Antibodies to htra1 and conjugates thereof

Abstract

Antibodies that bind to HTRA1 and conjugates thereof are provided. Also provided are methods of making and using the same.

Description

ANTIBODIES TO HTRA1 AND CONJUGATES THEREOFINCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Ser. No. 63 / 487,521, filed February 28, 2023, which is hereby incorporated by reference in its entirety.SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing XML in electronic format. The Sequence Listing XML is provided as a file entitled KDIAK190WOSeqList.xml, created January 30, 2024 which is 835,882 bytes in size. The information in the electronic format of the Sequence Listing XML is incorporated herein by reference in its entirety.BACKGROUNDField

[0003] The present disclosure relates to antibodies and conjugates thereof and methods of using and manufacturing said antibodies and conjugates thereof.

[0004] High-temperature requirement Al (HTRA1) is a secreted homo-oligomeric (trimer) serine protease. Each monomer contains an N-terminal insulin like growth factorbinding protein (IGFBP) / Kazal domain, a trypsin-like fold protease domain and a C-terminal PDZ domain. HTRA1 promiscuously cleaves a plethora of extracellular matrix (ECM) proteins and TGF-beta family members.SUMMARY

[0005] Provided herein is an antibody conjugate comprising (1) an anti-HTRAl antibody and (2) a phosphorylcholine containing polymer, wherein the polymer is covalently bonded to the antibody at a non-native cysteine outside a variable region of the antibody.

[0006] Also provided is an antibody conjugate comprising an anti-HTRAl immunoglobulin G (IgG) bonded to a polymer, which polymer comprises MPC monomers, wherein the anti-HTRAl antibody heavy chain comprises: a heavy chain variable region (VH)comprising an amino acid sequence at least 80% identical to any one of SEQ ID NOs:725, 742, 744, 745, 746, C-terminally fused to a heavy chain constant region (HC) comprising an amino acid sequence of SEQ ID NO:536, wherein the polymer is bonded to C326 of SEQ ID NO:536, and wherein the anti-HTRAl antibody light chain comprises: a light chain variable region (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO:748, C-terminally fused to a light chain constant region (LC) comprising an amino acid sequence of SEQ ID NO:537.

[0007] Further provided is an antibody conjugate comprising an anti-HTRAl immunoglobulin G (IgG) covalently bonded to a polymer, which polymer comprises MPC monomers, wherein the anti-HTRAl antibody heavy chain comprises: a heavy chain variable region (VH) comprising an amino acid sequence comprising SEQ ID NOs:725, 742, 744, 745, 746, C-terminally fused to a heavy chain constant region (HC) comprising an amino acid sequence of SEQ ID NO:536, wherein the polymer is bonded to C326 of SEQ ID NO:536, and wherein the anti-HTRAl antibody light chain comprises: a light chain variable region (VL) comprising an amino acid sequence comprising SEQ ID NO:748, C-terminally fused to a light chain constant region (LC) comprising an amino acid sequence of SEQ ID NO: 537.

[0008] Also provided is an anti-HTRAl antibody which comprises a heavy chain and a light chain, wherein the heavy chain comprises: a CDRnl having an amino acid sequence of a CDRHI in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2,6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1; a CDRu2 having an amino acid sequence of a CDRH2 in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1,7.4, 7.7, 7.12, 7.17, and 8.1; and a CDRH3 having an amino acid sequence of a CDRH3 in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, and wherein the anti-HTRAl antibody light chain comprises a light chain variable region (VL) comprising: a CDRLI having an amino acid sequence of a CDRLI in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1,7.5, 7.8, 7.13, 7.18, and 8.2; a CDRL2 having an amino acid sequence of a CDRL2 in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2; a CDRL3 having an amino acid sequence of a CDRL3 in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2.

