GGGGGRILPE VKVEGELGGS VTIKCPLPEM HVRIYLCREM AGSGTCGTVV STTNFIKAEY 60 KGRVTLKQYP RKNLFLVEVT QLTESDSGVY ACGAGMNTDR GKTQKVTLNV HSHHHHHH 118Sequence Number ( ID): 359Length: 129Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 129> mol type, protein> organism, synthetic constructResidues:CGGGGSGGGG SGGGGSRILP EVKVEGELGG SVTIKCPLPE MHVRIYLCRE MAGSGTCGTV 60 VSTTNFIKAE YKGRVTLKQY PRKNLFLVEV TQLTESDSGV YACGAGMNTD RGKTQKVTLN 120 VHSHHHHHH 129Sequence Number ( ID): 360Length: 124Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 124> mol type, protein> organism, synthetic constructResidues:CGGGGSHHHH HHGGGGSRIL PEVKVEGELG GSVTIKCPLP EMHVRIYLCR EMAGSGTCGT 60 VVSTTNFIKA EYKGRVTLKQ YPRKNLFLVE VTQLTESDSG VYACGAGMNT DRGKTQKVTL 120 NVHS 124Sequence Number ( ID): 361Length: 112Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 112> mol type, protein> organism, synthetic construct30131-WO-PCTResidues:GGGGGRILPE VKVEGELGGS VTIKCPLPEM HVRIYLCREM AGSGTCGTVV STTNFIKAEY 60 KGRVTLKQYP RKNLFLVEVT QLTESDSGVY ACGAGMNTDR GKTQKVTLNV HS 112Sequence Number ( ID): 362Length: 123Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 123> mol type, protein> organism, synthetic constructResidues:CGGGGSGGGG SGGGGSRILP EVKVEGELGG SVTIKCPLPE MHVRIYLCRE MAGSGTCGTV 60 VSTTNFIKAE YKGRVTLKQY PRKNLFLVEV TQLTESDSGV YACGAGMNTD RGKTQKVTLN 120 VHS 123Sequence Number ( ID): 363Length: 575Molecule Type: AAFeatures Location / Qualifiers:- source, 1. 575> mol type, protein> organism, Homo sapiensResidues:QVTLTESGPA LVKPKQPLTL TCTFSGFSLS TSRMRVSWIR RPPGKALEWL ARIDDDDKFY 60 WSTSRTRLSI SKNDSKNQW LIMINVNPVD TATYYCARW NSVMAGYYYY YMDVWGKGTT 120 VTVSSGSASA PTLFPLVSCE NSNPSSTVAV GCLAQDFLPD SITFSWKYNQ SQKISSTRGF 180 PSVLRGGKYA ATSQVLLPSK DVMQGTDEHV CKWVQHPNGN KQKNVPLPVI AELPPKVSVF 240 VPPRDGFFGN PRKSKLICQA TGFSPRQVWS LREGKQVGSG VTTDQVQAEA KESGPTTYKV 300 TSTLTIKESD WLGESMFTCR VDHRGLTFQQ NASSMCVPDQ DTAIRVFAIP PSFASIFLTK 360 STKLTCLVTD LTTYDSVTIS WTREENGAVK THTNISESHP NATFSAVGEA SICEDDDWSG 420 ERFTCTVTHT DLPSPLKQTI SRPKGVALHR PDVYLLPPAR EQLNLRESAT ITCLVTGFSP 480 ADVFVQWMQR GEPLSPEKYV TSAPMPEPQA PGRYFAHSIL TVSEEEWNTG QTYTCVVAHE 540ALPNRVTERT VDKSTGKPTL YNVSLVMSDT AGTCY 575Sequence Number ( ID): 364Length: 212Molecule Type: AA25530131-WO-PCTFeatures Location / Qualifiers:- source, 1.. 212> mol type, protein> organism, synthetic constructResidues:DIQMTQSPST LSASVGDRVT ITCSASSRVG YMHWYQQKPG KAPKLLIYDT SKLASGVPSR 60 FSGSGSGTEF TLTISSLQPD DFATYYCFQG SGYPFTFGGG TKVEIRTVAA PSVFIFPPSD 120 EQLKSGTASV VCLLNNFYPR EAKVQWKVDN ALQSGNSQES VTEQDSKDST YSLSSTLTLS 180 KADYEKHKVY ACEVTHQGLS SPVTKSFNRG EC 212Sequence Number ( ID): 365Length: 234Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 234> mol type protein> organism, synthetic constructResidues:QVTLTESGPA LVKPKQPLTL TCTFSGFSLS TSRMRVSWIR RPPGKALEWL ARIDDDDKFY 60 WSTSRTRLSI SKNDSKNQW LIMINVNPVD TATYYCARW NSVMAGYYYY YMDVWGKGTT 120 VTVSSGSASA PTLFPLVSCE NSNPSSTVAV GCLAQDFLPD SITFSWKYNQ SQKISSTRGF 180 PSVLRGGKYA ATSQVLLPSK DVMQGTDEHV CKWVQHPNGN KQKNVPLPVI AELP 234Sequence Number ( ID): 366Length: 212Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 212> mol type protein> organism, synthetic constructResidues:DIQMTQSPST LSASVGDRVT ITCSASSRVG YMHWYQQKPG KAPKLLIYDT SKLASGVPSR 60 FSGSGSGTEF TLTISSLQPD DFATYYCFQG SGYPFTFGGG TKVEIRTVAA PSVFIFPPSD 120 EQLKSGTASV VCLLNNFYPR EAKVQWKVDN ALQSGNSQES VTEQDSKDST YSLSSTLTLS 180 KADYEKHKVY ACEVTHQGLS SPVTKSFNRG EC 212Sequence Number ( ID): 367Length: 21025630131-WO-PCTMolecule Type: AAFeatures Location / Quali fiers:- source, 1.. 