Glycoengineered polypeptides targeting IGG4 autoantibodies and uses thereof

Abstract

Provided herein are glycoengineered polypeptides comprising a first moiety comprising one or more peptides that specifically binds to an IgG4 antibody (e.g., an IgG4 autoantibody) and a second moiety comprising one or more glycans conjugated to the first moiety at one or more glycosylation sites. Further provided herein are compositions comprising glycoengineered polypeptides and / or nucleic acids encoding the same, as well as methods of making and using the same.

Description

GLYCOENGINEERED POLYPEPTIDES TARGETING IGG4 AUTOANTIBODIES AND USES THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 631,250 filed on April 8, 2024, the entire contents of which are hereby incorporated herein in their entirety.BACKGROUND

[0002] Anti-immunoglobulin G4 (IgG4) autoantibodies are commonly found in autoimmune diseases such as pemphigus vulgaris and membranous nephropathy and are often implicated in disease pathogenesis.SUMMARY

[0003] The present disclosure identifies certain challenges with existing therapies used to treat diseases associated with immunoglobulin G4 (IgG4) autoantibodies.

[0004] Among other things, the present disclosure provides a glycoengineered polypeptide comprising: (i) a first moiety comprising one or more peptides that specifically binds to a human immunoglobulin G4 (IgG4 antibody), e.g., as disclosed herein; and (ii) a second moiety comprising one or more glycans conjugated to a first moiety at one or more glycosylation sites, e.g., as disclosed herein.

[0005] This disclosure further provides a composition comprising a glycoengineered polypeptide as described herein. Further provided herein is a polynucleotide encoding a glycoengineered peptide disclosed herein.

[0006] This disclosure also provides a Leishmania host cell expressing a glycoengineered polypeptide disclosed herein.

[0007] Also provided herein is a method of treating and / or preventing a disease associated with one or more IgG4 autoantibodies. This disclosure further provides a method of ameliorating one or more symptoms of a disease associated with one or more IgG4 autoantibodies.

[0008] In some embodiments of any of the glycoengineered polypeptides disclosed herein, polynucleotides encoding glycoengineered polypeptides, compositions comprising the same, or methods of using the same, a first moiety comprises one or more peptides that binds an IgG4 antibody at a CHI domain, a hinge domain, a CH2 domain, a CH3 domain, or any combination thereof. In some embodiments, a first moiety of a glycoengineered polypeptide disclosed herein binds to an IgG4 antibody at a CH2 domain and / or a CH3 domain.

[0009] In some embodiments of any of the glycoengineered polypeptides disclosed herein, polynucleotides encoding glycoengineered polypeptides, compositions comprising the same, or methods of using the same, a first moiety comprises one or more peptides that binds an IgG4 antibody with a higher affinity as compared to binding to a non-IgG4 antibody. In some embodiments, a first moiety binds to an IgG4 autoantibody with an affinity that is at least 10-fold stronger as compared to binding of a first moiety to a non-IgG4 antibody. In some embodiments, a non-IgG4 antibody comprises an antibody of a class other than IgG4 (e.g., an IgGl antibody, an IgG2 antibody, an IgG3 antibody, an IgA antibody, an IgM antibody, an IgD antibody, or an IgE antibody, or a fragment or complex of any of the foregoing). In some embodiments, a first moiety substantially does not bind to a non-IgG4 antibody.

[0010] In some embodiments of any of the glycoengineered polypeptides disclosed herein, polynucleotides encoding glycoengineered polypeptides, compositions comprising the same, or methods of using the same, a first moiety binds to an IgG4 antibody with an affinity of about 1 OpM to about 1 OOOnM.

[0011] In some embodiments of any of the glycoengineered polypeptides disclosed herein, polynucleotides encoding glycoengineered polypeptides, compositions comprising the same, or methods of using the same, a glycoengineered polypeptide is characterized in that administration of a glycoengineered polypeptide to a cell, tissue, or subject reduces a level of an IgG4 antibody as compared to: (1) an otherwise similar cell, tissue, or subject that has not been administered a glycoengineered polypeptide; or (2) the same cell, tissue or subject, prior to administration of a glycoengineered polypeptide. In some embodiments, a reduction in IgG4 antibody is at least 5%. In some embodiments, a reduction in IgG4 antibody is about 10% to about 99%.

[0012] In some embodiments of any of the glycoengineered polypeptides disclosed herein, polynucleotides encoding glycoengineered polypeptides, compositions comprising the same, ormethods of using the same, a glycoengineered polypeptide is characterized in that administration of a glycoengineered polypeptide to a cell, tissue, or subject does not alter (e.g., does not reduce) a level of a non-IgG4 antibody as compared to: (1) an otherwise similar cell, tissue, or subject that has not been administered the glycoengineered polypeptide; or (2) the same cell, tissue or subject, prior to administration of a glycoengineered polypeptide. In some embodiments, at least 75% of a non-IgG4 antibody remains (e.g., is detectable) after administration of a glycoengineered polypeptide as compared to a level measured prior to the administration.

[0013] In some embodiments of any of the glycoengineered polypeptides disclosed herein, polynucleotides encoding glycoengineered polypeptides, compositions comprising the same, or methods of using the same, a first moiety comprises an antibody agent. In some embodiments, an antibody agent comprises an antigen binding fragment. In some embodiments, an antibody agent comprises a full antibody, a Fab fragment, an scFv, a nanobody, a duobody, or a single domain antibody (e.g., a VHH).

[0014] In some embodiments of any of the glycoengineered polypeptides disclosed herein, polynucleotides encoding glycoengineered polypeptides, compositions comprising the same, or methods of using the same, an antibody agent of a first moiety comprises one, two or three light chain complementarity determining regions (LC CDRs) and / or one, two or three heavy chain complementary determining regions (HC CDRs). In some embodiments, an antibody agent of a first moiety comprises a LC CDR1, a LC CDR2 and a LC CDR3. In some embodiments, an antibody agent of a first moiety comprises: (i) a LC CDR1, LC CDR2, and LC CDR3 sequence provided in Table 1; (ii) a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to an LC CDR1, LC CDR2, and LC CDR3 sequence provided in Table 1; or (iii) a sequence having at least 5 substitutions relative to an LC CDR1, LC CDR2, and LC CDR3 sequence provided in Table 1. In some embodiments, an antibody agent of a first moiety comprises a HC CDR1, a HC CDR2 and a HC CDR3. In some embodiments, an antibody agent of a first moiety comprises: (i) a HC CDR1, HC CDR2, and HC CDR3 sequence provided in Table 2; (ii) a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identityto an HC CDR1, HC CDR2, and HC CDR3 sequence provided in Table 2; or (iii) a sequence having at least 5 substitutions relative to an HC CDR1, HC CDR2, and HC CDR3 sequence provided in Table 2. In some embodiments, an antibody agent of a first moiety comprises (a) a light chain (LC) comprising a sequence provided in Table 1, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions relative to a VL region provided in Table 1; and / or (b) a heavy chain (HC) comprising a sequence provided in Table 2, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity thereto or a sequence having at least 5, 10, or 20 substitutions relative to a VH region provided in Table 2.

[0015] In some embodiments of any of the glycoengineered polypeptides disclosed herein, polynucleotides encoding glycoengineered polypeptides, compositions comprising the same, or methods of using the same, a first moiety binds to a human IgG4 antibody. In some embodiments, a human IgG4 antibody is an IgG4 autoantibody or a fragment or a complex thereof.

[0016] In some embodiments, an IgG4 autoantibody comprises: an anti-PLA2R IgG4 autoantibody or a fragment or a complex thereof; an anti-THSD7A IgG4 autoantibody or a fragment or a complex thereof; an anti-NELL IgG4 autoantibody or a fragment or a complex thereof; an anti -NEP IgG4 autoantibody or a fragment or a complex thereof; an anti -EXT 1 IgG4 autoantibody or a fragment or a complex thereof; and / or an anti-EXT2 IgG4 autoantibody or a fragment or a complex thereof.

[0017] In some embodiments, an IgG4 autoantibody comprises an anti- AD AMTS 13 IgG4 autoantibody or a fragment or a complex thereof.

[0018] In some embodiments, an IgG4 autoantibody comprises an anti-desmoglein 1 IgG4 autoantibody or a fragment or a complex thereof; and / or an anti-desmoglein 3 IgG4 autoantibody or a fragment or a complex thereof.

[0019] In some embodiments, an IgG4 autoantibody comprises an anti-nicotinic acetylcholine receptor (nAChR) IgG4 autoantibody or a fragment or a complex thereof; an anti-muscle-specific kinase (MuSK) IgG4 autoantibody or a fragment or a complex thereof; and / or an anti- low-density lipoprotein receptor-related protein 4 (LRP4) IgG4 autoantibody or a fragment or a complex thereof.

[0020] In some embodiments of any of the glycoengineered polypeptides disclosed herein, polynucleotides encoding glycoengineered polypeptides, compositions comprising the same, or methods of using the same, a second moiety comprises one or more glycans that specifically bind to one or more endocytic receptors. In some embodiments, an endocytic receptor is or comprises an endocytic lectin. In some embodiments, an endocytic receptor is chosen from: an asialoglycoprotein receptor (ASGPR); a mannose binding receptor, a Cluster of Differentiation 206 (CD206) receptor; a DC-SIGN (Cluster of Differentiation 209 or CD209) receptor; a C-Type Lectin Domain Family 4 Member G (LSECTin) receptor; a macrophage inducible Ca2+- dependent lectin receptor (Mincle); a L-SIGN CD209L receptor; dectin- 1; dectin -2, langerin, macrophage mannose 2 receptor, BDCA-2, DCIR, MBL, MDL, MICL, CLEC2, DNGR1, CLEC12B, DEC-205, and mannose 6 phosphate receptor (M6PR), or a combination thereof.

[0021] In some embodiments, a second moiety comprises a glycan structure comprising a biantennary GalNAc. In some embodiments, a biantennary GalNac binds to an asialoglycoprotein receptor (ASGPR) or a fragment or variant thereof, or a complex comprising ASGPR. In some embodiments, an N-glycan has a structure ofwherein the black square represents an N-acetyl galactosamine (GalNAc), the white square represents an N-acetylglucosamine (GlcNAc) residue and the black circle represents a mannose (Man) residue, and wherein X represents an amino acid residue of a first moiety. In some embodiments, an N-glycan is conjugated to a glycoengineered polypeptide at least one, two, three, or four N-glycosylation sites. In some embodiments, an N-glycan is conjugated to a glycoengineered polypeptide at one, two, three, or four N-glycosylation sites. In some embodiments, an N-glycosylation site comprises a consensus sequence of N-X-S / T or N-X-C, wherein X is any amino acid except proline. In some embodiments, an N-glycosylation site is naturally occurring.

[0022] In some embodiments, an N-glycosylation site is engineered into an amino acid sequence of a first moiety. In some embodiments, an N-glycosylation site comprises a sequence of SEQ ID NO: 161, SEQ ID NO: 163, SEQ ID NO: 168, or SEQ ID NO: 169. In some embodiments, an endocytic receptor is or comprises ASGPR or a fragment or variant thereof, or a complex comprising ASGPR. In some embodiments, when an endocytic receptor is ASGPR, a glycan structure of a second moiety comprises a terminal GalNac.

[0023] In some embodiments of any of the glycoengineered polypeptides disclosed herein, polynucleotides encoding glycoengineered polypeptides, compositions comprising the same, or methods of using the same, a glycoengineered polypeptide is characterized in that when administered to a cell, tissue, or subject, a glycoengineered polypeptide which is bound to an IgG4 antibody (e.g., IgG4 autoantibody) or a complex comprising same via a first moiety, and to an endocytic receptor via a second moiety results in degradation of a IgG4 antibody or a complex comprising same. In some embodiments, degradation comprises internalization into a cell. In some embodiments, an IgG4 antibody (e.g., IgG4 autoantibody) or an immune complex comprising same and a glycoengineered polypeptide are internalized into a cell. In some embodiments, internalization occurs in an ASGPR-dependent manner. In some embodiments, a magnitude of internalization depends on an expression and / or an activity level of ASGPR. In some embodiments, degradation comprises lysosomal degradation. In some embodiments, an IgG4 antibody (e.g., IgG4 autoantibody) or an immune complex comprising same, and a glycoengineered polypeptide are internalized into a lysosome.

[0024] In some embodiments, a composition disclosed herein comprises a population of glycoengineered polypeptides as disclosed herein. In some embodiments, a population of glycoengineered polypeptides has an N-glycan profile that is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or about 100% homogeneous at one or more N-glycosylation site(s).

[0025] In some embodiments, a composition disclosed herein is a pharmaceutical composition.

[0026] The present disclosure further provides a method comprising delivering a pharmaceutical composition as disclosed herein to a cell, tissue, or subject.

[0027] Disclosed herein is a method of degrading an IgG4 antibody (e.g., an IgG4 autoantibody) or a complex comprising same comprising delivering a pharmaceutical composition as disclosed herein to a cell, tissue, or subject.

[0028] Also provided herein is a method of delivering an IgG4 antibody (e.g., an IgG4 autoantibody) or a complex comprising same to a lysosome comprising delivering a pharmaceutical composition as disclosed herein to a cell, tissue, or subject.

[0029] In some embodiments, any of the methods disclosed herein further comprise administering a pharmaceutical composition to a cell, tissue, or subject. In some embodiments, a subject has or is diagnosed as having a disease associated with one or more IgG4 autoantibodies. In some embodiments, a disease associated with one or more IgG4 autoantibodies comprises: Pemphigus Vulgaris / Folaceus; Muscle-specific kinase (MuSK) myasthenia gravis (MG), Idiopathic Thrombotic Thrombocytopenia Purpura (iTTP), idiopathic membranous nephropathy (iMN), Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), or Immunoglobulin G4- Related Disease (IgG4-RD).

[0030] In some embodiments, administration of a glycoengineered polypeptide disclosed herein or a pharmaceutical compositions comprising the same to a subject, reduces a level of an IgG4 autoantibody as compared to a subject who has not been administered a pharmaceutical composition or as compared to the same subject prior to administration of a pharmaceutical composition. In some embodiments, a reduction in IgG4 antibody is at least 5%. In some embodiments, a reduction in IgG4 antibody is about 10% to about 99%.

[0031] In some embodiments, administration of a glycoengineered polypeptide disclosed herein or a pharmaceutical compositions comprising the same to a subject substantially does not reduce a level of a non-IgG4 immunoglobulin as compared to a subject who has not been administered a pharmaceutical composition or as compared to the same subject prior to administration of a pharmaceutical composition. In some embodiments, at least 75% of a non-IgG4 immunoglobulin remains (e.g., is detectable) after administration of a pharmaceutical composition. In some embodiments, administration of a pharmaceutical composition reduces less than 10% of a non- IgG4 immunoglobulin as compared to a subject who has not been administered a pharmaceutical composition or as compared to the same subject prior to administration of a pharmaceutical composition.

[0032] In some embodiments, a non-IgG4 immunoglobulin is an immunoglobulin of a different IgG class as compared to IgG4.

[0033] In some embodiments, a non-IgG4 immunoglobulin is an immunoglobulin of a different isotype as compared to IgG4.

[0034] In some embodiments, a non-IgG4 immunoglobulin is or comprises IgGl, IgG2, IgG3, IgA, IgM, IgD or IgE, or a fragment or complex of any of the foregoing.

[0035] Additional features of glycoengineered polypeptides disclosed herein, nucleic acids encoding the same, composition comprising glycoengineered polypeptides or nucleic acids encoding the same, and methods of making and using the same are provided throughout the present disclosure.BRIEF DESCRIPTION OF THE DRAWING

[0036] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings(s) will be provided by the Office upon request and payment of the necessary fee.

[0037] The Figures described below, which together make up the Drawing, are for illustration purposes only, not for limitation.

[0038] FIGS. 1A-1C show immunodepletion of IgG isotypes from pooled healthy donor serum. Exemplary anti-IgG4 antibody agents were coated on magnetic beads followed by incubation with healthy donor serum. Samples were next placed on a magnet and supernatant collected to obtain the depleted sera. IgG content was measured by multiplex ELISA. Representative depletion of IgG isotypes is shown for a representative anti-IgG4 antibody agent from Bin 3 (FIG. 1A) and two distinct representative anti-IgG4 antibody agents from Bin-1 (FIGS. 1B-1C).

[0039] FIGS. 2A-2B show immunodepletion of autoantibodies from pMN serum. Exemplary anti-IgG4 antibody agents were coated on beads followed by incubation with pMN serum. Samples were next placed on a magnet and supernatant collected to obtain the depleted sera. Anti-PLA2R autoantibody in sample was evaluated by ELISA. Representative depletion of autoantibodies from the sera of 3 pMN patients for two distinct anti-IgG4 antibody agents in bin- 1 is shown in FIGS. 2A and 2B.

[0040] FIGS. 3A-3C show exemplary glycoengineered polypeptide binding to IgG4. Exemplary glycoengineered polypeptides binding to human purified IgG4 was evaluated by ELISA. Representative binding to human purified IgG4 are shown for a representative for each bin: FIG. 3A, bin-1; FIG. 3B, bin-2; and FIG. 3C, bin-3. An exemplary glycoengineered polypeptide is also referred to as a “G-LyTAC” herein.

[0041] FIG. 4 is a graph depicting binding affinity from a Surface Plasmon Resonance (SPR) assay for an exemplary glycoengineered anti-IgG4 Fab polypeptide in bin-3 for human IgG4 (hIgG4).