[0009] Provided herein is an anti-HTRAl antibody which comprises a heavy chain and a light chain, wherein the heavy chain comprises CDRHI : FYHVH (SEQ ID NO:830), CDRH2: SIYTSGYTEYASALES (SEQ ID NO:831), and CDRH3 : EGLQRVGVLDA (SEQ ID NO:834) or EGLQRVGVFDA (SEQ ID NO 832) or EGLQRVGVMDA (SEQ ID NO:833), and the light chain comprises CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO: 841), and CDRL3 : QQATYFPYT (SEQ ID NO: 839), and the heavy chain isotype is IgGl, wherein the IgGl constant region comprises one or more of the following mutations to modulate effector function (EU numbering): L234A, L235A, and G237A. Also provided is an anti-HTRAl antibody which comprises a heavy chain and a light chain, wherein the heavy chain comprises CDRHI : GFSLTFYH (SEQ ID NO: SEQ ID NO 825), CDRH2: IYTSGYT (SEQ ID NO:826), and CDRH3 : AREGLQRVGVFDA (SEQ ID NO 827) or AREGLQRVGVMDA (SEQ ID NO:828) or AREGLQRVGVLDA (SEQ ID NO:829), and the anti-HTRAl antibody light chain variable region comprises CDRLI : QSLLDEAGETY (SEQ ID NO:837), CDRL2: EV (SEQ ID NO:838), and CDRL3 : QQATYFPYT (SEQ ID NO:839), and the heavy chain isotype is IgGl, wherein the IgGl constant region comprises one or more of the following mutations to modulate effector function (EU numbering): L234A, L235A, and G237A. Also provided is an anti-HTRAl antibody which comprises a heavy chain and a light chain, wherein the heavy chain comprises CDRHI : GFSLTFY (SEQ ID NO: SEQ ID NO:835), CDRH2: YTSGY (SEQ ID NO:836), and CDRH3 : EGLQRVGVLDA (SEQ ID NO:834) or EGLQRVGVFDA (SEQ ID NO:832) or EGLQRVGVMDA (SEQ ID NO:833), and the anti-HTRAl antibody light chain variable region comprises CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO:841), and CDRL3 : QQATYFPYT (SEQ ID NO:839), wherein the IgGl constant region comprises one or more of the following mutations to modulate effector function (EU numbering): L234A, L235A, and G237A.

[0010] Further provided herein is an antibody comprising: a heavy chain amino acid variable region that comprises an amino acid sequence at least 80% identical to any one of SEQ ID NOs:725, 742, 744, 745, 746; and a light chain amino acid variable region that comprises an amino acid sequence at least 80% identical to SEQ ID NO:748.

[0011] Also provided is an antibody that binds to HTRA1, the antibody comprising: a CDRHI that is the CDRHI in any one of SEQ ID NOs:725, 742, 744, 745, 746;a CDRH2 that is the CDRH2 in any one of SEQ ID NOs:725, 742, 744, 745, 746; a CDRH3 that is the CDRH3 in any one of SEQ ID NOs:725, 742, 744, 745, 746; a CDRLI that is the CDRLI in SEQ ID NO:748; a CDRL2 that is the CDRL2 in SEQ ID NO:748; a CDRL3 that is the CDRL3 in SEQ ID NO:748; at least one of the following mutations (EU numbering): L234A, L235A, and G237A; and at least one of the following mutations(EU numbering): Q347C or L443C.

[0012] Further provided herein is a pharmaceutical composition that includes at least one of the antibody and / or antibody conjugate provided herein. Also provided is a method of treatment or prophylaxis of an ocular disease comprising administering the antibody conjugate and / or the antibody provided herein.

[0013] Also provided herein are methods of making at least one of the antibody conjugate provided herein.

[0014] Provided herein is a method of making an antibody conjugate comprising an anti-HTRAl antibody conjugated to a phosphorylcholine containing polymer, the method comprising the step of: conjugating an anti-HTRAl antibody to a phosphorylcholine containing polymer, wherein the anti-HTRAl antibody comprises a non-native cysteine residue outside a variable region of the antibody, wherein the phosphorylcholine containing polymer comprises a sulfhydryl specific reacting group selected from the group consisting of a maleimide, a vinylsulfone, an orthopyridyl-disulfide, and an iodoacetamide, and wherein the sulfhydryl specific reacting group on the phosphorylcholine containing polymer reacts with the cysteine residue on the anti-HTRAl antibody to make the antibody conjugate

[0015] Also provided is a method of producing an anti-HTRAl antibody, comprising: culturing a cell line comprising: a nucleic acid encoding a heavy chain comprising any one of the heavy chain variable region (VH) amino acid sequences shown in Figs. 21, 22A, 23A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1; and a nucleic acid encoding a light chain comprising any one of the light chain variable region (VL) amino acid sequences shown in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, under conditions wherein an antibody comprising the heavy chain and the light chain is produced; and recovering the antibody.