210> mol type, protein> organism, synthetic constructResidues:QVTLTESGPA LVKPKQPLTL TCTFSGFSLS TSRMRVSWIR RPPGKALEWL ARIDDDDKFY 60 WSTSRTRLSI SKNDSKNQW LIMINVNPVD TATYYCARW NSVMAGYYYY YMDVWGKGTT 120 VTVSSGSASA PTLFPLVSCE NSNPSSTVAV GCLAQDFLPD SITFSWKYNQ SQKISSTRGF 180 PSVLRGGKYA ATSQVLLPSK DVMQGTDEHV 210Sequence Number ( ID): 368Length: 341Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 341> mol type, protein> organism, synthetic constructResidues:PKVSVFVPPR DGFFGNPRKS KLICQATGFS PRQVWSLREG KQVGSGVTTD QVQAEAKESG 60 PTTYKVTSTL TIKESDWLGE SMFTCRVDHR GLTFQQNASS MCVPDQDTAI RVFAIPPSFA 120 SIFLTKSTKL TCLVTDLTTY DSVTISWTRE ENGAVKTHTN ISESHPNATF SAVGEASICE 180 DDDWSGERFT CTVTHTDLPS PLKQTISRPK GVALHRPDVY LLPPAREQLN LRESATITCL 240 VTGFSPADVF VQWMQRGEPL SPEKYVTSAP MPEPQAPGRY FAHSILTVSE EEWNTGQTYT 300 CVVAHEALPN RVTERTVDKS TGKPTLYNVS LVMSDTAGTC Y 341Sequence Number ( ID): 369Length: 318Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 318> mol type, protein> organism, synthetic constructResidues:PKVSVFVPPR DGFFGNPRKS KLICQATGFS PRQVWSLREG KQVGSGVTTD QVQAEAKESG 60 PTTYKVTSTL TIKESDWLGE SMFTCRVDHR GLTFQQNASS MCVPDQDTAI RVFAIPPSFA 120 SIFLTKSTKL TCLVTDLTTY DSVTISWTRE ENGAVKTHTN ISESHPNATF SAVGEASICE 180 DDDWSGERFT CTVTHTDLPS PLKQTISRPK GVALHRPDVY LLPPAREQLN LRESATITCL 24025730131-WO-PCTVTGFSPADVF VQWMQRGEPL SPEKYVTSAP MPEPQAPGRY FAHSILTVSE EEWNTGQTYT 300 CVVAHEALPN RVTERTVDSequence Number (ID): 370Length: 575Molecule Type: AAFeatures Location / Qualifiers:- source, 1..575> mol type, protein> organism, synthetic constructResidues:QVTLTESGPA LVKPKQPLTL TCTFSGFSLS TSRMRVSWIR RPPGKALEWL ARIDDDDKFY 60 WSTSRTRLSI SKNDSKNQW LIMINVNPVD TATYYCARW NSVMAGYYYY YMDVWGKGTT 120 VTVSSGSASA PTLFPLVSCE NSNPSSTVAV GCLAQDFLPD SITFSWKYNQ SQKISSTRGF 180 PSVLRGGKYA ATSQVLLPSK DVMQGTDEHV CKWVQHPNGN KQKNVPLPVI AELPPKVSVF 240 VPPRDGFFGN PRKSKLICQA TGFSPRQVWS LREGKQVGSG VTTDQVQAEA KESGPTTYKV 300 TSTLTIKESD WLGESMFTCR VDHRGLTFQQ NASSMCVPDQ DTAIRVFAIP PSFASIFLTK 360 STKLTCLVTD LTTYDSVTIS WTREENGAVK THTNISESHP NATFSAVGEA SICEDDDWSG 420 ERFTCTVTHT DLPSPLKQTI SRPKGVALHR PDVYLLPPAR EQLNLRESAT ITCLVTGFSP 480 ADVFVQWMQR GEPLSPEKYV TSAPMPEPQA PGRYFAHSIL TVSEEEWNTG QTYTCVVAHE 540ALPNRVTERT VDKSTGKPTL YNVSLVMSDT AGTCY 575Sequence Number (ID): 371Length: 572Molecule Type: AAFeatures Location / Qualifiers:- source, 1..572> mol type, protein> organism, synthetic constructResidues:QVTLRESGPA LVKPTQTLTL TCTFSGFSLS TAGMSVGWIR QPPGKALEWL ADIWWDDKKH 60 YNPSLKDRLT ISKDTSKNQV VLKVTNMDPA DTATYYCARD MIFNFYFDVW GQGTTVTVSS 120 SSGSASAPTL FPLVSCENSN PSSTVAVGCL AQDFLPDSIT FSWKYNQSQK ISSTRGFPSV 180 LRGGKYAATS QVLLPSKDVM QGTDEHVCKW VQHPNGNKQK NVPLPVIAEL PPKVSVFVPP 240 RDGFFGNPRK SKLICQATGF SPRQVWSLRE GKQVGSGVTT DQVQAEAKES GPTTYKVTST 300 LTIKESDWLG ESMFTCRVDH RGLTFQQNAS SMCVPDQDTA IRVFAIPPSF ASIFLTKSTK 360 LTCLVTDLTT YDSVTISWTR EENGAVKTHT NISESHPNAT FSAVGEASIC EDDDWSGERF 420 TCTVTHTDLP SPLKQTISRP KGVALHRPDV YLLPPAREQL NLRESATITC LVTGFSPADV 48025830131-WO-PCTFVQWMQRGEP LSPEKYVTSA PMPEPQAPGR YFAHSILTVS EEEWNTGQTY TCWAHEALP 540 NRVTERTVDK STGKPTLYNV SLVMSDTAGT CY 572Sequence Number (ID): 372Length: 9Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 9> mol type, protein> organism, synthetic construct- REGION, 1.. 