[0042] FIG. 5 is a panel of graphs depicting binding of a representative anti-IgG4 antibody agent from bin 3 and a corresponding exemplary glycoengineered polypeptide to different IgG subclasses and Ig isotypes.

[0043] FIG. 6 shows binding kinetics of an exemplary glycoengineered anti-IgG4 Fab polypeptide from bin-3 to ASGPR1 as determined by SPR.

[0044] FIGS. 7A-7B depict glycan content and purity analysis of exemplary glycoengineered polypeptides.

[0045] FIGS. 8A-8B show the internalization of an exemplary anti-IgG4 glycoengineered polypeptides by fluorescence microscopy. FIG. 8A is a panel of microscopy images. FIG. 8B isa graph showing internalization of the exemplary glycoengineered anti-IgG4 polypeptide across multiple doses (as indicated) and over time. In FIG. 8B, data points with 500nM are displayed with the top most line, followed by data points with 166.6nM and data points with 55.5nM (as indicated in the graph).

[0046] FIGS. 9A-9C depict internalization of exemplary glycoengineered anti-IgG4 polypeptides in HepG2 cells. Exemplary glycoengineered anti-IgG4 polypeptides were labelled with a pH sensitive dye (pHrodo) to monitor internalization and localization in the lysosome. HepG2 wt, ASGPRlko and ASGPR2ko cells were incubated with pHrodo-labelled- exemplary glycoengineered polypeptides for 3 hours followed by evaluation of internalization by flow cytometry. Representative data for 3 distinct binders from bin-2 are shown in FIGS. 9A, 9B, and 9C.

[0047] FIGS. 10A-10C show degradation of IgG4 in HepG2 cells. HepG2 cells were incubated with exemplary glycoengineered anti-IgG4 polypeptides alone or in complex with human purified IgG4 or recombinant IgG4 for 4h (TO). HepG2 cells were then washed and incubated for an additional l-24h to allow for complex degradation. Internalization of IgG4 was monitored by Western Blot. Representative data is shown for a bin-3 exemplary glycoengineered anti-IgG4 polypeptide (FIG. 10A), and two distinct exemplary glycoengineered anti-IgG4 polypeptides from Bin 1 (FIGS. 10B-C).

[0048] FIG. 11 is a graph showing IgG4 polypeptide levels in animals administered an exemplary glycoengineered anti-IgG4 polypeptide from bin 3.

[0049] FIG. 12 is a graph showing IgG4 polypeptide levels in animals administered an exemplary glycoengineered anti-IgG4 polypeptide from bin 1.

[0050] FIG. 13 is a graph showing IgG4 polypeptide levels in animals administered an exemplary glycoengineered anti-IgG4 polypeptide from bin 2.

[0051] FIGS. 14A-14F are graphs showing in vivo selective depletion of IgG4 in animals administered exemplary glycoengineered anti-IgG4 polypeptides. FIG. 14A: IgG4 levels in animals administered an exemplary glycoengineered anti-IgG4 polypeptide from bin-3. FIG. 14B: IgGl levels in animals administered an exemplary glycoengineered anti-IgG4 polypeptide from bin-3. FIG. 14C: IgGl levels in animals administered an exemplary glycoengineered anti-IgG4 polypeptide from bin-1. FIG. 14D: IgG2 levels in animals administered an exemplary glycoengineered anti-IgG4 polypeptide from bin-1. FIG. 14E: IgG3 levels in animals administered an exemplary glycoengineered anti-IgG4 polypeptide from bin-1. FIG. 14F: IgG4 levels in animals administered an exemplary glycoengineered anti-IgG4 polypeptide from bin-1.

[0052] FIGS. 15A-15B are each a pair of graphs depicting the levels of liver enzymes in animals administered an exemplary glycoengineered anti-IgG4 polypeptide. FIG. 15A: alanine aminotransferase (ALT) (left) and alkaline phosphatase (AP)(right) levels in animals administered (i.v.) different doses of an exemplary glycoengineered polypeptide from bin-2 or PBS vehicle. FIG. 15B: Aspartate aminotransferase (ASP) (left) and gamma-glutamyl transferase (GGT) (right) levels in animals administered (i.v.) different doses of an exemplary glycoengineered anti-IgG4 polypeptide from bin-2 or PBS vehicle.

[0053] FIG. 16 is a set of graphs depicting blood chemistry in animals administered an exemplary glycoengineered anti-IgG4 polypeptide. FIG. 16 depicts levels of creatine kinase (left panel), albumin (middle panel) and bilirubin (right panel), in animals administered an exemplary glycoengineered polypeptide from bin-2 (at an i.v. dose of 5mg / kg, 12.5 mg / kg, or 25mg / kg), or PBS vehicle.

[0054] FIGS. 17A-17B are graphs depicting depletion of IgG4 in animals administered an exemplary glycoengineered anti-IgG4 polypeptide. FIG. 17A: IgG4 levels in animals administered an exemplary glycoengineered anti-IgG4 polypeptide from bin-1 intravenously at different doses compared to animals administered PBS only. Serum samples were collected at the timepoints indicated and total IgG4 levels were quantified by ELISA. The graph shows the average ± SEM of % of IgG4 target remaining in serum, normalized to predose level, from N=3 animals / group. FIG. 17B: IgG4 levels in animals administered an exemplary glycoengineered anti-IgG4 polypeptide from bin-1 subcutaneously compared to animals administered PBS only. Serum samples were collected at the timepoints indicated and total IgG4 levels were quantified by ELISA. The graph shows the average ± SEM of % of IgG4 target remaining in serum, normalized to predose level, from N=3 animals / group.

[0055] FIGS. 18A-18B show tissue distribution of an exemplary glycoengineered anti-IgG4 polypeptide. FIG. 18A: Representative images of tissue distribution of an exemplary glycoengineered anti-IgG4 polypeptide from bin-1 assessed by ex vivo imaging of tissuescollected at 15 min, 1 hour, and 72 hours. FIG. 18B: Quantification of tissue distribution of the exemplary glycoengineered anti-IgG4 polypeptide from bin-1 at 1 hour. The y-axis represents fluorescence (Ph / s / cm2 / sr).

[0056] FIG. 19 shows a graph depicting the in vivo depletion of pathogenic pMN patient- derived autoantibodies using an exemplary glycoengineered anti-IgG4 polypeptide from bin-1.Definitions

[0057] In this application, unless otherwise clear from context, (i) the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; (iii) the terms “comprising” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; and (iv) the terms “about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (v) where ranges are provided, endpoints are included.

[0058] Glycans: As used herein, the term “glycan” refers to one or more saccharides or sugar chains that can be attached to a protein or lipid to form a glycoconjugate. A glycan conjugated to a protein forms a glycoprotein. A glycan conjugated to a nitrogen atom of an amino acid residue is an N-linked glycan and a glycan conjugated to an oxygen atom of an amino acid residue is an O-linked glycan. As will be appreciated by those of ordinary skill in the art, the structure of a glycan indicates if a specific glycan is an N-linked glycan.

[0059] Glycoengineered. As used herein, the term “glycoengineered,” or an equivalent thereof means a process of glycosylating a target protein (e.g., a glycoengineered polypeptide disclosed herein), or a target protein made by such process. In some embodiments, the process uses a host cell system that has one or more enzymes (e.g., pathways) that provides for glycosylation of the target protein; in some other embodiments, the process is performed by chemically attaching one or more glycans to a target protein, e.g., using Click chemistry. Such a host cell system can be genetically engineered to introduce a glycosylation pathway to selectively glycosylate a target protein with a particular glycan structure. A host cell used to generate a glycoengineered target protein can include, for example, a recombinant nucleic acid encoding a target protein; and arecombinant nucleic acid encoding a heterologous glycosyltransferase. The host cell system used for glycoengineering (e.g., to generate a glycoengineered protein) can introduce, eliminate or modify N-linked glycosylation. The host cell system used for glycoengineering (e.g, to generate a glycoengineered protein) can introduce, eliminate or modify O-linked glycosylation. The host cell used for glycoengineering or to generate a glycoengineered target protein can be a mammalian cell, an insect cell, a yeast cell, a bacterial cell, a plant cell, a microalgae, or a protozoa. The protozoa used for glycoengineering can be a species of Leishmania. A glycoengineered target protein also includes a target protein that has been engineered to be selectively glycosylated at one or more specific sites when generated in the host cell system.

[0060] Glycoengineered polypeptide: As used herein, a “glycoengineered polypeptide” is a polypeptide that mediates the internalization and / or degradation of a target protein by specifically binding to a target protein (e.g., an IgG4 antibody) and engaging with one or more endocytic receptors. In some embodiments, binding (e.g., simultaneous binding) of a glycoengineered polypeptide to a target protein and an endocytic receptor internalizes a target protein and / or activates one or more degradation pathways.

[0061] Glycosylation site: As used herein, the term “glycosylation site” refers to a site of glycosylation in a protein. Such a glycosylation site, also referred to as a glycosite herein, can be naturally present in the amino acid sequence of a protein or recombinantly engineered into the protein by addition or substitution or deletion of amino acids. In some embodiments, a glycosylation site is present in a so-called glycotag that is fused to a glycoengineered polypeptide disclosed herein. In certain embodiments, a glycotag is fused to a protein to create a bispecific binding protein. As used herein a glycotag refers to a peptide containing consensus N- glycosylation site sequence fused to N- or a C-terminal or both termini of a protein or polypeptide. In some embodiments, the glycotag is fused to the C-terminus of the of the glycoengineered polypeptide disclosed herein via a peptide linker. In some embodiments, the glycotag is fused to the N-terminus of the glycoengineered polypeptide disclosed herein via a peptide linker. In some embodiments, the peptide linker is a consensus peptide sequence. In some embodiments, the consensus peptide sequence is 1, 2, 3, 4, 5, 6, 7 or more amino acid residues in length. In some embodiments, the bifunctional protein provided herein contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more glycotags.

[0062] Endocytic receptor: As used herein, the term “endocytic receptor” refers to a receptor or a fragment thereof that binds to a target and internalizes the target into a cell. In some embodiments, an endocytic receptor recognizes and binds to one or more glycans on a target. In some embodiments, binding of an endocytic receptor to a target internalizes the target into a cell, e.g., into a lysosome or phagosome. In some embodiments, an endocytic receptor is or comprises an endocytic lectin. In some embodiments, an endocytic receptor is chosen from: an asialoglycoprotein receptor (ASGPR); a mannose binding receptor, a Cluster of Differentiation 206 (CD206) receptor; a DC-SIGN (Cluster of Differentiation 209 or CD209) receptor; a C-Type Lectin Domain Family 4 Member G (LSECTin) receptor; a macrophage inducible Ca2+- dependent lectin receptor (Mincle); a L-SIGN CD209L receptor; dectin- 1; dectin -2, langerin, macrophage mannose 2 receptor, BDCA-2, DCIR, MBL, MDL, MICL, CLEC2, CLEC10, DNGR1, CLEC12B, DEC-205, and mannose 6 phosphate receptor (M6PR), or a combination thereof.

[0063] Administration: As used herein, the term “administration” typically refers to the administration of a composition to a subject or system, for example to achieve delivery of an agent that is, or is included in or otherwise delivered by, the composition. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example an animal or a human. In some embodiments, an animal is a domestic animal, such as a companion animal, e.g., a dog or a cat; in some embodiments, an animal is an animal used in agriculture (e.g., farming [e.g., a cow, a sheep or a horse]) or for recreation. For example, in some embodiments, administration may be systemic or local. Those skilled in the art will be aware of appropriate administration routes for use with particular therapies described herein, for example which include bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e. g. intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc. In some embodiments, administration may be by injection (e.g., intramuscular, intravenous, or subcutaneous injection). In some embodiments, injection may involve bolus injection, drip, perfusion, or infusion. In some embodiments, administration may involve only asingle dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time. In some embodiments, an antibody agent can be formulated for oral delivery. For example, one with skill in the art will understand that an antibody agent disclosed herein can be formulated for oral delivery using technologies developed by Oramed (https: / / www.oramed.com / ) or Premas (https: / / www.premasbiotech.com / ).

[0064] Adult. As used herein, the term “adult” refers to a human eighteen years of age or older. In some embodiments, a human adult has a weight within the range of about 90 pounds to about 250 pounds.

[0065] Affinity. As is known in the art, “affinity” is a measure of the tightness with which two or more binding partners associate with one another. Those skilled in the art are aware of a variety of assays that can be used to assess affinity, and will furthermore be aware of appropriate controls for such assays. In some embodiments of a glycoengineered polypeptide disclosed herein, a first moiety comprising one or more peptides that specifically bind to a target autoantibody (e.g., an IgG4 autoantibody), has a high affinity to an autoantigen (e.g., a IgG4 autoantigen). In some embodiments, a high affinity is an affinity of about 50pM to about 200pM.In some embodiments, affinity is assessed in a quantitative assay. In some embodiments, a moderate affinity is an affinity of about 0.201nM to about 6nM. In some embodiments, affinity is assessed in a quantitative assay. In some embodiments, affinity is assessed over a plurality of concentrations (e.g., of one binding partner at a time). In some embodiments, affinity is assessed in the presence of one or more potential competitor entities (e.g., that might be present in a relevant - e.g., physiological - setting). In some embodiments, affinity is assessed relative to a reference (e.g., that has a known affinity above a particular threshold [a “positive control” reference] or that has a known affinity below a particular threshold [ a “negative control” reference”]. In some embodiments, affinity may be assessed relative to a contemporaneous reference; in some embodiments, affinity may be assessed relative to a historical reference. Typically, when affinity is assessed relative to a reference, it is assessed under comparable conditions.

[0066] Avidity: As is known in the art, “avidity” is a measure of the accumulated strength of multiple non-covalent interactions between two or more binding partners in a complex. Those skilled in the art are aware of a variety of assays that can be used to assess avidity, and will furthermore be aware of appropriate controls for such assays. In some embodiments, avidity can be determined by (1) a binding affinity of two or more binding partners in a complex; (2) valency of each of the binding partners in a complex; and / or (3) structural arrangements of two or more binding partners in a complex. In some embodiments, the avidity of binding between two or more binding partners is more than a sum of each binding affinity between the two or more binding partners. In some embodiments, avidity is also referred to as apparent affinity or functional affinity. In some embodiments of a glycoengineered polypeptide disclosed herein, a second moiety comprising one or more glycans which can bind to a receptor (e.g., an endocytic receptor) contributes to binding avidity of the glycoengineered polypeptide. In some embodiments, an endocytic receptor is ASGPR or a fragment or variant thereof. In some embodiments, avidity is assessed in a quantitative assay. In some embodiments, avidity is assessed over a plurality of concentrations. In some embodiments, avidity is assessed in the presence of one or more potential competitor entities (e.g., that might be present in a relevant - e.g., physiological - setting). In some embodiments, avidity may be assessed relative to a contemporaneous reference; in some embodiments, avidity may be assessed relative to a historical reference. Typically, when avidity is assessed relative to a reference, it is assessed under comparable conditions.

[0067] Agent. As used herein, the term “agent”, may refer to a physical entity or phenomenon. In some embodiments, an agent may be characterized by a particular feature and / or effect. In some embodiments, an agent may be a compound, molecule, or entity of any chemical class including, for example, a small molecule, polypeptide, nucleic acid, saccharide, lipid, metal, or a combination or complex thereof. In some embodiments, the term “agent” may refer to a compound, molecule, or entity that comprises a polymer. In some embodiments, the term may refer to a compound or entity that comprises one or more polymeric moieties. In some embodiments, the term “agent” may refer to a compound, molecule, or entity that is substantially free of a particular polymer or polymeric moiety. In some embodiments, the term may refer to a compound, molecule, or entity that lacks or is substantially free of any polymer or polymeric moiety.

[0068] Amino acid: in its broadest sense, as used herein, refers to any compound and / or substance that can be incorporated into a polypeptide chain, e.g., through formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure H2N- C(H)(R)-COOH. In some embodiments, an amino acid is a naturally- occurring amino acid. In some embodiments, an amino acid is a non-natural amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid. “Standard amino acid” refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides. “Nonstandard amino acid” refers to any amino acid, other than the standard amino acids, regardless of whether it is prepared synthetically or obtained from a natural source. In some embodiments, an amino acid, including a carboxy- and / or amino-terminal amino acid in a polypeptide, can contain a structural modification as compared with the general structure above. For example, in some embodiments, an amino acid may be modified by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and / or substitution (e.g., of the amino group, the carboxylic acid group, one or more protons, and / or the hydroxyl group) as compared with the general structure. In some embodiments, such modification may, for example, alter the circulating half-life of a polypeptide containing the modified amino acid as compared with one containing an otherwise identical unmodified amino acid. In some embodiments, such modification does not significantly alter a relevant activity of a polypeptide containing the modified amino acid, as compared with one containing an otherwise identical unmodified amino acid. As will be clear from context, in some embodiments, the term “amino acid” may be used to refer to a free amino acid; in some embodiments it may be used to refer to an amino acid residue of a polypeptide.

[0069] Animal: as used herein refers to a member of the animal kingdom. In some embodiments, "animal" refers to humans; unless otherwise specified, in many embodiments, a human may be of either gender and / or at any stage of development. In some embodiments, "animal" refers to non-human animals; unless otherwise specified, in many embodiments, a nonhuman animal may be of any gender and / or at any stage of development. In certain embodiments, a non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, and / or a pig). In some embodiments, an animal may be, for example, a mammal, a bird, a reptile, an amphibian, a fish, an insect, a worm, etc..In some embodiments, an animal may be a transgenic animal, genetically engineered animal, and / or a clone.