[0016] Provided herein is an antibody that specifically binds to HTRA1, wherein the antibody inhibits a protease activity of HTRA1. Also provided is an antibody thatspecifically binds to HTRA1 , wherein the antibody binds to HTRA1 with a binding affinity (KD) of 1.0 x IO’10M or less.

[0017] Provided herein is an antibody that specifically binds to HTRA1, wherein the antibody does not bind a loop A peptide of HTRA1. Also provided is an antibody that specifically binds to HTRA1, wherein the antibody does not bind a loop A peptide of HTRA1 and wherein the antibody inhibits a protease activity of HTRA1.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG. 1 is a bar graph showing antibody binding to an ELISA plate coated with Loop A peptide, according to some non-limiting embodiments of the present disclosure.

[0019] FIG. 2 is a collection of Bar graphs showing the inhibitory activity profiling of various antibodies in a FRET -based (H2-Opt) blocking assay, according to some nonlimiting embodiments of the present disclosure.

[0020] FIG. 3 is a collection of graphs showing HTRA1 activity dose response curves as measured in H2-Opt assays, according to some non-limiting embodiments of the present disclosure. The graphs plot HTRA1 activity (RFU / s) as function of the antibody concentration (M).

[0021] FIG. 4 is a collection of images showing SDS-PAGE monitoring of the amount of intact casein in the presence of HTRA1 and HTRA1 antibody mixtures, according to some non-limiting embodiments of the present disclosure.

[0022] FIGS. 5A-5C are graphs showing size exclusion chromatography in line with SEC-MALS to assess antibody and HTRA1 complex molar mass, according to some nonlimiting embodiments of the present disclosure. Chromatograms plot UV traces indicating molar mass (g / mol) as function of time (minutes).

[0023] FIG. 6A is a collection of images showing SDS-PAGEs in oxidized and reduced conditions, according to some non-limiting embodiments of the present disclosure.

[0024] FIG. 6B is a collection of graphs showing HTRA1 activity dose response curves as measured in H2-Opt assays, according to some non-limiting embodiments of the present disclosure. The graphs plot HTRA1 activity (RFU / s) as function of the antibody concentration (M).

[0025] FIG. 7A is an image showing preparation of a vector backbone from pLL45 (Hu_aHTRAl_36_l-pCDisplay4) phagemid by Sa l and As / SI digestion.

[0026] FIG. 7B is an image showing PCR amplification of VH and VL library, CL- pelB fragment.

[0027] FIG. 7C is a schematic diagram showing phage display Fab library assembly, according to some non-limiting embodiments of the present disclosure.

[0028] FIG. 8 is a graph of polyclonal phage ELISA showing the enrichment of phage pools in library Genl panning, according to some non-limiting embodiments of the present disclosure. The phage pools of library Genl, 5 rounds of panning outputs and parental pLL44 were tested for binding to HTRA1 (white bars), HTRA3 (gray bars) and uncoated surface (black bars).

[0029] FIGS. 9A and 9B are collection of graphs showing BIAcore analysis of HTRA1 binding to aHTRAl_36-IgG captured on anti-HuIgG chip (FIG. 9A) and anti-Fab- VHH Chip (FIG. 9B), according to some non-limiting embodiments of the present disclosure. Binding data in the sensorgrams are presented in gray and kinetic fitting curves are in black.

[0030] FIGS. 9C and 9D are collection of graphs showing BIAcore analysis of HTRA1 binding to aHTRAl_36-Fab captured on anti-HuIgG chip (FIG. 9C) and anti-Fab- VHH Chip (FIG. 9D), according to some non-limiting embodiments of the present disclosure. Binding data in the sensorgrams are presented in gray and kinetic fitting curves are in black.