9> note, VHH CDR1Residues:SGRTFSNYN 9Sequence Number (ID): 373Length: 8Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 8> mol type, protein> organism, synthetic construct- REGION, 1.. 8> note, VHH CDR2Residues:ISGSGSST 8Sequence Number ( ID): 374Length: 10Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 10> mol type, protein> organism, synthetic construct- REGION, 1.. 10> note, VHH CDR2Residues:AISGSGSSTD 1025930131-WO-PCTSequence Number (ID): 375Length: 14Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 14> mol type, protein> organism, synthetic construct- REGION, 1.. 14> note, VHH CDR2Residues:VAAISGSGSS TDYA 14Sequence Number (ID): 376Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, synthetic construct- REGION, 1.. 16> note, VHH CDR3Residues:AYRGSDHYTG RRNYNY 16Sequence Number ( ID): 377Length: 13Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 13> mol type, protein> organism, synthetic construct- MOD_RES, 1> note, K is PEG4-biotin-modifiedResidues:KSYNNNNHVS NRN 13Sequence Number ( ID): 37826030131-WO-PCTLength: 10Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 10> mol type, protein> organism, synthetic construct- MOD_RES, 1> note, K is PEG4-biotin-modifiedResidues:KKGWISANDW 10Sequence Number (ID): 379Length: 10Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 10> mol type, protein> organism, synthetic construct- MOD_RES, 1> note, K is PEG4-biotin-modifiedResidues:KEAVYSKDWL 10Sequence Number ( ID): 380Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, synthetic constructResidues:RTVVSTTNFI KMNTDF 16Sequence Number ( ID): 381Length: 20Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 2026130131-WO-PCT> mol type, protein> organism, synthetic construct- MOD_RES, 20> note, K is PEG3-click-beta-GN3-modifiedResidues:TNFIKAEYKG RVTLKQYPRK 20Sequence Number (ID): 382Length: 16Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 16> mol type, protein> organism, synthetic construct- SITE, 1> note, N-terminal acetylResidues:TVVSTTNFIK MNTDRR 16Sequence Number ( ID): 383Length: 32Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 32> mol type, protein> organism, synthetic constructResidues:MHVRIYLCRE MAGSGTCGTV VSTTNFIKAE YK 32Sequence Number ( ID): 384Length: 31Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 31> mol type, protein> organism, synthetic construct- MOD_RES, 1> note, K is PEG4-biotin-modified26230131-WO-PCTResidues:KGGGSMHVRI YLCREMAGSG TCGTVVSTTN FSequence Number (ID): 385Length: 31Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 31> mol type, protein> organism, synthetic construct- MOD_RES, 31> note, K is PEG4-biotin-modifiedResidues:MHVRIYLCRE MAGSGTCGTV VSTTNFGGGS KSequence Number (ID): 386Length: 30Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 30> mol type, protein> organism, synthetic constructResidues:SGTCGTVVST TNFIKAEYKG GGGSGMNTDRSequence Number ( ID): 387Length: 31Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 31> mol type, protein> organism, synthetic constructResidues:RIYLCREMAG SGTCGTVVST TNFGGGSMNT DSequence Number ( ID): 388Length: 31Molecule Type: AA26330131-WO-PCTFeatures Location / Qualifiers:- source, 1.. 