[0070] Antibody agent: As used herein, the term “antibody agent” refers to a polypeptide that includes canonical immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen. In the case of an anti-IgG4 antibody agent, the antigen that is bound by the anti-IgG4 antibody agent is an IgG4 antibody (e.g., an IgG4 autoantibody). As is known in the art, intact antibodies as produced in nature are approximately 150 kD tetrameric agents comprised of two identical heavy chain polypeptides (about 50 kD each) and two identical light chain polypeptides (about 25 kD each) that associate with each other into what is commonly referred to as a “Y-shaped” structure. Each heavy chain is comprised of at least four domains (each about 110 amino acids long)- an amino-terminal variable (VH) domain (located at the tips of the Y structure), followed by three constant domains: CHI, CH2, and the carboxy -terminal CH3 (located at the base of the Y’s stem). A short region, known as the “switch”, connects the heavy chain variable and constant regions. The “hinge” connects CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region connect the two heavy chain polypeptides to one another in an intact antibody. Each light chain is comprised of two domains - an amino-terminal variable (VL) domain, followed by a carboxy-terminal constant (CL) domain, separated from one another by another “switch”. Intact antibody tetramers are comprised of two heavy chain-light chain dimers in which the heavy and light chains are linked to one another by a single disulfide bond; two other disulfide bonds connect the heavy chain hinge regions to one another, so that the dimers are connected to one another and the tetramer is formed. Naturally-produced antibodies are also glycosylated, typically on the CH2 domain. Each domain in a natural antibody has a structure characterized by an “immunoglobulin fold” formed from two beta sheets (e.g., 3-, 4-, or 5-stranded sheets) packed against each other in a compressed antiparallel beta barrel. Each variable domain contains three hypervariable loops known as “complementarity determining regions” (CDR1, CDR2, and CDR3) and four somewhat invariant “framework” regions (FR1, FR2, FR3, and FR4). When natural antibodies fold, the FR regions form the beta sheets that provide the structural framework for the domains, and the CDR loop regions from both the heavy and light chains are brought together in three- dimensional space so that they create a single hypervariable antigen binding site located at the tip of the Y structure. The Fc region of naturally-occurring antibodies binds to elements of thecomplement system, and also to receptors on effector cells, including for example effector cells that mediate cytotoxicity. As is known in the art, affinity and / or other binding attributes of Fc regions for Fc receptors can be modulated through glycosylation or other modification. In some embodiments, antibodies produced and / or utilized in accordance with the present disclosure include glycosylated Fc domains, including Fc domains with modified or engineered such glycosylation. In some embodiments, antibodies produced and / or utilized in accordance with the present disclosure include one or more modifications on an Fc domain, e.g., an effector null mutation, e.g., a LALA, LAGA, FEGG, AAGG, or AAGA mutation. For purposes of the present disclosure, in certain embodiments, any polypeptide or complex of polypeptides that includes sufficient immunoglobulin domain sequences as found in natural antibodies can be referred to and / or used as an “antibody”, whether such polypeptide is naturally produced (e.g., generated by an organism reacting to an antigen), or produced by recombinant engineering, chemical synthesis, or other artificial system or methodology. In some embodiments, an antibody is polyclonal; in some embodiments, an antibody is monoclonal. In some embodiments, an antibody has constant region sequences that are characteristic of dog, cat, mouse, rabbit, primate, or human antibodies. In some embodiments, antibody sequence elements are human, humanized, primatized, chimeric, etc, as is known in the art. Moreover, the term “antibody” as used herein, can refer in appropriate embodiments (unless otherwise stated or clear from context) to any of the art-known or developed constructs or formats for utilizing antibody structural and functional features in alternative presentation. For example, in some embodiments, an antibody utilized in accordance with the present invention is in a format selected from, but not limited to, intact IgA, IgG, IgE or IgM antibodies; bi- or multi- specific antibodies (e.g., Zybodies®, etc); antibody fragments such as Fab fragments, Fab’ fragments, F(ab’)2 fragments, Fd’ fragments, Fd fragments, and isolated CDRs or sets thereof; single chain Fvs; polypeptide-Fc fusions; single domain antibodies (e.g., VHH [e.g., a camelid VHH] or NAR) alternative scaffolds or antibody mimetics (e.g., anticalins, FN3 monobodies, DARPins, Affibodies, Affilins, Affimers, Affitins, Alphabodies, Avimers, Fynomers, Im7, VLR, VNAR, Trimab, CrossMab, Trident); nanobodies, binanobodies, F(ab’)2, Fab’, di-sdFv, trifunctional antibodies, diabodies, and minibodies, etc. In some embodiments, relevant formats may be or include: Adnectins®; Affibodies®; Affilins®; Anticalins®; Avimers®; BiTE®s; cameloid antibodies; Centyrins®; ankyrin repeat proteins or DARPINs®; dual-affinity re-targeting (DART) agents; Fynomers®; shark single domainantibodies such as IgNAR; immune mobilixing monoclonal T cell receptors against cancer (ImmTACs); KALBITOR®s; MicroProteins; Nanobodies® minibodies; masked antibodies (e.g., Probodies®); Small Modular ImmunoPharmaceuticals (“SMIPs™ ); single chain or Tandem diabodies (TandAb®); TCR-like antibodies;, Trans-bodies®; TrimerX®; VHHs. In some embodiments, an antibody may lack a covalent modification (e.g., attachment of a glycan) that it would have if produced naturally. In some embodiments, an antibody format is or comprises a VHH, e.g., a camelid VHH. In some embodiments, a VHH is a multivalent VHH, e.g., a bivalent VHH. In some embodiments, an antibody comprises a single domain antibody, e.g., comprising one or more additional domains such as an Fc, a half-Fc (e.g., comprising an interchain cysteine mutant), an albumin domain, or combinations thereof. In some embodiments, an antibody comprises a single chain Fv, e.g., comprising one or more additional domains such as an Fc, a half-Fc (e.g., comprising an interchain cysteine mutant), an albumin domain, or combinations thereof. In some embodiments, an antibody comprises a polypeptide- Fc fusion. In some embodiments, an antibody may contain a covalent modification (e.g., attachment of a glycan, a pay load [e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc], or other pendant group [e.g., poly-ethylene glycol, etc.]).

[0071] Antibody fragment. As used herein, an “antibody fragment” refers to a portion of an antibody or antibody agent as described herein and typically refers to a portion that includes an antigen-binding portion or variable region thereof. An antibody fragment may be produced by any means. For example, in some embodiments, an antibody fragment may be enzymatically or chemically produced by fragmentation of an intact antibody or antibody agent. Alternatively, in some embodiments, an antibody fragment may be recombinantly produced (e.g., by expression of an engineered nucleic acid sequence. In some embodiments, an antibody fragment may be wholly or partially synthetically produced. In some embodiments, an antibody fragment (particularly an antigen-binding antibody fragment) may have a length of at least about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 amino acids or more, in some embodiments at least about 200 amino acids.

[0072] Antigen. The term “antigen”, as used herein, refers to an agent that elicits an immune response; and / or (ii) an agent that binds to a T cell receptor (e.g., when presented by an MHC molecule) or to an antibody. In some embodiments, an antigen elicits a humoral response (e.g.,including production of antigen-specific antibodies); in some embodiments, an elicits a cellular response (e.g., involving T-cells whose receptors specifically interact with the antigen). In some embodiments, and antigen binds to an antibody and may or may not induce a particular physiological response in an organism. In general, an antigen may be or include any chemical entity such as, for example, a small molecule, a nucleic acid, a polypeptide, a carbohydrate, a lipid, a polymer (in some embodiments other than a biologic polymer [e.g., other than a nucleic acid or amino acid polymer) etc. In some embodiments, an antigen is or comprises a polypeptide. In some embodiments, an antigen is or comprises a glycan. Those of ordinary skill in the art will appreciate that, in general, an antigen may be provided in isolated or pure form, or alternatively may be provided in crude form (e.g., together with other materials, for example in an extract such as a cellular extract or other relatively crude preparation of an antigen-containing source). In some embodiments, antigens utilized in accordance with the present invention are provided in a crude form. In some embodiments, an antigen is a recombinant antigen.

[0073] Approximately: As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0074] Binding. Those skilled in the art will appreciate that the term “binding”, as used herein, typically refers to a non-covalent association between or among two or more entities. “Direct” binding involves physical contact between entities or moieties; indirect binding involves physical interaction by way of physical contact with one or more intermediate entities. Binding between two or more entities can typically be assessed in any of a variety of contexts - including where interacting entities or moieties are studied in isolation or in the context of more complex systems (e.g., while covalently or otherwise associated with a carrier entity and / or in a biological system or cell).

[0075] CDR: as used herein, refers to a complementarity determining region within an antibody variable region. There are three CDRs in each of the variable regions of the heavy chain and thelight chain, which are designated CDR1, CDR2 and CDR3, for each of the variable regions. A "set of CDRs" or "CDR set" refers to a group of three or six CDRs that occur in either a single variable region capable of binding the antigen or the CDRs of cognate heavy and light chain variable regions capable of binding the antigen. Certain systems have been established in the art for defining CDR boundaries (e.g., Kabat, Chothia, etc.); those skilled in the art appreciate the differences between and among these systems and are capable of understanding CDR boundaries to the extent required to understand and to practice the claimed subject matter.

[0076] Composition: Those skilled in the art will appreciate that the term “composition” may be used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form - e.g., gas, gel, liquid, solid, etc.

[0077] Comprising: A composition or method described herein as "comprising" one or more named elements or steps is open-ended, meaning that the named elements or steps are essential, but other elements or steps may be added within the scope of the composition or method. To avoid prolixity, it is also understood that any composition or method described as "comprising" (or which "comprises") one or more named elements or steps also describes the corresponding, more limited composition or method "consisting essentially of' (or which "consists essentially of') the same named elements or steps, meaning that the composition or method includes the named essential elements or steps and may also include additional elements or steps that do not materially affect the basic and novel characteristic(s) of the composition or method. It is also understood that any composition or method described herein as "comprising" or "consisting essentially of' one or more named elements or steps also describes the corresponding, more limited, and closed-ended composition or method "consisting of' (or "consists of') the named elements or steps to the exclusion of any other unnamed element or step. In any composition or method disclosed herein, known or disclosed equivalents of any named essential element or step may be substituted for that element or step.

[0078] Conjugate: The term “conjugate” as used herein refers to linking of one moiety to another moiety by in vitro methods (e.g., chemical synthesis) or in vivo (e.g., in a cell). In some embodiments, a moiety comprising one or more glycans (e.g., a second moiety) is conjugated to a different moiety, for example, at one or more glycosylation sites in vivo in a cell. In someembodiments, a moiety comprising one or more glycans (e.g., a second moiety) is conjugated to a different moiety, for example, at one or more glycosylation sites by chemical conjugation.

[0079] Domain: The term “domain” as used herein refers to a section or portion of an entity. In some embodiments, a “domain” is associated with a particular structural and / or functional feature of the entity so that, when the domain is physically separated from the rest of its parent entity, it substantially or entirely retains the particular structural and / or functional feature. Alternatively or additionally, a domain may be or include a portion of an entity that, when separated from that (parent) entity and linked with a different (recipient) entity, substantially retains and / or imparts on the recipient entity one or more structural and / or functional features that characterized it in the parent entity. In some embodiments, a domain is a section or portion of a molecule (e.g., a small molecule, carbohydrate, lipid, nucleic acid, or polypeptide). In some embodiments, a domain is a section of a polypeptide; in some such embodiments, a domain is characterized by a particular structural element (e.g., a particular amino acid sequence or sequence motif, alpha-helix character, alpha-sheet character, coiled-coil character, random coil character, etc.), and / or by a particular functional feature (e.g., binding activity, enzymatic activity, folding activity, signaling activity, etc.).

[0080] Epitope: as used herein, includes any moiety that is specifically recognized by an immunoglobulin (e.g., antibody or receptor) binding component. In some embodiments, an epitope is comprised of a plurality of chemical atoms or groups on an antigen. In some embodiments, such chemical atoms or groups are surface-exposed when the antigen adopts a relevant three-dimensional conformation. In some embodiments, such chemical atoms or groups are physically near to each other in space when the antigen adopts such a conformation. In some embodiments, at least some such chemical atoms are groups are physically separated from one another when the antigen adopts an alternative conformation (e.g., is linearized).

[0081] Functional: As used herein, a “functional” biological molecule is a biological molecule in a form in which it exhibits a property and / or activity by which it is characterized.

[0082] Fragment: A “fragment” of a material or entity as described herein has a structure that includes a discrete portion of the whole, but lacks one or more moieties found in the whole. In some embodiments, a fragment consists of such a discrete portion. In some embodiments, a fragment consists of or comprises a characteristic structural element or moiety found in thewhole. In some embodiments, a polymer fragment comprises or consists of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 or more monomeric units (e.g., residues) as found in the whole polymer. In some embodiments, a polymer fragment comprises or consists of at least about 5%, 10%, 15%, 20%, 25%, 30%, 25%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more of the monomeric units (e.g., residues) found in the whole polymer. The whole material or entity may in some embodiments be referred to as the “parent” of the fragment.

[0083] Homology: As used herein, the term “homology” refers to the overall relatedness between polymeric molecules, e.g., between polypeptide molecules. In some embodiments, polymeric molecules such as antibodies are considered to be “homologous” to one another if their sequences are at least 80%, 85%, 90%, 95%, or 99% identical. In some embodiments, polymeric molecules are considered to be “homologous” to one another if their sequences are at least 80%, 85%, 90%, 95%, or 99% similar.

[0084] Human. In some embodiments, a human is an embryo, a fetus, an infant, a child, a teenager, an adult, or a senior citizen.

[0085] Humanized: as is known in the art, the term "humanized" is commonly used to refer to antibodies (or antibody components) whose amino acid sequence includes VH and VL region sequences from a reference antibody raised in a non-human species (e.g., a mouse), but also includes modifications in those sequences relative to the reference antibody intended to render them more "human-like" , i.e., more similar to human germline variable sequences. In some embodiments, a "humanized" antibody (or antibody component) is one that immunospecifically binds to an antigen of interest and that has a framework (FR) region having substantially the amino acid sequence as that of a human antibody, and a complementary determining region (CDR) having substantially the amino acid sequence as that of a non-human antibody. A humanized antibody comprises substantially all of at least one, and typically two, variable domains (Fab, Fab', F(ab')2, FabC, Fv) in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin (i.e., donor immunoglobulin) and all or substantially all of the framework regions are those of a human immunoglobulin consensussequence. In some embodiments, a humanized antibody also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin constant region. In some embodiments, a humanized antibody contains both the light chain as well as at least the variable domain of a heavy chain. The antibody also may include a CHI , hinge, CH2, CH3, and, optionally, a CH4 region of a heavy chain constant region. In some embodiments, a humanized antibody only contains a humanized VL region. In some embodiments, a humanized antibody only contains a humanized VH region. In some certain embodiments, a humanized antibody contains humanized VH and VL regions.

[0086] Identity . As used herein, the term “identity” refers to the overall relatedness between polymeric molecules, e.g., between nucleic acid molecules e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. In some embodiments, polymeric molecules are considered to be “substantially identical” to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical. Calculation of the percent identity of two nucleic acid or polypeptide sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or substantially 100% of the length of a reference sequence. The nucleotides at corresponding positions are then compared. When a position in the first sequence is occupied by the same residue (e.g., nucleotide or amino acid) as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller (CABIOS, 1989, 4: 11-17), which has been incorporated into the ALIGN program (version 2.0). In some exemplary embodiments, nucleic acid sequence comparisons made with the ALIGN program use a PAM120 weight residue table, a gap length penalty of 12and a gap penalty of 4. The percent identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna.CMP matrix.

[0087] “Improve,'1'’ “increase'', “inhibit” or “reduce”: As used herein, the terms “improve”, “increase”, “inhibit’, “reduce”, or grammatical equivalents thereof, indicate values that are relative to a baseline or other reference measurement. In some embodiments, an appropriate reference measurement may be or comprise a measurement in a particular system (e.g., in a single individual) under otherwise comparable conditions absent presence of (e.g., prior to and / or after) a particular agent or treatment, or in presence of an appropriate comparable reference agent. In some embodiments, an appropriate reference measurement may be or comprise a measurement in comparable system known or expected to respond in a particular way, in presence of the relevant agent or treatment.

[0088] Peptide: The term “peptide” as used herein refers to a polypeptide that is typically relatively short, for example having a length of less than about 100 amino acids, less than about 50 amino acids, less than about 40 amino acids less than about 30 amino acids, less than about 25 amino acids, less than about 20 amino acids, less than about 15 amino acids, or less than 10 amino acids.

[0089] Pharmaceutical composition . As used herein, the term “pharmaceutical composition” refers to a composition in which an active agent is formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, a pharmaceutical composition may be specially formulated for administration in a particular form (e.g., in a solid form or a liquid form), and / or may be specifically adapted for, for example: oral administration (for example, as a drenche [aqueous or non-aqueous solutions or suspensions], tablet, capsule, bolus, powder, granule, paste, etc, which may be formulated specifically for example for buccal, sublingual, or systemic absorption); parenteral administration (for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation, etc); topical application (for example, as a cream, ointment, patch or spray appliedfor example to skin, lungs, or oral cavity); intravaginal or intrarectal administration (for example, as a pessary, suppository, cream, or foam); ocular administration; nasal or pulmonary administration, etc.

[0090] Polypeptide: As used herein refers to a polymeric chain of amino acids. In some embodiments, a polypeptide has an amino acid sequence that occurs in nature. In some embodiments, a polypeptide has an amino acid sequence that does not occur in nature. In some embodiments, a polypeptide has an amino acid sequence that is engineered in that it is designed and / or produced through action of the hand of man. In some embodiments, a polypeptide may comprise or consist of natural amino acids, non-natural amino acids, or both. In some embodiments, a polypeptide may comprise or consist of only natural amino acids or only nonnatural amino acids. In some embodiments, a polypeptide may comprise D-amino acids, L- amino acids, or both. In some embodiments, a polypeptide may comprise only D-amino acids. In some embodiments, a polypeptide may comprise only L-amino acids. In some embodiments, a polypeptide may include one or more pendant groups or other modifications, e.g., modifying or attached to one or more amino acid side chains, at the polypeptide’s N-terminus, at the polypeptide’s C-terminus, or any combination thereof. In some embodiments, such pendant groups or modifications may be selected from the group consisting of acetylation, amidation, lipidation, methylation, pegylation, etc., including combinations thereof. In some embodiments, a polypeptide may be cyclic, and / or may comprise a cyclic portion. In some embodiments, a polypeptide is not cyclic and / or does not comprise any cyclic portion. In some embodiments, a polypeptide is linear. In some embodiments, a polypeptide may be or comprise a stapled polypeptide. In some embodiments, the term “polypeptide” may be appended to a name of a reference polypeptide, activity, or structure; in such instances it is used herein to refer to polypeptides that share the relevant activity or structure and thus can be considered to be members of the same class or family of polypeptides. For each such class, the present specification provides and / or those skilled in the art will be aware of exemplary polypeptides within the class whose amino acid sequences and / or functions are known; in some embodiments, such exemplary polypeptides are reference polypeptides for the polypeptide class or family. In some embodiments, a member of a polypeptide class or family shows significant sequence homology or identity with, shares a common sequence motif (e.g., a characteristic sequence element) with, and / or shares a common activity (in some embodiments at a comparable level orwithin a designated range) with a reference polypeptide of the class; in some embodiments with all polypeptides within the class). For example, in some embodiments, a member polypeptide shows an overall degree of sequence homology or identity with a reference polypeptide that is at least about 30-40%, and is often greater than about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more and / or includes at least one region (e.g., a conserved region that may in some embodiments be or comprise a characteristic sequence element) that shows very high sequence identity, often greater than 90% or even 95%, 96%, 97%, 98%, or 99%. Such a conserved region usually encompasses at least 3-4 and often up to 20 or more amino acids; in some embodiments, a conserved region encompasses at least one stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more contiguous amino acids. In some embodiments, a relevant polypeptide may comprise or consist of a fragment of a parent polypeptide. In some embodiments, a useful polypeptide as may comprise or consist of a plurality of fragments, each of which is found in the same parent polypeptide in a different spatial arrangement relative to one another than is found in the polypeptide of interest (e.g., fragments that are directly linked in the parent may be spatially separated in the polypeptide of interest or vice versa, and / or fragments may be present in a different order in the polypeptide of interest than in the parent), so that the polypeptide of interest is a derivative of its parent polypeptide.

[0091] Reference: As used herein describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0092] Specific binding: As used herein, the term “specific binding” refers to an ability to discriminate between possible binding partners in the environment in which binding is to occur. A binding agent that interacts with one particular target when other potential targets are present is said to "bind specifically" to the target with which it interacts. In some embodiments, specific binding is assessed by detecting or determining degree of association between the binding agent and its partner; in some embodiments, specific binding is assessed by detecting or determining degree of dissociation of a binding agent-partner complex; in some embodiments, specific binding is assessed by detecting or determining ability of the binding agent to compete an alternative interaction between its partner and another entity. In some embodiments, specific binding is assessed by performing such detections or determinations across a range of concentrations.

[0093] Specific: The term “specific”, when used herein with reference to an agent having an activity, is understood by those skilled in the art to mean that the agent discriminates between potential target entities or states. For example, an in some embodiments, an agent is said to bind “specifically” to its target if it binds preferentially with that target in the presence of one or more competing alternative targets. In many embodiments, specific interaction is dependent upon the presence of a particular structural feature of the target entity (e.g., an epitope, a cleft, a binding site). It is to be understood that specificity need not be absolute. In some embodiments, specificity may be evaluated relative to that of the binding agent for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is evaluated relative to that of a reference specific binding agent. In some embodiments specificity is evaluated relative to that of a reference non-specific binding agent. In some embodiments, the agent or entity does not detectably bind to the competing alternative target under conditions of binding to its target entity. In some embodiments, binding agent binds with higher on-rate, lower off-rate, increased affinity, decreased dissociation, and / or increased stability to its target entity as compared with the competing alternative target(s).

[0094] Specificity. As is known in the art, “specificity” is a measure of the ability of a particular ligand to distinguish its binding partner from other potential binding partners.

[0095] Substantially: As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One ofordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0096] Substantial identity: as used herein refers to a comparison between amino acid or nucleic acid sequences. As will be appreciated by those of ordinary skill in the art, two sequences are generally considered to be "substantially identical" if they contain identical residues in corresponding positions. As is well known in this art, amino acid or nucleic acid sequences may be compared using any of a variety of algorithms, including those available in commercial computer programs such as BLAS TN for nucleotide sequences and BLASTP, gapped BLAST, and PSLBLAST for amino acid sequences. Exemplary such programs are described in Altschul et al., Basic local alignment search tool, J. Mol. Biol., 215(3): 403-410, 1990; Altschul et al., Methods in Enzymology; Altschul et al., Nucleic Acids Res. 25:3389-3402, 1997; Baxevanis et al., Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins, Wiley, 1998; and Misener, et al, (eds.), Bioinformatics Methods and Protocols (Methods in Molecular Biology, Vol. 132), Humana Press, 1999. In addition to identifying identical sequences, the programs mentioned above typically provide an indication of the degree of identity. In some embodiments, two sequences are considered to be substantially identical if at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more of their corresponding residues are identical over a relevant stretch of residues. In some embodiments, the relevant stretch is a complete sequence. In some embodiments, the relevant stretch is at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 or more residues. In the context of a CDR, reference to "substantial identity" typically refers to a CDR having not more than a small number (e.g., 3, 2, or 1) an amino acid sequence changes relative to that of a reference CDR. In some embodiments, a CDR that is substantially identical to a reference CDR differs from that reference CDR by one or more amino acid changes at the end of the reference CDR; in some such embodiments, the relevant CDR is identical to the reference CDR other than at one or both ends. As is known in the art, CDR elements typically have a length within a range of a few amino acids (e.g., 3, 4, 5, 6, or 7) to about 20 or 30 amino acids (see, for example, Collis et al. J. Mol. Biol. 325:337, 2003, incorporated herein byreference); thus, in some embodiments, a CDR may be considered to be substantially identical to a reference CDR when it shares at least about 80% (or less for a shorter CDR), at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100% identity with the reference CDR.

[0097] Substantial sequence homology . The phrase “substantial homology” is used herein to refer to a comparison between amino acid or nucleic acid sequences. As will be appreciated by those of ordinary skill in the art, two sequences are generally considered to be “substantially homologous” if they contain homologous residues in corresponding positions. Homologous residues may be identical residues. Alternatively, homologous residues may be non-identical residues will appropriately similar structural and / or functional characteristics. For example, as is well known by those of ordinary skill in the art, certain amino acids are typically classified as “hydrophobic” or “hydrophilic” amino acids., and / or as having “polar” or “non-polar” side chains. Substitution of one amino acid for another of the same type may often be considered a “homologous” substitution. Typical amino acid categorizations are summarized below:

[0098] As is well known in the pertinent art, amino acid or nucleic acid sequences may be compared using any of a variety of algorithms, including those available in commercial computer programs such as BLAS TN for nucleotide sequences and BLASTP, gapped BLAST, and PSL BLAST for amino acid sequences. Exemplary such programs are described in Altschul, et al., Basic local alignment search tool, J. Mol. Biol., 215(3): 403-410, 1990; Altschul, et al., Methods in Enzymology; Altschul, et al., "Gapped BLAST and PSLBLAST: a new generation of protein database search programs", Nucleic Acids Res. 25:3389-3402, 1997; Baxevanis, et al., Bioinformatics : A Practical Guide to the Analysis of Genes and Proteins, Wiley, 1998; and Misener, et al., (eds.), Bioinformatics Methods and Protocols (Methods in Molecular Biology, Vol. 132), Humana Press, 1999. In addition to identifying homologous sequences, the programs mentioned above typically provide an indication of the degree of homology. In someembodiments, two sequences are considered to be substantially homologous if at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more of their corresponding residues are homologous over a relevant stretch of residues. In some embodiments, the relevant stretch is a complete sequence. In some embodiments, the relevant stretch is at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, at least 250, at least 275, at least 300, at least 325, at least 350, at least 375, at least 400, at least 425, at least 450, at least 475, at least 500 or more residues.

[0099] Treat: As used herein, the term “treat,” “treatment,” or “treating” is used to refer to one or more of partial or complete alleviation, amelioration, relief, inhibition, prevention, delay of onset of, reduction in severity of and / or reduction in frequency (e.g., incidence) of one or more symptoms or features of a disease, disorder, and / or condition. In some embodiments, treatment may be prophylactic; for example may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits early signs of the disease, disorder, and / or condition, and may, for example, decrease risk of developing pathology associated with the disease, disorder, and / or condition and / or delay onset and / or decrease rate of development or worsening of one or more features of a disease, disorder and / or condition.

[0100] Treatment. As used herein, the term “treatment” (also “treat” or “treating”) refers to administration of a therapy that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and / or condition and / or of a subject who exhibits only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more signs of the relevant disease, disorder and / or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder,and / or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors, e.g., that are statistically correlated with increased risk of development of the relevant disease, disorder, and / or condition. Thus, in some embodiments, treatment may be prophylactic; in some embodiments, treatment may be therapeutic.

[0101] Variant: The term “variant”, as used herein, refers to a molecule or entity (e.g., that are or comprise a nucleic acid, protein, or small molecule) that shows significant structural identity with a reference molecule or entity but differs structurally from the reference molecule or entity, e.g., in the presence or absence or in the level of one or more chemical moieties as compared to the reference molecule or entity. In some embodiments, a variant also differs functionally from its reference molecule or entity. In many embodiments, whether a particular molecule or entity is properly considered to be a “variant” of a reference is based on its degree of structural identity with the reference molecule. As will be appreciated by those skilled in the art, a biological or chemical reference molecule in typically characterized by certain characteristic structural elements. A variant, by definition, is a distinct molecule or entity that shares one or more such characteristic structural elements but differs in at least one aspect from the reference molecule or entity. To give but a few examples, a polypeptide may have a characteristic sequence element comprised of a plurality of amino acids having designated positions relative to one another in linear or three-dimensional space and / or contributing to a particular structural motif and / or biological function; a nucleic acid may have a characteristic sequence element comprised of a plurality of nucleotide residues having designated positions relative to one another in linear or three-dimensional space. In some embodiments, a variant polypeptide or nucleic acid may differ from a reference polypeptide or nucleic acid as a result of one or more differences in amino acid or nucleotide sequence and / or one or more differences in chemical moieties (e.g., carbohydrates, lipids, phosphate groups) that are covalently components of the polypeptide or nucleic acid (e.g., that are attached to the polypeptide or nucleic acid backbone). In some embodiments, a variant polypeptide or nucleic acid shows an overall sequence identity with a reference polypeptide or nucleic acid that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 99%. In some embodiments, a variant polypeptide or nucleic acid does not share at least one characteristic sequence element with a reference polypeptide or nucleic acid. In some embodiments, a reference polypeptide or nucleic acid has one or more biological activities. In some embodiments, a variant polypeptide or nucleic acid shares one or more of the biologicalactivities of the reference polypeptide or nucleic acid. In some embodiments, a variant polypeptide or nucleic acid lacks one or more of the biological activities of the reference polypeptide or nucleic acid. In some embodiments, a variant polypeptide or nucleic acid shows a reduced level of one or more biological activities as compared to the reference polypeptide or nucleic acid. In some embodiments, a polypeptide or nucleic acid of interest is considered to be a “variant” of a reference polypeptide or nucleic acid if it has an amino acid or nucleotide sequence that is identical to that of the reference but for a small number of sequence alterations at particular positions. Typically, fewer than about 20%, about 15%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, or about 2% of the residues in a variant are substituted, inserted, or deleted, as compared to the reference. In some embodiments, a variant polypeptide or nucleic acid comprises about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 substituted residues as compared to a reference. Often, a variant polypeptide or nucleic acid comprises a very small number (e.g., fewer than about 5, about 4, about 3, about 2, or about 1) number of substituted, inserted, or deleted, functional residues (e.g., residues that participate in a particular biological activity) relative to the reference. In some embodiments, a variant polypeptide or nucleic acid comprises not more than about 5, about 4, about 3, about 2, or about 1 addition or deletion, and, in some embodiments, comprises no additions or deletions, as compared to the reference. In some embodiments, a variant polypeptide or nucleic acid comprises fewer than about 25, about 20, about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 10, about 9, about 8, about 7, about 6, and commonly fewer than about 5, about 4, about 3, or about 2 additions or deletions as compared to the reference. In some embodiments, a reference polypeptide or nucleic acid is one found in nature. In some embodiments, a reference polypeptide or nucleic acid is a human polypeptide or nucleic acid.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0102] Disclosed herein are glycoengineered polypeptides and compositions comprising the same having the ability to degrade one or more IgG4 antibodies (e.g., IgG4 autoantibodies) by binding to IgG4 antibodies with a first moiety (e.g., an anti-IgG4 antibody) and binding to an endocytic receptor with a second moiety comprising one or more glycans, thus targeting theIgG4 antibody (or a complex thereof) for degradation. As exemplified herein, a glycoengineered polypeptide is engineered by introduction of one or more glycosylation sites on a glycoengineered polypeptide, resulting in an engineered glycosylation profile that mediates endocytic receptor degradation of the glycoengineered polypeptides and the target to which it binds.

[0103] In accordance with various embodiments, by customizing the N-glycosylation, a glycoengineered polypeptide described herein: 1) has homogeneous glycosylation; 2) can degrade large targets such as immune complexes; 3) has a defined ligand-to-antibody ratio; 4) has defined glycosylation sites; 5) can activate more diverse and powerful degradation receptors; and / or 6) can engage in protein degradation in a highly optimized manner. In some embodiments, a glycoengineered polypeptide may be employed as a novel therapeutic to treat autoimmune diseases, e.g., a disease associated with IgG4 autoantibodies such as Pemphigus Vulgaris / Folaceus; Muscle-specific kinase (MuSK) myasthenia gravis (MG); Idiopathic Thrombotic Thrombocytopenia Purpura (iTTP); idiopathic membranous nephropathy (iMN); Chronic Inflammatory Demyelinating Polyneuropathy (CIDP); or Immunoglobulin G4-Related Disease (IgG4-RD).IgG4 antibodies (e.g., IgG4 autoantibodies)

[0104] Immunoglobulin 4 (IgG4) is one of four human IgG subclasses and has several unique functional characteristics. IgG4 is also the least common of the 4 subclasses of IgG. It exhibits low affinity for complement and for most Fc receptors, see Huijbers MG et al., (2018) Annals of the NY Academy of Sciences, pp. 92-103, the entire contents of which are hereby incorporated by reference. IgG4 generally has a high affinity for its antigen, with binding occurring in a monovalent fashion, as IgG4 can exchange Fab-arms with other IgG4 molecules. Because of these characteristics, IgG4 is believed to block its targets and prevent inflammation, which, depending on the setting, can have a protective or pathogenic effect (Huijbers 2018).

[0105] While the majority of antibody-mediated autoimmune diseases are thought to be caused by IgGl and IgG3 autoantibodies, in recent years new autoantibodies associated with a spectrum of autoimmune diseases have been discovered and a majority of these autoantibodies were found to be IgG4 (Huijbers 2018). Exemplary IgG4-mediated autoimmune diseases and associatedantigens are provided in Table 2 of Huijbers 2018. For example, IgG4-mediated autoimmune diseases include but are not limited to, thrombotic thrombocytopenic purpura, chronic inflammatory polyneuropathy, limbic encephalitis, neuromotonia, Morvan syndrome, pemphigus follaceus, pemphigus vulgaris, parasomnia, myasthenia gravis, and membranous nephropathy.

[0106] The present disclosure provides glycoengineered polypeptides comprising a first moiety that comprises an antibody agent that binds to an IgG4 antibody (e.g., an IgG4 autoantibody). Exemplary anti-IgG4 antibodies that can be used in a first moiety of a glycoengineered polypeptide described herein are provided in Tables 1 and 2.

[0107] This disclosure further provides the insight that exemplary anti-IgG4 antibodies provided herein can be useful in treating and / or preventing diseases associated IgG4 autoantibodies, e.g., as disclosed herein. In some embodiments, exemplary anti-IgG4 antibodies disclosed herein preferentially bind to IgG4 with minimal or substantially no binding (e.g., no detectable binding) to non-IgG4 antibodies (e.g., antibodies of a different IgG subclass or antibodies of a different isotype).