31> mol type, protein> organism, synthetic constructResidues:RIYLCREMAG SGTCGTVVST TNFGGGSMNT D 31Sequence Number (ID): 389Length: 33Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 33> mol type, protein> organism, synthetic constructResidues:MHVRGGGGSS GTCGTVVSTT NFGGGGSGMN TDR 33Sequence Number (ID): 390Length: 33Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 33> mol type, protein> organism, synthetic constructResidues:MHVRGGGGSS GTCGTVVSTT NFGGGGSGMN TDR 33Sequence Number ( ID): 391Length: 26Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 26> mol type, protein> organism, synthetic construct- MOD_RES, 1> note, K is PEG4-biotin-modifiedResidues:KGGGGSTCGT VVSTTNFGGG GSMNTD 2630131-WO-PCTSequence Number (ID): 392Length: 26Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 26> mol type, protein> organism, synthetic construct- MOD_RES, 26> note, K is PEG4-biotin-modifiedResidues:TCGTVVSTTN FGGGGSMNTD GGGGSK 26Sequence Number (ID): 393Length: 19Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 19> mol type, protein> organism, synthetic construct- SIGNAL, 1.. 19> note, Signal peptide for IgM Fab fragments (native Rituxan signal peptide) Residues:MGWSLILLFL VAVATRVLS 19Sequence Number ( ID): 394Length: 19Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 19> mol type, protein> organism, synthetic construct- SIGNAL, 1.. 19> note, Signal peptide for IgM Fc domains (H7 signal peptide)Residues:MEFGLSWVFL VALFRGVQC 1926530131-WO-PCTSequence Number (ID): 395Length: 19Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 19> mol type, protein> organism, synthetic construct- SIGNAL, 1.. 19> note, Signal peptide for IgM FL (native Rituxan signal peptide) Residues:MGWSLILLFL VAVATRVLS 19Sequence Number (ID): 396Length: 232Molecule Type: AAFeatures Location / Qualifiers:- source, 1..232> mol type, protein> organism, synthetic constructResidues:EPKSADKTHT CPPCPAPEAA GGPSVFLFPP KPKDTLMISR TPEVTCVVVD VSHEDPEVKF 60 NWYVDGVEVH NAKTKPREEQ YNSTYRVVSV LTVLHQDWLN GKEYCKVSN KALAAPIEKT 120 ISKAKGQPRE PQVYTLPPSR DELTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP 180 PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP GK 232Sequence Number ( ID): 397Length: 5Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 5> mol type, protein> organism, synthetic constructResidues:GGGGS 5Sequence Number ( ID): 398Length: 10Molecule Type: AA26630131-WO-PCTFeatures Location / Qualifiers:- source, 1.. 10> mol type, protein> organism, synthetic constructResidues:GGGGSGGGGS 10Sequence Number (ID): 399Length: 15Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 15> mol type, protein> organism, synthetic constructResidues:GGGGSGGGGS GGGGS 15Sequence Number (ID): 400Length: 20Molecule Type: AAFeatures Location / Qualifiers:- source, 1.. 20> mol type, protein> organism, synthetic constructResidues:GGGGSGGGGS GGGGSGGGGS 20Sequence Number ( ID): 401Length: 25Molecule Type: AAFeatures Location / Quali...