[0108] In some embodiments, an anti-IgG4 antibody disclosed herein binds to an IgG4 antibody (e.g., an IgG4 autoantibody) at one or more of: a CHI domain, a hinge domain, a CH2 domain or a CH3 domain.

[0109] An exemplary IgG4 polypeptide sequence is provided as SEQ ID NO: 201, corresponding to UniProt Accession Number P01861 : ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLELQLEESCAEAQDGELDGLWTTITIFITLFLLS VCYSATVTFFKVKWIFSSWDLKQTIVPDYRNMIRQGA (SEQ ID NO: 201).

[0110] An IgG4 polypeptide comprises the following domains: a CHI domain, and Ig-like 1 domain, a hinge domain, a CH2 domain, an Ig-like 2 domain, a CH3 domain and an Ig-like 3 domain.

[0111] In some embodiments, a CHI domain comprises the sequence ofASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRV (SEQ ID NO: 202).

[0112] In some embodiments, an Ig-like 1 domain comprises the sequence ofPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSVVTVPSSSLGTI<TYTCNVDHI<PSNTI<VDI<RVE (SEQ ID NO: 203).

[0113] In some embodiments, a CHI domain comprises the sequence ofASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC (SEQ ID NO: 214).

[0114] In some embodiments, a CHI domain comprises the sequence ofASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSWTVPSSNFGTQTYTCNVDHKPSNTKVDKTVE (SEQ ID NO: 216).

[0115] In some embodiments, a CHI domain comprises the sequence ofASTKGPSVFPLAPCSRSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSWTVPSSSLGTQTYTCNVNHKPSNTKVDKRVE (SEQ ID NO: 217).

[0116] In some embodiments, a CHI domain comprises the sequence ofASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTKTYTCNVDHI<PSNTI<VDI<RVE (SEQ ID NO: 218).

[0117] In some embodiments, a hinge domain comprises the sequence of ESKYGPPCPSCP (SEQ ID NO: 204).

[0118] In some embodiments, a CH2 domain comprises the sequence ofAPEELGGPSVELEPPI<PI<DTLMISRTPEVTCVVVDVSQEDPEVQENWYVDGVEVHNAI<T KPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEI<TISI<AI< (SEQ ID NO: 205).

[0119] In some embodiments, an Ig-like 2 domain comprises the sequence ofPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS (SEQ ID NO: 206).

[0120] In some embodiments, a CH3 domain comprises the sequence of GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLEL (SEQ ID NO: 207).

[0121] In some embodiments, an Ig-like 3 domain comprises the sequence of PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLS (SEQ ID NO: 208).

[0122] In some embodiments, a first moiety of a glycoengineered polypeptide is or comprises an anti-IgG4 antibody agent. In some embodiments, a first moiety of a glycoengineered polypeptide is or comprises an antigen binding fragment of an anti-IgG4 antibody agent. In some embodiments, a first moiety of a glycoengineered polypeptide is or comprises a variable light (VL) polypeptide. In some embodiments, a first moiety of a glycoengineered polypeptide is or comprises a variable heavy (VH) polypeptide. In some embodiments, a first moiety of a glycoengineered polypeptide is or comprises a VL polypeptide and a VH polypeptide. In some embodiments, a first moiety of a glycoengineered polypeptide is or comprises a Fab fragment, a Fab’ fragment, a F(ab’)2 fragment, a Fd’ fragment, or a Fd fragment. In some embodiments, a first moiety of a glycoengineered polypeptide is or comprises a Fab fragment. In some embodiments, a first moiety of a glycoengineered polypeptide is or comprises an scFv. In some embodiments, a first moiety of a glycoengineered polypeptide is or comprises a single domain antibody (e.g., a VHH or a VNAR) or a fragment thereof. In some embodiments, a first moiety of a glycoengineered polypeptide is or comprises a diabody. In some embodiments, a first moiety of a glycoengineered polypeptide is or comprises a nanobody. In some embodiments, a first moiety of a glycoengineered polypeptide is or comprises an Fc fusion.

[0123] In some embodiments, an antibody agent is a monoclonal or polyclonal antibody. In some embodiments, an antibody agent is a recombinant antibody. In some embodiments, an antibody agent is humanized, chimeric or fully human.

[0124] In some embodiments, an anti-IgG4 antibody agent further comprises one or more additional antigen binding domains. In some embodiments, the one or more additional antigen binding domains bind to an antigen other than an Ig4 antibody (e.g., other than a CHI, hinge,CH2 and / or CH3 domain of an IgG4 antibody). In some embodiments, an anti-IgG4 antibody agent is a multi-specific antibody agent, e.g., a bispecific or a trispecific antibody agent).

[0125] In some embodiments, an anti-IgG4 antibody agent further comprises one or more domains such as an extracellular domain, a hinge domain, a transmembrane domain and / or an intracellular domain. In some embodiments, an anti-IgG4 antibody agent is a chimeric receptor which binds to an IgG4 antibody (e.g., an IgG4 autoantibody).

[0126] Additional exemplary formats of glycoengineered polypeptides disclosed herein is disclosed in WO2024 / 068753, filed on September 27, 2023 entitled "Targeted Glycan-Mediated Protein Degradation” and WO2024 / 068768, filed on September 27, 2023 entitled “Glycoengineered Leishmania Host Cells,” each of which are hereby incorporated by reference in their entireties.Glycoengineered polypeptides

[0127] Disclosed herein are glycoengineered polypeptides comprising: (a) a first moiety comprising one or more peptides that specifically binds to an IgG4 antibody (e.g., IgG4 autoantibody) or a fragment or a complex thereof; and (b) a second moiety comprising one or more glycans conjugated to the first moiety at one or more glycosylation sites.

[0128] In some embodiments, a glycoengineered polypeptide disclosed herein comprises a first moiety, a second moiety and one or more additional elements. In some embodiments, a glycoengineered polypeptide comprises: an N-glycosylation site, a linker, a spacer, a signal peptide, a tag, a half-life extender or a combination thereof.

[0129] In some embodiments, a glycoengineered polypeptide comprises one or more N- glycosylation sites in a first moiety. In some embodiments, a first moiety comprises one or more N-glycosylation sites that are naturally occurring and / or one or more N-glycosylation sites that are engineered into a first moiety.

[0130] In some embodiments, an engineered N-glycosylation site (also referred to herein as a glycosite or a glycotag) is or comprises the sequence of GGGGANSTAPAPAPAHHHHHHHHHH (SEQ ID NO: 161).

[0131] In some embodiments, an engineered N-glycosylation site is or comprises the sequence of GGGGANSTAPAPAPA (SEQ ID NO: 163).

[0132] In some embodiments, an engineered N-glycosylation site is or comprises the sequence of GGGGANSTAPAPAPAPAPAPAGGGGANSTAPAPAPA (SEQ ID NO: 168).

[0133] In some embodiments, an engineered N-glycosylation site is or comprises the sequence of GGGGANSTAPAPAPAPAPAPAPAPAPAANSTAPAPAPAHHHHHHAPAPAPA (SEQ ID NO: 169).

[0134] In some embodiments, a glycoengineered polypeptide comprises a linker. In some embodiments, a linker comprises a Gly-Ser linker, or an EAAAK linker. In some embodiments, a linker comprises a (Gly-Gly-Gly-Gly-Ser)n linker, wherein n is an integer between 0 to 20.

[0135] In some embodiments, a glycoengineered polypeptide comprises a spacer. In some embodiments, a spacer comprises one or more nucleotides which separates a first nucleic acid sequence from a subsequent nucleic acid sequence.

[0136] In some embodiments, a spacer comprises a nucleic acid sequence which encodes one or more peptides that separates a first encoded polypeptide sequence from a subsequent encoded polypeptide sequence.

[0137] In some embodiments, a glycoengineered polypeptide comprises a signal peptide, e.g., as disclosed herein. In some embodiments, a signal peptide is a native signal peptide. In some embodiments, a signal peptide is not a native signal peptide.

[0138] In some embodiments, a signal peptide is derived from a Leishmania species. In certain embodiments, a signal peptide is derived from Leishmania tarentolae. In certain embodiments, a signal peptide is derived from Leishmania major.

[0139] In certain embodiments, the signal peptide is an invertase signal peptide derived from Leishmania tarentolae.

[0140] In certain embodiments, the signal peptide is an alkaline phosphatase signal peptide derived from Leishmania major.

[0141] In certain embodiments, a signal peptide comprises an amino acid sequence of SEQ ID NO: 164, or a portion thereof. In certain embodiments, a signal peptide comprises an amino acidsequence of SEQ ID NO: 165, or a portion thereof. In certain embodiments, a signal peptide comprises an amino acid sequence of SEQ ID NO: 166, or a portion thereof. In certain embodiments, a signal peptide comprises an amino acid sequence of SEQ ID NO: 162, or a portion thereof. In certain embodiments, a signal peptide is processed and removed from a glycoengineered polypeptide.

[0142] Exemplary signal peptide: SPinv, a modified signal peptide from Leishmania tarentolae invertase, SEQ ID NO: 164: MIASSVRHAVILLLVAVAMMAAVIA.

[0143] Exemplary signal peptide: SPinv, the native signal peptide from Leishmania tarentolae invertase, SEQ ID NO: 165: MIASSVRHAVILLLVAVAMMAAAVIA.

[0144] Exemplary signal peptide: native signal peptide from Leishmania major alkaline phosphatase, SEQ ID NO: 166: MASRLVRVLAAAMLVAAAVS.

[0145] Exemplary signal peptide: native signal peptide derived from Leishmania tarentolae invertase Spinv4, SEQ ID NO: 162: MIASSVRHAVILLLVAVAMMGGVIA.

[0146] In some embodiments, a glycoengineered polypeptide comprises a tag. In some embodiments, a tag is a moiety that can be used for purifying and / or identifying a glycoengineered polypeptide disclosed herein. In some embodiments, a tag is not a glycotag. In some embodiments, a tag comprises a His tag, a Myc tag, or a GST tag. In some embodiments, a tag comprises a cleavable tag.

[0147] In some embodiments, a tag is a His tag (HHHHHHHHHH; SEQ ID NO: 167).

[0148] In some embodiments, a half-life extender comprises albumin or a fragment or a variant thereof.

[0149] In some embodiments, a half-life extender comprises a Fc domain, e.g., with or without mutations in an Fc domain.First moiety

[0150] In some embodiments, a glycoengineered polypeptide comprises a first moiety comprising one or more peptides that specifically binds to an IgG4 antibody (e.g., an IgG4 autoantibody) or a fragment thereof.

[0151] In some embodiments, a glycoengineered polypeptide comprises a first moiety comprising one or more antibody agents that specifically binds to an IgG4 antibody (e.g., an IgG4 autoantibody) or a fragment thereof. In some embodiments, one or more antibody agents comprise an antigen binding fragment.

[0152] In some embodiments, an antibody agent comprises a full antibody, a Fab fragment, an scFv, a nanobody, a duobody, or a single domain antibody (e.g., a VHH).

[0153] In some embodiments, an antibody agent is or comprises a Fab fragment.

[0154] In some embodiments, an antibody agent comprises a light chain polypeptide (e.g., a light chain variable region (VL)) and / or a heavy chain polypeptide (e.g.., a heavy chain variable region (VH)).Light chain (e.g, light chain variable region(VL)) polypeptides

[0155] The present disclosure provides polypeptides comprising light chain (LC) sequences (e.g., light chain variable region sequence(s)) that, for example, may be useful as a first moiety in glycoengineered polypeptides described herein targeting hIgG4 antibodies (e.g., hIgG4 autoantibodies); in some such embodiments, such provided polypeptides are useful and / or included in such glycoengineered polypeptides as described herein.

[0156] In some embodiments, a glycoengineered polypeptide comprises a first moiety comprising a LC polypeptide comprising one or more CDRs and / or one or more framework regions. In some embodiments, a LC polypeptide comprises a light chain variable region (VL) polypeptide.

[0157] In some embodiments, a glycoengineered polypeptide comprises a first moiety comprising a LC polypeptide comprising at least one LC CDR provided in Table 1 or a sequence with at least 85% identity thereto. In some embodiments, a LC polypeptide comprises one, two or three LC CDRs (e.g., a LC CDR1, a LC CDR2 and / or a LC CDR3). In some embodiments, a LC polypeptide comprises a LC CDR1. In some embodiments, a LC polypeptide comprises a LC CDR2. In some embodiments, a LC polypeptide comprises a LC CDR3. In some embodiments, a LC polypeptide comprises a LC CDR1, a LC CDR2 and a LC CDR3.

[0158] In some embodiments, a LC polypeptide having a LC CDR1, a LC CDR2 and a LC CDR3, e.g., in a first moiety of a glycoengineered polypeptide, is capable of binding (e.g., specifically binding) to a hIgG4 antibody, e.g., a hIgG4 autoantibody.

[0159] In some embodiments, a glycoengineered polypeptide comprises a first moiety comprising a LC polypeptide further comprises one or more framework regions, and / or a constant region.

[0160] In some embodiments, a glycoengineered polypeptide comprises a first moiety comprising a LC polypeptide comprising a light chain constant region and / or a heavy chain constant region. In some embodiments, a LC polypeptide comprises a light chain constant region or a portion thereof, (e.g., a lambda light chain constant region or a variant or portion thereof; or a kappa light chain constant region or a variant or a portion thereof).

[0161] In some embodiments, a LC polypeptide comprises a light chain comprising the sequence RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 215).

[0162] In some embodiments, a LC polypeptide comprises a light chain comprising the sequence GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPS KQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:219).

[0163] In some embodiments, a LC polypeptide comprises a light chain comprising the sequence GQPKAAPS VTLFPPS SEELQ ANKATLVCLISDF YPGAVTVAWKAD S SPVKAGVETTTPS KQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:220).

[0164] In some embodiments, a LC polypeptide comprises a light chain comprising the sequence GQPKAAPS VTLFPPS SEELQ ANKATLVCLISDF YPGAVTVAWKAD S SPVKAGVETTTPS KQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:221).

[0165] In some embodiments, a LC polypeptide comprises (i) an LC CDR1 sequence provided in Table 1, (ii) a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%identity to an LC CDR1 sequence provided inTable 1; or (iii) a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to an LC CDR1 sequence provided in Table 1

[0166] In some embodiments, a LC polypeptide comprises (i) an LC CDR2 sequence provided in Table 1, (ii) a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to an LC CDR2 sequence provided in Table 1; or (iii) a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to an LC CDR2 sequence provided in Table 1

[0167] In some embodiments, a LC polypeptide comprises (i) an LC CDR3 sequence provided in Table 1, (ii) a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to an LC CDR3 sequence provided in Table 1; or (iii) a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to an LC CDR3 sequence provided in Table 1

[0168] In some embodiments, a LC polypeptide comprises (i) an LC CDR1, LC CDR2, and LC CDR3 sequence provided in Table l;(ii) a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to an LC CDR1, LC CDR2, and LC CDR3 sequence provided in Table 1; or (iii) a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to an LC CDR1, LC CDR2, and LC CDR3 sequence provided in Table 1.

[0169] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 111, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 111 ; (ii) an LC CDR2 of SEQ ID NO: 125, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 125; and / or (iii) an LC CDR3 of SEQ ID NO: 136, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 136.

[0170] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO:112, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:112; (ii) an LC CDR2 of SEQ ID NO: 126, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 126; and / or (iii) an LC CDR3 of SEQ ID NO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 137.

[0171] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO:113, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 113; (ii) an LC CDR2 of SEQ ID NO: 127, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or asequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 127; and / or (iii) an LC CDR3 of SEQ ID NO: 138, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 138.

[0172] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 114, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 114; (ii) an LC CDR2 of SEQ ID NO: 126, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 126; and / or (iii) an LC CDR3 of SEQ ID NO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 137.

[0173] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 112, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 112; (ii) an LC CDR2 of SEQ ID NO: 128, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g.,conservative substitutions)) relative to SEQ ID NO: 128; and / or (iii) an LC CDR3 of SEQ ID NO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 137.

[0174] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 112, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 112; (ii) an LC CDR2 of SEQ ID NO: 126, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 126; and / or (iii) an LC CDR3 of SEQ ID NO: 139, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 139.

[0175] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 112, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 112; (ii) an LC CDR2 of SEQ ID NO: 129, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 129; and / or (iii) an LC CDR3 of SEQ IDNO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 137.

[0176] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 115, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 115; (ii) an LC CDR2 of SEQ ID NO: 126, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 126; and / or (iii) an LC CDR3 of SEQ ID NO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 137.

[0177] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 112, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 112; (ii) an LC CDR2 of SEQ ID NO: 130, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 130; and / or (iii) an LC CDR3 of SEQ ID NO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%,at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 137.

[0178] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 116, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 116; (ii) an LC CDR2 of SEQ ID NO: 131, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 131; and / or (iii) an LC CDR3 of SEQ ID NO: 140, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 140.

[0179] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 116, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 116; (ii) an LC CDR2 of SEQ ID NO: 131, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 131; and / or (iii) an LC CDR3 of SEQ ID NO: 141, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 141.

[0180] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 116, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 116; (ii) an LC CDR2 of SEQ ID NO: 131, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 131; and / or (iii) an LC CDR3 of SEQ ID NO: 142 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 142.

[0181] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 116, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 116; (ii) an LC CDR2 of SEQ ID NO: 131, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 131; and / or (iii) an LC CDR3 of SEQ ID NO: 143 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 143.

[0182] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 117, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 117; (ii) an LC CDR2 of SEQ ID NO: 131, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 131; and / or (iii) an LC CDR3 of SEQ ID NO: 144 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 144.

[0183] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 117, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 117; (ii) an LC CDR2 of SEQ ID NO: 131, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 131; and / or (iii) an LC CDR3 of SEQ ID NO: 143 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 143.

[0184] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 118, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 118; (ii) an LC CDR2 of SEQ ID NO: 132, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 132; and / or (iii) an LC CDR3 of SEQ ID NO: 145 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 145.

[0185] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 118, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 118; (ii) an LC CDR2 of SEQ ID NO: 133, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 133; and / or (iii) an LC CDR3 of SEQ ID NO: 145 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 145.

[0186] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 119, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 119; (ii) an LC CDR2 of SEQ ID NO: 134, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 134; and / or (iii) an LC CDR3 of SEQ ID NO: 146 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 146.

[0187] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 119, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 119; (ii) an LC CDR2 of SEQ ID NO: 134, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 134; and / or (iii) an LC CDR3 of SEQ ID NO: 147 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 147.

[0188] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 120, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 120; (ii) an LC CDR2 of SEQ ID NO: 134, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 134; and / or (iii) an LC CDR3 of SEQ ID NO: 148 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 148.

[0189] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 119, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 119; (ii) an LC CDR2 of SEQ ID NO: 135, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 135; and / or (iii) an LC CDR3 of SEQ ID NO: 148 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 148.

[0190] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO:121, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 121 ; (ii) an LC CDR2 of SEQ ID NO: 134, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 134; and / or (iii) an LC CDR3 of SEQ ID NO: 148 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 148.

[0191] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO:122, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 122; (ii) an LC CDR2 of SEQ ID NO: 134, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 134; and / or (iii) an LC CDR3 of SEQ ID NO: 148 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 148.

[0192] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO:123, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 123; (ii) an LC CDR2 of SEQ ID NO: 134, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 134; and / or (iii) an LC CDR3 of SEQ ID NO: 147 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 147.

[0193] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO:124, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 124; (ii) an LC CDR2 of SEQ ID NO: 134, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 134; and / or (iii) an LC CDR3 of SEQ ID NO: 147 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 147.

[0194] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 152, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 152; (ii) an LC CDR2 of SEQ ID NO: 153, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 153; and / or (iii) an LC CDR3 of SEQ ID NO: 140 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 140.

[0195] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 199, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 199; (ii) an LC CDR2 of SEQ ID NO: 134, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 134; and / or (iii) an LC CDR3 of SEQ ID NO: 200 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 200.

[0196] In some embodiments, a LC polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 119, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 119; (ii) an LC CDR2 of SEQ ID NO: 134, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 134; and / or (iii) an LC CDR3 of SEQ ID NO: 148 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 148.

[0197] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 85, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 85.

[0198] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 86, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 86.

[0199] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 87, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, atleast 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 87.

[0200] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 88, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 88.

[0201] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 89, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 89.

[0202] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 90, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 90.

[0203] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 91, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 91.

[0204] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 92, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 92.

[0205] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 93, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 93.

[0206] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 94, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 94.

[0207] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 95, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 95.

[0208] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 96, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 96.

[0209] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 97, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 97.

[0210] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 98, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 98.

[0211] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 99, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 99.

[0212] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 100, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 100.

[0213] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 101, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 101.

[0214] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 102, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 102.

[0215] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 103, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 103.

[0216] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 104, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 104.

[0217] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 105, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 105.

[0218] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 106, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 106.

[0219] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 107, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 107.

[0220] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 108, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 108.

[0221] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 109, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 109.

[0222] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 110, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 110.

[0223] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 195, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 195.

[0224] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 191, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 191.

[0225] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 155, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 155.

[0226] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 157, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 157.

[0227] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 158, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 158.

[0228] In some embodiments, a LC polypeptide comprises the sequence of SEQ ID NO: 160, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 160.

[0229] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a LC polypeptide comprising a VL sequence of SEQ ID NO: 85 or a sequence with at least 85% identity thereto and a constant region of SEQ ID NO: 215 or a sequence with at least 85% thereto.

[0230] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a LC polypeptide comprising a VL sequence of SEQ ID NO: 85 or a sequence with at least 85% identity thereto and a constant region of SEQ ID NO: 220 or a sequence with at least 85% thereto.

[0231] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a LC polypeptide comprising a VL sequence of SEQ ID NO: 94 or a sequence with at least 85% identity thereto and a constant region of SEQ ID NO: 215 or a sequence with at least 85% thereto.

[0232] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a LC polypeptide comprising a VL sequence of SEQ ID NO: 94 or a sequence with at least 85% identity thereto and a constant region of SEQ ID NO: 220 or a sequence with at least 85% thereto.

[0233] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a LC polypeptide comprising a VL sequence of SEQ ID NO: 87 or a sequence with at least 85% identity thereto and a constant region of SEQ ID NO: 215 or a sequence with at least 85% thereto.

[0234] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a LC polypeptide comprising a VL sequence of SEQ ID NO: 87 or a sequence with at least 85% identity thereto and a constant region of SEQ ID NO: 220 or a sequence with at least 85% thereto.

[0235] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a LC polypeptide comprising a VL sequence of SEQ ID NO: 88 or a sequence with at least 85% identity thereto and a constant region of SEQ ID NO: 215 or a sequence with at least 85% thereto.

[0236] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a LC polypeptide comprising a VL sequence of SEQ ID NO: 88 or a sequence with at least 85% identity thereto and a constant region of SEQ ID NO: 220 or a sequence with at least 85% thereto.

[0237] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a LC polypeptide comprising a VL sequence of SEQ ID NO: 89 or a sequence with at least 85% identity thereto and a constant region of SEQ ID NO: 215 or a sequence with at least 85% thereto.

[0238] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a LC polypeptide comprising a VL sequence of SEQ ID NO: 89 or a sequence with at least 85% identity thereto and a constant region of SEQ ID NO: 220 or a sequence with at least 85% thereto.

[0239] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a LC polypeptide comprising a VL sequence of SEQ ID NO: 86 or a sequence with at least 85% identity thereto and a constant region of SEQ ID NO: 215 or a sequence with at least 85% thereto.

[0240] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a LC polypeptide comprising a VL sequence of SEQ ID NO: 86 or a sequence with at least 85% identity thereto and a constant region of SEQ ID NO: 220 or a sequence with at least 85% thereto.

[0241] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a LC polypeptide comprising a CDR1 having the consensus sequence RASQX1IX2X3X4LX5 (SEQ ID NO: 170), wherein Xi is chosen from T, S, or G; X2 is chosen from S or R; X3 is chosen from S or K; X4 is chosen from Y or F, and X5 is chosen from N, S, or A.

[0242] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a LC polypeptide comprising a CDR2 having the consensus sequence X1X2SX3LX4X5, (SEQ ID NO: 171), wherein Xi is chosen from A, D, or G; X2 is chosen from A, T, or G; X3 is chosen from S, T, or M; X4 is chosen from L or Q; and X5 is chosen from S or A.

[0243] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a LC polypeptide comprising a CDR3 having the consensus sequence QQX1X2X3X4PX5T (SEQ ID NO: 209), wherein Xi is chosen from S, T, or L; X2 is chosen from Y or N; X3 is chosen from S, or N; and X4 is chosen from S, T, A, P or Y; and X5 is chosen from L or F.

[0244] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a LC polypeptide comprising a CDR1 having the consensus sequence SGSSSNIGHNYVXi (SEQ ID NO: 172), wherein Xi is chosen from N or A.

[0245] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a LC polypeptide comprising a CDR3 having the consensus sequence GSYDXiSGSTRV (SEQ ID NO: 173), wherein Xi is chosen from L, I, N, T or S.

[0246] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a LC polypeptide comprising a CDR1 having the consensus sequence RSSX1SLX2X3SDGX4TYLX5 (SEQ ID NO: 174), wherein Xi is chosen from Q, L, or H; X2 is chosen from V or L; X3 is chosen from Y or F; X4 is chosen from N or H; and X5 is chosen from N, H, or I.

[0247] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a LC polypeptide comprising a CDR2 having the consensus sequence XiVSNRDS (SEQ ID NO: 175), wherein Xi is chosen from K or E.

[0248] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a LC polypeptide comprising a CDR3 having the consensus sequence X1QX2X3X4X5PX6T (SEQ ID NO: 176), wherein Xi is chosen from M or Q; X2 is chosen from G, S, T, or L; X3 is chosen from S, T, Y, or N; X4 is chosen from H, S, or N; X5 is chosen from W, S, T, A, Y, or P; and Xe is chosen from P, I, L, or F.Table 1: Exemplary Light chain polypeptide sequencesHeavy chain (e.g., heavy chain variable region(VH)) polypeptides

[0249] The present disclosure provides polypeptides comprising heavy chain (HC) sequences (e.g., heavy chain variable region sequence(s)) that, for example, may be useful as a first moiety in glycoengineered polypeptides described herein targeting h!gG4 antibodies (e.g., h!gG4 autoantibodies); in some such embodiments, such provided polypeptides are useful and / or included in such glycoengineered polypeptides as described herein.

[0250] In some embodiments, a glycoengineered polypeptide comprises a first moiety comprising a HC polypeptide comprising one or more CDRs and / or one or more framework regions. In some embodiments, a HC polypeptide comprises a heavy chain variable region (VH) polypeptide.

[0251] In some embodiments, a glycoengineered polypeptide comprises a first moiety comprising a HC polypeptide comprising at least one HC CDR of an anti-IgG4 antibody agent as provided in Table 2 or a sequence with at least 85% identity thereto. In some embodiments, an HC polypeptide comprises one, two or three HC CDRs (e.g., an HC CDR1, an HC CDR2 and / or an HC CDR3). In some embodiments, an HC polypeptide comprises an HC CDR1. In some embodiments, an HC polypeptide comprises an HC CDR2. In some embodiments, an HC polypeptide comprises an HC CDR3. In some embodiments, an HC polypeptide comprises an HC CDR1, an HC CDR2 and an HC CDR3.

[0252] In some embodiments, a glycoengineered polypeptide comprises a first moiety comprising a HC polypeptide comprising an HC CDR1, an HC CDR2 and an HC CDR3 is capable of binding (e.g., specifically binding) to hIgG4 antibody, e.g., a hIgG4 autoantibody.

[0253] In some embodiments, a glycoengineered polypeptide comprises a first moiety comprising a HC polypeptide further comprises one or more framework regions, and / or a heavy chain constant region, or a portion or a variant thereof (e.g., a CHI, CH2 and / or CH3 region). In some embodiments, an HC polypeptide comprises a CHI, a CH2 or a CH3 or a combination thereof. In some embodiments, an HC polypeptide comprises a CH2 and CH3, e.g., an Fc domain.

[0254] In some embodiments, a Fc domain comprises a mammalian Fc domain. In some embodiments, a Fc domain comprises a dog, a cat, a mouse, a rat, a rabbit, a primate or a human Fc domain. In some embodiments, a Fc domain comprises a human Fc domain. In some embodiments, a Fc domain comprises a dog Fc domain. In some embodiments, a Fc domain comprises a cat Fc domain. In some embodiments, an Fc domain is chosen from an Fc domain of an immunoglobulin isotype. In some embodiments, an immunoglobulin isotype comprises IgA, IgD, IgG, IgM, or IgE. In some embodiments, an Fc domain comprises an Fc domain of an IgG, e.g., a human IgG. In some embodiments, an IgG is or comprises IgGl, lgG2, lgG3, or lgG4.

[0255] In some embodiments, an Fc region is a wildtype Fc region, e.g., a wildtype human Fc region. In some embodiments, an Fc region comprises a variant, e.g., an Fc region comprising an addition, substitution, or deletion of at least one amino acid residue in an Fc region which results in, e.g., reduced or ablated affinity for at least one Fc receptor.

[0256] The Fc region of an antibody interacts with a number of receptors or ligands including Fc Receptors (e.g., FcyRI, FcyRIIA, FcyRIIIA), the complement protein Clq, and other molecules such as proteins A and G. These interactions are essential for a variety of effector functions and downstream signaling events including: antibody dependent cell-mediated cytotoxicity (ADCC), Antibody-dependent cellular phagocytosis (ADCP) and complement dependent cytotoxicity (CDC).

[0257] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 33, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 33; (ii) an HC CDR2 of SEQ ID NO: 45, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 45; and / or (iii) an HC CDR3 of SEQ ID NO: 61 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 61.

[0258] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 33, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:33; (ii) an HC CDR2 of SEQ ID NO: 45, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 45; and / or (iii) an HC CDR3 of SEQ ID NO: 62 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 62.

[0259] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 33, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 33; (ii) an HC CDR2 of SEQ ID NO: 46, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 46; and / or (iii) an HC CDR3 of SEQ ID NO: 61 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 61.

[0260] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 33, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 33; (ii) an HC CDR2 of SEQ ID NO: 47, or a sequence with at least 85%, at least 86%, at least87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 47; and / or (iii) an HC CDR3 of SEQ ID NO: 61 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 61.

[0261] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 33, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 33; (ii) an HC CDR2 of SEQ ID NO: 45, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 45; and / or (iii) an HC CDR3 of SEQ ID NO: 63 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 63.

[0262] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 33, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 33; (ii) an HC CDR2 of SEQ ID NO: 45, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 45; and / or (iii) an HC CDR3 of SEQ ID NO:64 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:64.

[0263] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 33, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 33; (ii) an HC CDR2 of SEQ ID NO: 45, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 45; and / or (iii) an HC CDR3 of SEQ ID NO:65 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:65.

[0264] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 34, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 34; (ii) an HC CDR2 of SEQ ID NO: 48, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or asequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 48; and / or (iii) an HC CDR3 of SEQ ID NO:66 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:66.

[0265] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 34, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 34; (ii) an HC CDR2 of SEQ ID NO: 48, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 48; and / or (iii) an HC CDR3 of SEQ ID NO:67 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:67.

[0266] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 34, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 34; (ii) an HC CDR2 of SEQ ID NO: 48, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g.,conservative substitutions)) relative to SEQ ID NO: 48; and / or (iii) an HC CDR3 of SEQ ID NO:68 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:68.

[0267] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 34, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 34; (ii) an HC CDR2 of SEQ ID NO: 48, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 48; and / or (iii) an HC CDR3 of SEQ ID NO:69 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:69.

[0268] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 34, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 34; (ii) an HC CDR2 of SEQ ID NO: 48, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 48; and / or (iii) an HC CDR3 of SEQ ID NO:7 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 70.

[0269] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 192, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 192; (ii) an HC CDR2 of SEQ ID NO: 193, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 193; and / or (iii) an HC CDR3 of SEQ ID NO: 71 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 71.

[0270] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 35, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 35; (ii) an HC CDR2 of SEQ ID NO: 49, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 49; and / or (iii) an HC CDR3 of SEQ ID NO: 72 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:72.

[0271] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 35, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 35; (ii) an HC CDR2 of SEQ ID NO: 49, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 49; and / or (iii) an HC CDR3 of SEQ ID NO:73 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:73.

[0272] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 36, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 36; (ii) an HC CDR2 of SEQ ID NO: 50, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 50; and / or (iii) an HC CDR3 of SEQ ID NO:74 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 74.

[0273] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 36, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 37; (ii) an HC CDR2 of SEQ ID NO: 50, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 50; and / or (iii) an HC CDR3 of SEQ ID NO:74 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 74.

[0274] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 37, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 36; (ii) an HC CDR2 of SEQ ID NO: 50, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 50; and / or (iii) an HC CDR3 of SEQ ID NO:75 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g.,substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:74.

[0275] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 36, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 36; (ii) an HC CDR2 of SEQ ID NO: 50, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 50; and / or (iii) an HC CDR3 of SEQ ID NO: 75 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:75.

[0276] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 38, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 38; (ii) an HC CDR2 of SEQ ID NO: 51, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 51; and / or (iii) an HC CDR3 of SEQ ID NO: 74 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g.,substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:74.

[0277] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 38, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 38; (ii) an HC CDR2 of SEQ ID NO: 52, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 52; and / or (iii) an HC CDR3 of SEQ ID NO: 75 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:75.

[0278] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 39, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 39; (ii) an HC CDR2 of SEQ ID NO: 51, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 51; and / or (iii) an HC CDR3 of SEQ ID NO: 74 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g.,substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 74.

[0279] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 38, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 38; (ii) an HC CDR2 of SEQ ID NO: 52, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 52; and / or (iii) an HC CDR3 of SEQ ID NO:76 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 76.

[0280] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 40, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 40; (ii) an HC CDR2 of SEQ ID NO: 53, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 53; and / or (iii) an HC CDR3 of SEQ ID NO:77 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g.,substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:77.

[0281] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 41, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 41; (ii) an HC CDR2 of SEQ ID NO: 54, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 54; and / or (iii) an HC CDR3 of SEQ ID NO:78 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:78.

[0282] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 42, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 42; (ii) an HC CDR2 of SEQ ID NO: 55, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 55; and / or (iii) an HC CDR3 of SEQ ID NO:79 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g.,substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:79.

[0283] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 43, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 43; (ii) an HC CDR2 of SEQ ID NO: 56, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 56; and / or (iii) an HC CDR3 of SEQ ID NO:80 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:80.

[0284] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 42, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 42; (ii) an HC CDR2 of SEQ ID NO: 57, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 57; and / or (iii) an HC CDR3 of SEQ ID NO:81 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g.,substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:81.