Claims

CLAIMS1. A composition of matter (bifunctional degrader agent) comprising:a target-binding moiety that can bind to IgM,a cellular receptor-binding moiety that can bind to hepatocytes or other degrading cells through asialoglycoprotein receptors (ASGPR) of hepatocytes or other cell receptors on the surface of hepatocytes or other degrading cells in a subject or patient, anda linker moiety connecting the IgM-binding moiety and the cellular receptor-binding moiety.

2. The composition of matter of Claim 1, having a structure of:[AGN101], or[AGN102]or a pharmaceutically acceptable salt thereof, wherein:each of a and b is independently an integer of 1 or greater;each AT or ABT is an IgM-binding moiety or a fragment thereof;L is a linker moiety; andeach TBT is independently a cellular receptor-binding moiety that binds to hepatocytes or other degrading cells through asialoglycoprotein receptors (ASGPR) of hepatocytes or other cell receptors on the surface degrading cells in a subject or patient.

3. The composition of matter of Claim 2, wherein a is 1, b is 3, and each TBT comprises an N-acetyl-D-galactosamine (GalNAc) moiety.

4. The composition of matter of Claim 1, wherein the composition of matter has a structure selected from the group consisting of AGN7557, AGN7558, AGN7559, AGN7560, AGN7561, AGN7562, AGN7600, and AGN1742028030131-WO-PCT5. The composition of matter of Claim 1, wherein the IgM-binding moiety is an IgM antigen-binding protein, an antigen-binding protein variant, or an antigen-binding fragment thereof.