[0285] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 42, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 42; (ii) an HC CDR2 of SEQ ID NO: 58, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 58; and / or (iii) an HC CDR3 of SEQ ID NO:82 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:82.

[0286] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 42, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 42; (ii) an HC CDR2 of SEQ ID NO: 59, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 59; and / or (iii) an HC CDR3 of SEQ ID NO:83 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g.,substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:83.

[0287] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 44, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 44; (ii) an HC CDR2 of SEQ ID NO: 60, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 60; and / or (iii) an HC CDR3 of SEQ ID NO: 84 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO:84.

[0288] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 196, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 196; (ii) an HC CDR2 of SEQ ID NO: 197, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 197; and / or (iii) an HC CDR3 of SEQ ID NO: 198 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 198.

[0289] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 42, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 42; (ii) an HC CDR2 of SEQ ID NO: 188, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 188; and / or (iii) an HC CDR3 of SEQ ID NO: 189 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 189.

[0290] In some embodiments, a HC polypeptide comprises: (i) an HC CDR1 of SEQ ID NO: 149, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 149; (ii) an HC CDR2 of SEQ ID NO: 150, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 150; and / or (iii) an HC CDR3 of SEQ ID NO: 151 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto or a sequence having at least 5 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 151.

[0291] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 1, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 1.

[0292] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 2, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 2.

[0293] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 3, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 3.

[0294] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 4, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 4.

[0295] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 5, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 5.

[0296] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 6, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 6.

[0297] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 7, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 7.

[0298] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 8, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 8.

[0299] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 9, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 9.

[0300] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 10, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 10.

[0301] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 11, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 11.

[0302] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 12, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 12.

[0303] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 13, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 13.

[0304] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 14, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 14.

[0305] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 15, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 15.

[0306] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 16, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 16.

[0307] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 17, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 17.

[0308] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 18, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 18.

[0309] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 19, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 19.

[0310] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 20, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 20.

[0311] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 21, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 21.

[0312] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 22, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 22.

[0313] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 23, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 23.

[0314] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 24, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 24.

[0315] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 25, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 25.

[0316] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 26, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 26.

[0317] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 27, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 27.

[0318] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 28, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 28.

[0319] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 29, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 29.

[0320] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 30, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 30.

[0321] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 31, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 31.

[0322] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 32, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 32.

[0323] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 194, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 194.

[0324] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 190, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 190.

[0325] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 154, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations(e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 154.

[0326] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 156, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 156.

[0327] In some embodiments, a HC polypeptide comprises the sequence of SEQ ID NO: 159, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity thereto, or a sequence having at least 5, 10, or 20 alterations (e.g., substitutions, deletions or insertions (e.g., conservative substitutions)) relative to SEQ ID NO: 159.

[0328] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a HC polypeptide comprising a VH sequence of SEQ ID NO: 1 or a sequence with at least 85% thereto and a constant region of SEQ ID NO: 214 or a sequence with at least 85% thereto.

[0329] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a HC polypeptide comprising a VH sequence of SEQ ID NO: 2 or a sequence with at least 85% thereto and a constant region of SEQ ID NO: 214 or a sequence with at least 85% thereto.

[0330] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a HC polypeptide comprising a VH sequence of SEQ ID NO: 3 or a sequence with at least 85% thereto and a constant region of SEQ ID NO: 214 or a sequence with at least 85% thereto.

[0331] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a HC polypeptide comprising a VH sequence of SEQ ID NO: 17 or a sequence with at least 85% thereto and a constant region of SEQ ID NO: 214 or a sequence with at least 85% thereto.

[0332] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a HC polypeptide comprising a VH sequence of SEQ ID NO: 16 or a sequence with at least 85% thereto and a constant region of SEQ ID NO: 214 or a sequence with at least 85% thereto.

[0333] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a HC polypeptide comprising a VH sequence of SEQ ID NO: 13 or a sequence with at least 85% thereto and a constant region of SEQ ID NO: 214 or a sequence with at least 85% thereto.

[0334] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: a HC polypeptide comprising a VH sequence of SEQ ID NO: 14 or a sequence with at least 85% thereto and a constant region of SEQ ID NO: 214 or a sequence with at least 85% thereto.

[0335] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a HC polypeptide comprising a CDR1 having the consensus sequence X1YX2MX3 (SEQ ID NO: 177), wherein Xi is chosen from T or D; X2 is chosen from A, S, or T; and X3 is chosen from S or N.

[0336] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a HC polypeptide comprising a CDR2 having the consensus sequenceXIX2X3X4X5X6X7X8X9XIOYXI 1X12X13 X14KX15 (SEQ ID NO: 178), wherein Xi is chosen from A, Y, D, or S; X2 is chosen from I or V; X3 is chosen from S or Y; X4 is chosen from G, S, Y, or H; X5 is chosen from S or R; Xe is chosen from G or S; X7 is chosen from D, R, T, or S; X8is chosen from N, T, or Y; X9 is chosen from T, I, H, or Y; X10 is chosen from Y, F, or is absent; Xu is A or N; X12 is D, P, A, or S; X13 is A or S; X14 is V or L; and X15 is G or S.

[0337] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a HC polypeptide comprising a CDR3 having the consensus sequence X1DWNFX2DX3 (SEQ ID NO:179), wherein Xi is chosen from M or L; X2 is chosen from F or H; and X3 is chosen from Y, F, and M.

[0338] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a HC polypeptide comprising a CDR1 having the consensus sequence X1X2TFSX3X4 (SEQ ID NO:180), wherein Xi is chosen from G or V; X2 is chosen from F or G; X3 is chosen from S or Q; and X4 is chosen from Y, A, or F.

[0339] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a HC polypeptide comprising a CDR3 having the consensus sequence MTX1WTLDX2 (SEQ ID NO:181), wherein Xi is chosen from T, F, or W; and X2 is chosen from Y or L.

[0340] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a HC polypeptide comprising a CDR1 having the consensus sequence X1YX2MN (SEQ ID NO: 182), wherein Xi is chosen from D or T; and X2 is chosen from S or T.

[0341] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a HC polypeptide comprising a CDR3 having the consensus sequence SLGX1PHDX2 (SEQ ID NO: 183), wherein Xi is chosen from Y or F; and X2 is chosen from Y or G.

[0342] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a HC polypeptide comprising a CDR1 having the consensus sequence SXiAIS (SEQ ID NO: 184), wherein Xi is chosen from A or Y.

[0343] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a HC polypeptide comprising a CDR2 having the consensus sequence GIIPXiFGEAAYAQKFQG (SEQ ID NO: 185), wherein Xi is chosen from E or V.

[0344] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a HC polypeptide comprising a CDR1 having the consensus sequence SSRYYWXi (SEQ ID NO: 186), wherein Xi is chosen from G, D, or A.

[0345] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a HC polypeptide comprising a CDR3 having the consensus sequence X1GAX2X3EGDY (SEQ ID NO: 187), wherein Xi is chosen from E or D; X2 is chosen from S or E; and X3 is chosen from P or V.Table 2: Exemplary heavy chain polypeptide sequencesCombined light chain and heavy chain polypeptides

[0346] In some embodiments, a glycoengineered polypeptide comprises a first moiety comprising a light chain comprising a variable region comprising one, two or three LC CDRs and a heavy chain comprising a variable region comprising one, two or three HC CDRs. In some embodiments, a glycoengineered polypeptide comprises a first moiety comprising a light chain comprising a LC CDR1, a LC CDR2 and a LC CDR3, and a heavy chain comprising an HC CDR1, an HC CDR2 and HC CDR3.

[0347] In some embodiments, the first moiety of a glycoengineered polypeptide comprising a light chain comprising an LC CDR1, a LC CDR2 and a LC CDR3, and a heavy chain comprising an HC CDR1, an HC CDR2 and HC CDR3 is able to specifically bind to a IgG4 antibody (e.g., an IgG4 autoantibody) or a fragment thereof.

[0348] In some embodiments, a first moiety of a glycoengineered polypeptide comprises a VL sequence provided in Table 1 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5, 10, or 20 substitutions relative to a VL sequence provided in Table 1; and a VH sequence provided in Table 2 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto, or a sequence having at least 5, 10, or 20 substitutions relative to a VH sequence provided in Table 2.

[0349] In some embodiments, a first moiety of a glycoengineered polypeptide comprises one, two, or three LC CDRs provided in Table 1 or a sequence with at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto; and one, two, or three HC CDRs provided in Table 2, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto.

[0350] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (a) a light chain comprising: (i) an LC CDR1 provided in Table 1 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to an LC CDR1 provided in Table 1; (ii) an LC CDR2 provided in Table 1 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to an LC CDR2 provided in Table 1; and / or (iii) an LC CDR3 provided in Table 1 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to an LC CDR3 provided in Table 1; and (b) a heavy chain comprising: (i) an HC CDR1 provided in Table 2 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to an HC CDR1 provided in Table 2; (ii) an HC CDR2 provided in Table 2 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to an HC CDR2 provided in Table 2; and / or (iii) an HC CDR3 provided in Table 2 or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to an HC CDR3 provided in Table 2.

[0351] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 111, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 111 ; an LC CDR2 of SEQ ID NO: 125, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 125; and an LC CDR3 of SEQ ID NO: 136, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 136; and (ii) an HC CDR1 of SEQ ID NO: 33, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 33; an HC CDR2 of SEQ ID NO: 45, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 45; and an HC CDR3 of SEQ ID NO: 61, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 61.

[0352] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 111, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 111 ; an LC CDR2 of SEQ ID NO: 125, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ IDNO: 125; and an LC CDR3 of SEQ ID NO: 136, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 136; and (ii) an HC CDR1 of SEQ ID NO: 33, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 33; an HC CDR2 of SEQ ID NO: 45, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 45; and an HC CDR3 of SEQ ID NO: 62, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 62.

[0353] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 111, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 111 ; an LC CDR2 of SEQ ID NO: 125, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ IDNO: 125; and an LC CDR3 of SEQ ID NO: 136, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 136; and (ii) an HC CDR1 of SEQ ID NO: 33, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 33; an HC CDR2 of SEQ ID NO: 46, or a sequence with at least 85%, atleast 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 46; and an HC CDR3 of SEQ ID NO: 61, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 61.

[0354] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 111, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 111 ; an LC CDR2 of SEQ ID NO: 125, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ IDNO: 125; and an LC CDR3 of SEQ ID NO: 136, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 136; and (ii) an HC CDR1 of SEQ ID NO: 33, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 33; an HC CDR2 of SEQ ID NO: 47, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 47; and an HC CDR3 of SEQ ID NO: 61, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 61.

[0355] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 111, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 111 ; an LC CDR2 of SEQ ID NO: 125, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 125; and an LC CDR3 of SEQ ID NO: 136, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 136; and (ii) an HC CDR1 of SEQ ID NO: 33, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 33; an HC CDR2 of SEQ ID NO: 45, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 45; and an HC CDR3 of SEQ ID NO: 63, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 63.

[0356] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 111, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 111 ; an LC CDR2 of SEQ ID NO: 125, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ IDNO: 125; and an LC CDR3 of SEQ ID N O: 136, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 136; and (ii) an HC CDR1 of SEQ ID NO: 33, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 33; an HC CDR2 of SEQ ID NO: 45, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 45; and an HC CDR3 of SEQ ID NO: 64, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 64.

[0357] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 111, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 111 ; an LC CDR2 of SEQ ID NO: 125, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 125; and an LC CDR3 of SEQ ID NO: 136, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 136; and (ii) an HC CDR1 of SEQ ID NO: 33, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 33; an HC CDR2 of SEQ ID NO: 45, or a sequence with at least 85%, atleast 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 45; and an HC CDR3 of SEQ ID NO: 65, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 65.

[0358] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 112, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 112; an LC CDR2 of SEQ ID NO: 126, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ IDNO: 126; and an LC CDR3 of SEQ ID NO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 137; and (ii) an HC CDR1 of SEQ ID NO: 34, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 34; an HC CDR2 of SEQ ID NO: 48, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 48; and an HC CDR3 of SEQ ID NO: 66, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 66.

[0359] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 112, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 112; an LC CDR2 of SEQ ID NO: 126, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 126; and an LC CDR3 of SEQ ID NO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 137; and (ii) an HC CDR1 of SEQ ID NO: 34, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 34; an HC CDR2 of SEQ ID NO: 48, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 48; and an HC CDR3 of SEQ ID NO: 67, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 67.

[0360] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 112, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 112; an LC CDR2 of SEQ ID NO: 126, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ IDNO: 126; and an LC CDR3 of SEQ ID NO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 137; and (ii) an HC CDR1 of SEQ ID NO: 34, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 34; an HC CDR2 of SEQ ID NO: 48, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 48; and an HC CDR3 of SEQ ID NO: 68, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 68.

[0361] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 112, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 112; an LC CDR2 of SEQ ID NO: 126, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ IDNO: 126; and an LC CDR3 of SEQ ID NO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 137; and (ii) an HC CDR1 of SEQ ID NO: 34, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 34; an HC CDR2 of SEQ ID NO: 48, or a sequence with at least 85%, atleast 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 48; and an HC CDR3 of SEQ ID NO: 69, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 69.

[0362] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 112, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 112; an LC CDR2 of SEQ ID NO: 126, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ IDNO: 126; and an LC CDR3 of SEQ ID NO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 137; and (ii) an HC CDR1 of SEQ ID NO: 34, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 34; an HC CDR2 of SEQ ID NO: 48, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 48; and an HC CDR3 of SEQ ID NO: 70, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 70.

[0363] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 113, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 113; an LC CDR2 of SEQ ID NO: 127, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 127; and an LC CDR3 of SEQ ID NO: 138, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 138; and (ii) an HC CDR1 of SEQ ID NO: 192, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 192; an HC CDR2 of SEQ ID NO: 193, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 193; and an HC CDR3 of SEQ ID NO: 71, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 71.

[0364] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 113, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 113; an LC CDR2 of SEQ ID NO: 127, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ IDNO: 127; and an LC CDR3 of SEQ ID NO: 138, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 138; and (ii) an HC CDR1 of SEQ ID NO: 35, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 35; an HC CDR2 of SEQ ID NO: 49, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 49; and an HC CDR3 of SEQ ID NO: 72, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 72.

[0365] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 114, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 114; an LC CDR2 of SEQ ID NO: 126, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 126; and an LC CDR3 of SEQ ID NO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 137; and (ii) an HC CDR1 of SEQ ID NO: 35, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 35; an HC CDR2 of SEQ ID NO: 49, or a sequence with at least 85%, atleast 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 49; and an HC CDR3 of SEQ ID NO: 72, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 72.

[0366] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 112, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 112; an LC CDR2 of SEQ ID NO: 128, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ IDNO: 128; and an LC CDR3 of SEQ ID NO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 137; and (ii) an HC CDR1 of SEQ ID NO: 35, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 35; an HC CDR2 of SEQ ID NO: 49, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 49; and an HC CDR3 of SEQ ID NO: 72, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 72.

[0367] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 112, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 112; an LC CDR2 of SEQ ID NO: 126, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 126; and an LC CDR3 of SEQ ID NO: 139, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 139; and (ii) an HC CDR1 of SEQ ID NO: 35, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 35; an HC CDR2 of SEQ ID NO: 49, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 49; and an HC CDR3 of SEQ ID NO: 72, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 72.

[0368] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 112, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 112; an LC CDR2 of SEQ ID NO: 129, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ IDNO: 129; and an LC CDR3 of SEQ ID NO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 137; and (ii) an HC CDR1 of SEQ ID NO: 35, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 35; an HC CDR2 of SEQ ID NO: 49, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 49; and an HC CDR3 of SEQ ID NO: 72, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 72.

[0369] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 112, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 112; an LC CDR2 of SEQ ID NO: 129, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ IDNO: 129; and an LC CDR3 of SEQ ID NO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 137; and (ii) an HC CDR1 of SEQ ID NO: 35, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 35; an HC CDR2 of SEQ ID NO: 49, or a sequence with at least 85%, atleast 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 49; and an HC CDR3 of SEQ ID NO: 73, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 73.

[0370] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 112, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 112; an LC CDR2 of SEQ ID NO: 126, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ IDNO: 126; and an LC CDR3 of SEQ ID NO: 139, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 139; and (ii) an HC CDR1 of SEQ ID NO: 35, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 35; an HC CDR2 of SEQ ID NO: 49, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 49; and an HC CDR3 of SEQ ID NO: 73, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 73.

[0371] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 115, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 115; an LC CDR2 of SEQ ID NO: 126, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 126; and an LC CDR3 of SEQ ID NO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 137; and (ii) an HC CDR1 of SEQ ID NO: 35, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 35; an HC CDR2 of SEQ ID NO: 49, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 49; and an HC CDR3 of SEQ ID NO: 72, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 72.

[0372] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 112, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 112; an LC CDR2 of SEQ ID NO: 130, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ IDNO: 130; and an LC CDR3 of SEQ ID NO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 137; and (ii) an HC CDR1 of SEQ ID NO: 35, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 35; an HC CDR2 of SEQ ID NO: 49, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 49; and an HC CDR3 of SEQ ID NO: 72, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 72.

[0373] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 112, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 112; an LC CDR2 of SEQ ID NO: 126, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ IDNO: 126; and an LC CDR3 of SEQ ID NO: 137, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 137; and (ii) an HC CDR1 of SEQ ID NO: 35, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 35; an HC CDR2 of SEQ ID NO: 49, or a sequence with at least 85%, atleast 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 49; and an HC CDR3 of SEQ ID NO: 72, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 72.