6. The composition of matter of Claim 1, wherein the IgM-binding moiety comprises a VHH moiety conjugated to the linker moiety, wherein one or two peptides comprising one or more epitopes are conjugated to one or each of the protein chains of the VHH moiety.

7. The composition of matter of Claim 1, wherein the IgM-binding moiety comprises a VHH nanobody8. The composition of matter of Claim 1, wherein the IgM-binding moiety comprises one or more autoimmune antibody-binding peptides and functional fragments thereof.

9. The composition of matter of Claim 1, wherein the IgM-binding moiety comprises a structure selected from the group consisting of ABT7229 (SEQ ID NO: 197), ABT7231 (SEQ ID NO: 199), ABT7232 (SEQ ID NO: 200), ABT7233 (SEQ ID NO: 201), ABT7322 (SEQ ID NO: 209), ABT7323 (SEQ ID NO: 210), and ABT7316 (SEQ ID NO: 201).

10. The composition of matter of Claim 1, wherein the cellular receptor-binding moiety comprises an ASGPR binding group connected through an amine group.

11. The composition of matter of Claim 1, wherein the cellular receptor-binding moiety comprises an ASGPR binding group according to the chemical structure:or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.30131-WO-PCT12. The composition of matter of Claim 1, wherein the cellular receptor-binding moiety has the following structure:where RAis a C1-C3 alkyl group optionally substituted with 1-5 halo groups (preferably RAis a methyl or ethyl group optionally substituted with from 1-3 fluoro groups);ZAis -(CH2)IM, -O-(CH2)IM, S-(CH2)IM, NRM-(CH2)IM, C(O)-(CH2)IM- a PEG group containing from 1 to 8 preferably 1-4 ethylene glycol residues or a -C(O)(CH2)IMNRM group (preferably a PEG containing group comprising from 1 to 8 ethylene glycol, preferably 2-4 ethylene glycol residues) where IM and RMare the same as above; andZB is absent, (CH2)IM, C(O)-(CH2)IM- or C(O)-(CH2)IM-NRM, where IM and RM are the same as above.

13. The composition of matter of Claim 1, wherein the ASGPR binding group comprises N-acetyl-D-galactosamine.

14. The composition of matter of Claim 1, wherein the cellular receptor-binding moiety has a structure selected from the group consisting of TBT6506, TBT3070, and TBT6544.

15. The composition of matter of any of Claims 1-14, for use as a medicament.

16. The composition of matter of any of Claims 1-14, for use in treating a disease state or condition associated with the upregulation of IgM in a subject.28230131-WO-PCT17. The composition of matter of any of Claims 1-14, for use in treating a disease selected from the Markush group consisting of IgM monoclonal gammopathy of undetermined significance (IgM MGUS), AL amyloidosis, anti-MAG neuropathy, Bing-Neel syndrome, CANOMAD syndrome, cold agglutinin disease, connective tissue diseases such as lupus, cryoglobulinemia, chronic lymphocytic leukemia (CLL), non-MAGPN, plasma cell dyscrasia, POEMS syndrome, Schnitzler syndrome, smoldering multiple myeloma, splenic marginal zone lymphoma, Tempi syndrome, and Waldenstrom macroglobulinaemia.

18. A pharmaceutical composition, comprising a composition of matter of any of Claims 1-14 and a pharmaceutically acceptable excipient.

19. A method of making the composition of matter of any of Claims 1-14.

20. A method of removing IgM in a subject or patient in need comprising administering to the subject or patient an agent of any of the preceding Claims 1-14.

21. A method of treating a disease state or condition associated with the upregulation of IgM in a subject or patient in need by administering to the subject or the patient in need of such treatment a therapeutically effective amount of a composition of matter of any of the preceding Claims 1-14.