[0374] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 116, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 116; an LC CDR2 of SEQ ID NO: 131, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ IDNO: 131; and an LC CDR3 of SEQ ID NO: 140, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 140; and (ii) an HC CDR1 of SEQ ID NO: 36, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 36; an HC CDR2 of SEQ ID NO: 50, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 50; and an HC CDR3 of SEQ ID NO: 74, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 74.

[0375] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 116, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 116; an LC CDR2 of SEQ ID NO: 131, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 131; and an LC CDR3 of SEQ ID NO: 141, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 141; and (ii) an HC CDR1 of SEQ ID NO: 36, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 36; an HC CDR2 of SEQ ID NO: 50, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 50; and an HC CDR3 of SEQ ID NO: 74, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 74.

[0376] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 116, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 116; an LC CDR2 of SEQ ID NO: 131, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ IDNO: 131; and an LC CDR3 of SEQ ID NO: 140, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 140; and (ii) an HC CDR1 of SEQ ID NO: 37, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 37; an HC CDR2 of SEQ ID NO: 50, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 50; and an HC CDR3 of SEQ ID NO: 74, or a sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% thereto or a sequence having at least 5 substitutions relative to SEQ ID NO: 74.

[0377] In some embodiments, a first moiety of a glycoengineered polypeptide comprises: (i) an LC CDR1 of SEQ ID NO: 116, or a sequence with at leas...

Claims

What is claimed is1. A glycoengineered polypeptide comprising:(a) a first moiety comprising one or more peptides that specifically binds to a human immunoglobulin G4 (IgG4) antibody; and(b) a second moiety comprising one or more glycans conjugated to the first moiety at one or more glycosylation sites.

2. The glycoengineered polypeptide of claim 1, wherein:(i) the IgG4 antibody is an IgG4 autoantibody or a fragment or a complex thereof; and / or(ii) the first moiety comprises one or more peptides that binds the IgG4 antibody at a CHI domain, a hinge domain, a CH2 domain, a CH3 domain, or any combination thereof optionally, wherein the first moiety binds the IgG4 antibody at the CH2 domain and / or the CH3 domain.

3. The glycoengineered polypeptide of claim 1 or 2, wherein the first moiety comprises one or more peptides that binds the IgG4 antibody with a higher affinity as compared to binding to a non-IgG4 antibody optionally, wherein the first moiety binds to an IgG4 autoantibody:(i) with an affinity that is at least 10-fold stronger as compared to binding of the first moiety to a non-IgG4 antibody; and / or(ii) with an affinity of at least 2-fold higher compared to binding affinity of the first moiety to a non-IgG4 antibody when detected by surface plasmon resonance (SPR).

4. The glycoengineered polypeptide of claim 3, wherein the non-IgG4 antibody comprises an antibody of a class other than IgG4 (e.g., an IgGl antibody, an IgG2 antibody, an IgG3 antibody, an IgA antibody, an IgM antibody, an IgD antibody, or an IgE antibody, or a fragment or complex of any of the foregoing).

5. The glycoengineered polypeptide of any one of claims 1-4, wherein the first moiety binds to an IgG4 antibody with an affinity of about lOpM to about lOOOnM.

6. The glycoengineered polypeptide of any one of the preceding claims, characterized in that:(i) administration of the glycoengineered polypeptide to a cell, tissue, or subject reduces the level of the IgG4 antibody as compared to: (1) an otherwise similar cell, tissue, or subject that has not been administered the glycoengineered polypeptide; or (2) the same cell, tissue or subject, prior to administration of the glycoengineered polypeptide, optionally wherein the reduction in IgG4 antibody is at least 5%; and / or(ii) administration of the glycoengineered polypeptide to a cell, tissue, or subject does not alter (e.g., does not reduce) the level of a non-IgG4 antibody as compared to: (1) an otherwise similar cell, tissue, or subject that has not been administered the glycoengineered polypeptide; or (2) the same cell, tissue or subject, prior to administration of the glycoengineered polypeptide, optionally wherein at least 75% of a non-IgG4 antibody remains (e.g., is detectable) after administration of the glycoengineered polypeptide as compared to a level measured prior to the administration.

7. The glycoengineered polypeptide of any one of the preceding claims, wherein the first moiety comprises an antibody agent, optionally wherein the antibody agent comprises an antigen binding fragment.

8. The glycoengineered polypeptide of claim 7, wherein the antibody agent comprises a full antibody, a Fab fragment, an scFv, a nanobody, a duobody, or a single domain antibody (e.g., a VHH).

9. The glycoengineered polypeptide of claim 7 or 8, wherein the antibody agent of the first moiety comprises one, two and / or three light chain complementarity determining regions (LC CDRs) and / or one, two and / or three heavy chain complementary determining regions (HC CDRs).

10. The glycoengineered polypeptide of claim 9, comprising:(i) a LC CDR1, LC CDR2, and LC CDR3 sequence provided in Table 1;(ii) a sequence with at least 85% identity to an LC CDR1, LC CDR2, and LC CDR3 sequence provided in Table 1; or(iii) a sequence having at least 5 substitutions relative to an LC CDR1 , LC CDR2, and LC CDR3 sequence provided in Table 1.

11. The glycoengineered polypeptide of claim 9 or 10, comprising:(i) a HC CDR1, HC CDR2, and HC CDR3 sequence provided in Table 2;(ii) a sequence with at least 85% identity to an HC CDR1, HC CDR2, and HC CDR3 sequence provided in Table 2; or(iii) a sequence having at least 5 substitutions relative to an HC CDR1, HC CDR2, and HC CDR3 sequence provided in Table 2.

12. The glycoengineered polypeptide of any one of claims 7-11, wherein the antibody agent of the first moiety comprises:(a) a light chain (LC) comprising a VL region sequence provided in Table 1, or a sequence with at least 85% identity thereto, or a sequence having at least 5 substitutions relative to a VL region provided in Table 1; and / or(b) a heavy chain (HC) comprising a VH region sequence provided in Table 2, or a sequence with at least 85% identity thereto, or a sequence having at least 5 substitutions relative to a VH region provided in Table 2.

13. The glycoengineered polypeptide of any one of claims 2-12, wherein the IgG4 autoantibody comprises: an anti-PLA2R IgG4 autoantibody or a fragment or a complex thereof; an anti-THSD7A IgG4 autoantibody or a fragment or a complex thereof; an anti-NELL IgG4 autoantibody or a fragment or a complex thereof; an anti-NEP IgG4 autoantibody or a fragment or a complex thereof; an anti-EXTl IgG4 autoantibody or a fragment or a complex thereof; an anti-EXT2 IgG4 autoantibody or a fragment or a complex thereof; an anti-ADAMTS13 IgG4 autoantibody or a fragment or a complex thereof; an anti-desmoglein 1 IgG4 autoantibody or a fragment or a complex thereof;an anti-desmoglein 3 IgG4 autoantibody or a fragment or a complex thereof; an anti-nicotinic acetylcholine receptor (nAChR) IgG4 autoantibody or a fragment or a complex thereof; an anti-muscle-specific kinase (MuSK) IgG4 autoantibody or a fragment or a complex thereof; and / or an anti-low-density lipoprotein receptor-related protein 4 (LRP4) IgG4 autoantibody or a fragment or a complex thereof.

14. The glycoengineered polypeptide of any one of the preceding claims, wherein the second moiety comprising one or more glycans specifically binds to one or more endocytic receptors.

15. The glycoengineered polypeptide of claim 14, wherein the endocytic receptor is or comprises an endocytic lectin, optionally wherein the endocytic receptor comprises: an asialoglycoprotein receptor (ASGPR), a mannose binding receptor, a Cluster of Differentiation 206 (CD206) receptor, a DC- SIGN (Cluster of Differentiation 209 or CD209) receptor, a C-Type Lectin Domain Family 4 Member G (LSECTin) receptor, a macrophage inducible Ca2+-dependent lectin receptor (Mincle), a L-SIGN CD209L receptor, dectin- 1, dectin -2, langerin, macrophage mannose 2 receptor, BDCA-2, DCIR, MBL, MDL, MICL, CLEC2, DNGR1, CLEC12B, DEC-205, mannose 6 phosphate receptor (M6PR), or any fragment or any combination thereof.

16. The glycoengineered polypeptide of any one of the preceding claims, wherein the one or more glycans comprises a terminal GlcNac, a terminal GalNac, a terminal Gal, or any combination thereof.

17. The glycoengineered polypeptide of any one of the preceding claims, wherein the one or more glycans is an N-glycan, optionally wherein the N-glycan is linked to the glycoengineered polypeptide at 1, 2, 3, 4 or 5 N-glycosylation sites.

18. The glycoengineered polypeptide of any one of the preceding claims, wherein the one or more glycans comprise a glycan structure comprising: GlcNAc2-Man3-GlcNAc2, GalNAc2-GlcNAc2-Man3-GlcNAc2, Gal2-GlcNAc2-Man3-GlcNAc2, GlcNAcl-Man3-GlcNAc2, Gal2-GlcNAc2-Man3-GlcNAc2, Gall- GlcNAc2-Man3-GlcNAc2, GalNAcl-GlcNAc2-Man3- GlcNAc2, GlcNAc3-Man3-GlcNAc2, GlcNAc4-Man3-GlcNAc2, Gal3-GlcNAc3-Man3- GlcNAc2, GalNAc3-GlcNAc3-Man3-GlcNAc2, GalNAc4-GlcNAc4-Man3-GlcNAc2, Gal4- GlcNAc4-Man3-GlcNAc2, or Man-6-P -N-glycan.

19. The glycoengineered polypeptide of claim 18, wherein the glycan structure comprises a monoantennary structure, biantennary structure, a triantennary structure, or a tetraantennary structure.

20. The glycoengineered polypeptide of claim 19, wherein the glycan structure comprises a biantennary structure, optionally wherein the glycan structure comprises a biantennary GalNAc.

21. The glycoengineered polypeptide of claim 20, wherein the biantennary GalNac binds to ASGPR or a fragment or variant thereof, or a complex comprising ASGPR.

22. The glycoengineered polypeptide of any one of claims 17-21, wherein the N-glycan has a structure of:wherein the black square represents an N-acetyl galactosamine (GalNAc), the white square represents an N-acetylglucosamine (GlcNAc) residue and the black circle represents a mannose (Man) residue, and wherein X represents an amino acid residue of the first moiety.

23. The glycoengineered polypeptide of any one of claims 17-22, wherein the N-glycan is conjugated to the glycoengineered polypeptide at at least one, two, three, or four N-glycosylation sites, optionally wherein the N-glycosylation site comprises a consensus sequence of N-X-S / T or N-X-C, wherein X is any amino acid except proline.

24. The glycoengineered polypeptide of claim 23, wherein the N-glycosylation site is naturally occurring.

25. The glycoengineered polypeptide of claim 23, wherein the N-glycosylation site is engineered into the amino acid sequence of the first moiety, optionally wherein the N- glycosylation site comprises a sequence of SEQ ID NO: 161, SEQ ID NO: 163, SEQ ID NO: 168, or SEQ ID NO: 169.

26. The glycoengineered polypeptide of any one of claims 14-25, wherein the endocytic receptor is or comprises ASGPR or a fragment or variant thereof, or a complex comprising ASGPR, optionally, wherein the glycoengineered polypeptide binds to ASGPR with an affinity of at least about 1 micromolar (pM).

27. The glycoengineered polypeptide of any one of the preceding claims, wherein the polypeptide comprises one or more additional elements, optionally wherein the additional element comprises a linker, a signal peptide, a tag, a half-life extender or combinations thereof.

28. The glycoengineered polypeptide of any one of the preceding claims, wherein the second moiety is conjugated to the first moiety at at least one, two, three, or four N-glycosylation sites.

29. The glycoengineered polypeptide of any one of claims 1 -28, wherein the second moiety is conjugated to the first moiety in vivo.

30. The glycoengineered polypeptide of claim 29, wherein the conjugation occurs in a cell optionally wherein the cell is a leishmania cell.

31. The glycoengineered polypeptide of any one of claims 1 -28, wherein the second moiety is conjugated to the first moiety by chemical conjugation optionally wherein, chemical conjugation comprises click chemistry.

32. The glycoengineered polypeptide of any one of claims 7-31, wherein the antibody agent has a glycan to protein ratio of 2 to 1 , 4 to 1 , 6 to 1, 8 to 1 , or 10 to 1.

33. The glycoengineered polypeptide of any one of claims 7-32, wherein the antibody agent comprises one or more additional antigen binding fragments, optionally wherein the one or more additional antigen binding fragments bind to an antigen other than an IgG4 antibody.

34. The glycoengineered polypeptide of any one of claims 7-33, wherein the first moiety comprises an antibody agent conjugated to one or more additional domains, optionally wherein the one or more additional domains comprises an extracellular domain, a hinge domain, a transmembrane domain and / or an intracellular domain.

35. A polynucleotide encoding the glycoengineered polypeptide of any one of the preceding claims.

36. The polynucleotide of claim 35, wherein the polynucleotide comprises a portion of a nucleotide sequence encoding a glycoengineered polypeptide or a codon-optimized version thereof.

37. A composition comprising a glycoengineered polypeptide of any one of claims 1-34.

38. A composition comprising a population of glycoengineered polypeptides of any one of claims 1-34, wherein the population of glycoengineered polypeptides has an N-glycan profilethat is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or about 100% homogeneous at one or more of the N- glycosylation site(s).

39. The composition of claim 38, wherein the composition is a pharmaceutical composition.

40. A Leishmania host cell expressing a glycoengineered polypeptide of any one of claims 1- 34, wherein the cell comprises a polynucleotide sequence encoding a glycoengineered polypeptide.

41. A method comprising: delivering a pharmaceutical composition of claim 39 to a cell, tissue, or subject.

42. The method of claim 41, wherein the subject has or is diagnosed as having a disease associated with one or more IgG4 autoantibodies, optionally wherein the disease associated with one or more IgG4 autoantibodies comprises: Pemphigus Vulgaris / Folaceus; Muscle-specific kinase (MuSK) myasthenia gravis (MG), Idiopathic Thrombotic Thrombocytopenia Purpura (iTTP), idiopathic membranous nephropathy (iMN), Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), or Immunoglobulin G4-Related Disease (IgG4-RD).

43. The method of claim 42, wherein the method is a treatment method or a prevention method.

44. A method of treating and / or preventing a disease associated with one or more IgG4 autoantibodies the method comprising: delivering a pharmaceutical composition of claim 39 to a cell, tissue, or subject.

45. A method of degrading an IgG4 antibody (e.g., an IgG4 autoantibody) or a complex comprising the same, the method comprising: delivering a pharmaceutical composition of claim 39 to a cell, tissue, or subject.

46. A method of delivering an IgG4 antibody (e.g., an IgG4 autoantibody) or a complex comprising the same to a lysosome, the method comprising: delivering a pharmaceutical composition of claim 39 to a cell, tissue, or subject.

47. The method of any one of claims 41-46, wherein the glycoengineered polypeptide is capable of simultaneously binding to an IgG4 antibody (e.g., IgG4 autoantibody) with the first moiety and binding to an endocytic receptor-expressing cell with the second moiety, thereby causing the IgG4 antibody (e.g., IgG4 autoantibody) to be internalized into a cell.

48. The method of claim 47, wherein internalization comprises transporting to a lysosome and / or degradation.

49. The method of claim 47 or 48, wherein the IgG4 antibody (e.g., IgG4 autoantibody) and the glycoengineered polypeptide are internalized.

50. The method of any one of claims 41-48, wherein binding of the first moiety to an IgG4 antibody (e.g., IgG4 autoantibody) or a complex comprising the same and binding of the second moiety to an endocytic receptor results in degradation of the IgG4 antibody or a complex comprising the same.

51. The method of claim 50, wherein degradation occurs in vivo.

52. The method of claim 50 or 51, wherein degradation occurs in a liver cell.

53. The method of any one of claims 41-52, wherein delivering comprises administering the pharmaceutical composition to the cell, tissue or subject, optionally wherein the administration step comprises intravenous injection, intraperitoneal injection, subcutaneous injection, transdermal injection, or intramuscular injection.

54. The method of any one of claims 53, wherein the method comprises administering the pharmaceutical composition in combination with one or more additional therapies.

55. A method comprising, assessing a level of an IgG4 antibody (e.g., IgG4 autoantibody) in a sample from a subject, and administering a pharmaceutical composition of claim 39, if the level of the IgG4 antibody (e.g., IgG4 autoantibody) is higher than a comparator, optionally, wherein the comparator comprises a predetermined reference sample such as a sample obtained from an otherwise similar subject who does not have a disease associated with one or more IgG4 autoantibodies, or a symptom of a disease associated with one or more IgG4 autoantibodies.

56. The method of any one of claims 41-55, wherein the subject is a mammal.

57. Use of a pharmaceutical composition of claim 39, in the manufacture of a medicament for delivering the pharmaceutical composition to a cell, tissue or subject.

58. The pharmaceutical composition of claim 39, for use in delivering the pharmaceutical composition to a cell, tissue or subject.

59. Use of a pharmaceutical composition of claim 39, in the manufacture of a medicament for treating and / or preventing a disease associated with one or more IgG4 autoantibodies.

60. The pharmaceutical composition of claim 39, for use in treating and / or preventing a disease associated with one or more IgG4 autoantibodies.

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