22. A method of treating a disease in patient in need by administering to the patient in need of such treatment a therapeutically effective amount of a composition of matter of any of the preceding Claims 1-14, wherein the disease is selected from the group consisting of IgM monoclonal gammopathy of undetermined significance (IgM MGUS), AL amyloidosis, anti-MAG neuropathy, Bing-Neel syndrome, CANOMAD syndrome, cold agglutinin disease, connective tissue diseases such as lupus, cryoglobulinemia, chronic lymphocytic leukemia (CLL), non-MAGPN, plasma cell dyscrasia, POEMS syndrome, Schnitzler syndrome, smoldering multiple myeloma, splenic marginal zone lymphoma, Tempi syndrome, and Waldenstrom macroglobulinaemia.28330131-WO-PCT23. A composition comprising:a first composition of matter comprising:an IgM-binding moiety,a cellular receptor-binding moiety capable of binding to hepatocytes or other degrading cells through asialoglycoprotein receptors (ASGPR) of hepatocytes or other cell receptors on surface degrading cells, anda linker moiety connecting the IgM-binding moiety and the cellular receptor-binding moiety, andat least one additional composition of matter comprising:a cellular receptor-binding moiety capable of binding to hepatocytes or other degrading cells through asialoglycoprotein receptors (ASGPR) of hepatocytes or other cell receptors on surface degrading cells, anda linker moiety connecting the cellular receptor-binding moiety and capable of binding to an IgM-binding moiety.

24. A composition of matter having the structure of Formulas (I) or (II):VHH-[CONl]-Cys-S-[maleimide]-[LINKER]-[CON2]-[ASGPR](I)FcµR-[CON1]-Cys-S-[maleimide]-[LINKER]-[CON2]-[ASGPR](H)wherein, in Formulas (I) and (II):VHH is a moiety having SEQ ID NO: XX,FcµR is a moiety having SEQ ID NO: XY,[CONI] is a connecting moiety selected from a single chemical bond or a peptide moiety comprising an amino acid selected from the group consisting of G, E, L, P, Q, S, and T,[LINKER] is a linking moiety,[CON2] is a connecting moiety, wherein28430131-WO-PCT[LINKER] and [CON2] independently comprises a moiety selected from the group consisting of:[ASGPR] is an asialoglycoprotein binding moiety comprising a group having by Formula (Ila):

25. A composition of matter may have the structure of Formula (III):VHH-[CON1]-[IgG1Fc]-NH-[LINKER]-[CON2]-[ASGPR](HI)FcµR-[CON1]-[IgG1Fc]-NH-[LINKER]-[CON2]-[ASGPR](IV)wherein, in Formulas (III) and (IV):VHH is a moiety having SEQ ID NO: 212 (ABT7518),FcµR is a moiety having SEQ ID NO: 357 (ABT7519),[CONI] is a connecting moiety selected from a single chemical bond or a peptide moiety comprising an amino acid selected from the group consisting of G, E, L, P, Q, S, and T,[IgGlFc] is an IgGl fragment crystallizable region having SEQ ID NO:

396. [For example, the sequence identity with SEQ ID NO: 4 may be 80% or greater, 85% or greater, 90% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater.][LINKER] is a linking moiety,[CON2] is a connecting moiety, wherein28530131-WO-PCT[LINKER] and [CON2] independently comprises a moiety selected from the group consisting of:[ASGPR] is an asialoglycoprotein binding moiety comprising a group having by Formula (Ila):

26. A composition of matter may have the structure of Formula (V) and (VI):VHH-[CON1]-[LPETG]-[LINKER]-[CON2]-[ASGPR](V)FcµR-[CON1]-[LPETG]-[LINKER]-[CON2]-[ASGPR](VI)wherein, in Formulas (V) and (VI):VHH is a moiety having SEQ ID NO: XX,FcµR is a moiety having SEQ ID NO: XY,[CONI] is a connecting moiety selected from a single chemical bond or a peptide moiety comprising an amino acid selected from the group consisting of G, E, L, P, Q, S, and T,[LINKER] is a linking moiety,[CON2] is a connecting moiety, wherein28630131-WO-PCT[LINKER] and [CON2] independently comprises a moiety selected from the group consisting of:[ASGPR] is an asialoglycoprotein binding moiety comprising a group having by Formula (Ila):

27. A composition of matter having Formula (I):Formula (I)wherein,each is an IgM binding moiety or a fragment thereof;fs) (A) ( c )eachvis a means for connecting and30131-WO-PCTeach is a peptide moiety having SEQ ID NO: 396 or a sequence having95% sequence identity therewith, wherein the moieties are linked together via -<-s — s-f—two disulfide bridges S as shown in Formula (II), wherein one disulfide bridge links [ C j cysteine residues located in position 11 of SEQ ID NO: 396 of each moiety, and wherein the other disulfide bridge links cysteine residues located in position 14 of SEQ ID NO: 396 ofeach moiety;each J — - is a means for connecting (C) and ©x—, wherein(c)eachis connected to via a side chain amino group of a lysineresidueformeachis an asialoglycoprotein receptor (" ASGPR") binding moiety comprising an N-acetyl- D-galactosamine (" GalNAc") group having Formula (II):Formula (II)28830131-WO-PCT28. The composition of matter of Claim 27, wherein eachhas the sequence of SEQ ID NO: 4.

29. The composition of matter of Claim 27, wherein eachis a single chemical bond or a peptide connecting moiety comprising an amino acid selected from the group consisting of G, E, L, P, Q, S, and T.

30. The composition of matter of Claim 27, wherein eachcomprises the sequence of SEQ ID NO: 403.

31. The composition of matter of Claim 27, wherein each comprises the sequence of SEQ ID NO: 396.

32. The composition of matter of Claim 27, wherein eachcomprises a moiety selected from the group consisting of:wherein,X2are independently CH2, O, S, NR4, C(O), S(O), S(O)2, S(O)2O, OS(O)2, or OS(O)2O;X3are independently O, S, NR4, wherein R4is H or a C1-C3 alkyl; andk and n are independently 1 to 25.28930131-WO-PCT33. The composition of matter of Claim 27, wherein eachfurther comprises a moiety selected from the group consisting of:wherein,X2are independently CH2, O, S, NR4, C(O), S(O), S(O)2, S(O)2O, OS(O)2, or OS(O)2O;X3are independently O, S, NR4, wherein R4is H or a C1-C3 alkyl;k and n are independently 1 to 25.

34. The composition of matter of Claim 27, wherein eachcomprises one or more -(O)C-[(CH2)nO]m(CH2)nNH-, - [(CH2)nO]m(CH2)nNHC(O)[(CH2)nO]m-, and -[(CH2)nO]m(CH2)n{NHC(O)[(CH2)nO]m}p(CH2)nC(O)NH-, wherein each m and n are independently 1 to 10.

35. The composition of matter of Claim 27, wherein eachcomprises one or more - [(CH2)n- O]m-, wherein each m and n are independently 1 to 10.The composition of matter of Claim 27, wherein eachcomprises-(CH2)n-O-(CH2CH2O)n-(CH2)n-, wherein each n is independently 1 to 10.30131-WO-PCT37. The composition of matter of Claim 27, wherein eachcomprises a group having by Formula (Ila):wherein,ZBis absent, -(CH2)IM-, -C(=O)-(CH2)IM-, or -C(=O)-(CH2)IM-NRM-;RMis H or C1-C3alkyl; andeach occurrence of IM is independently 1, 2, or 3.30131-WO-PCTFormula (V)40. The composition of matter of Claim 27, wherein the lysine residue oflocated in position 31 or position 33 of SEQ ID NO: 396.29230131-WO-PCT41. The composition of matter of Claim 1, wherein the cysteine residues in positions 46 and 106 of SEQ ID NO: 396 are connected to form a disulfide bridge, and wherein the cysteine residues in positions 152 and 210 of SEQ ID NO: 396 are connected to form a disulfide bridge.29330131-WO-PCT

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