[0031] FIG. 9E is a table showing the kinetic parameters of aHTRAl_36 in Fab and IgG format on different capture surfaces, according to some non-limiting embodiments of the present disclosure.

[0032] FIGS. 10A and 10B are a collection of graphs showing H2-Opt based HTRA1 inhibition with IgG variants from library Genl, according to some non-limiting embodiments of the present disclosure.

[0033] FIG. 10C is a table showing the antibody half maximal inhibitory concentration (ICso) of HTRA1 in FIGS. 10A and 10B.

[0034] FIG. 11A is a graph showing polyclonal phage ELISA of library Gen2 panning, according to some non-limiting embodiments of the present disclosure. The phage pools of library Gen2, 4 rounds of panning outputs and GEN1-P1D6 were tested for binding to HTRA1 (white bars), HTRA3 (gray bars) and uncoated surface (black bars).

[0035] FIG. 1 IB is a graph showing polyclonal phage ELISA of optimized R3 phage outputs in comparison to Lib Gen2, phage outputs from R1-R3 and parental pLL44, according to some non-limiting embodiments of the present disclosure.

[0036] FIGS. 12A-12C are a collection of BIAcore sensorgrams showing the kinetics of HTRA1 binding to parental pLL44 (FIG. 12A), GEN1-P1D6 (FIG. 12B) and Gen2- P1D1 (FIG. 12C) from PPE preps, according to some non-limiting embodiments of the present disclosure. The equilibrium dissociation constant (KD) is shown. Gen2-P1D1 and GEN1- P1D6 are clones from phage display screening and have highly improved affinity in comparison to parental pLL44.

[0037] FIGS. 13A-13B are a collection of graphs showing BIAcore analysis of HTRA1 monomeric mutant and HTRA1 trimeric wild type binding to aHTRAl_36 and selected IgG variants from library Genl (HC5 / LC4, HC6 / LC4, HC7 / LC4) and Gen2 (HC13 / LC11, HC13 / LC8), according to some non-limiting embodiments of the present disclosure. Binding data in the sensorgrams are presented in gray and kinetic fitting curves are in black.

[0038] FIG. 14A is a graph showing sequence alignment of the catalytic domains of HTRA1 and its human homologs. The conserved residues were highlighted in grey. FIGS. 14B and 14C are a collection of graphs showing BIAcore kinetic analysis of molecules HC17 / LC21 and HC41 / LC21 binding to human HTRA1 homologues HTRA2, HTRA3 and HTRA4, according to some non-limiting embodiments of the present disclosure. Binding data in the sensorgrams are presented in gray and kinetic fitting curves are in black.

[0039] FIGS. 15A and 15B are a graph and a table showing polyreactivity profile of molecules HC17 / LC21 and HC41 / LC21 on selected general antigens (cardiolipin, KLH, LPS, ssDNA, dsDNA, and insulin), according to some non-limiting embodiments of the present disclosure. OG1950 and A_S574 serve as negative and positive controls. ELISA scores are shown in FIG. 15B.

[0040] FIGS. 15C and 15D are a graph and a table showing polyreactivity profile of molecules HC17 / LC21 and HC41 / LC21 on baculovirus particle (BVP), according to some non-limiting embodiments of the present disclosure. OG1950 and A_S574 serve as negative and positive controls. BVP scores are shown in FIG. 15D.

[0041] FIGS. 16A-16C are a collection of graphs and tables showing the potency of selected molecules before and after conjugation to the biopolymer OG1802. HC17 / LC21 (FIG. 16A), HC41 / LC21 (FIG. 16B) and HC40 / LC21 (FIG. 16C) were tested by H2-Opt assay, according to some non-limiting embodiments of the present disclosure. The half maximal inhibitory concentration (IC50) is shown in the tables.

[0042] FIGS. 17A and 17B are a collection of plots showing SEC-MALS chromatograms, according to some non-limiting embodiments of the present disclosure. The black curves display the UV profile of antibody elution. The gray curves show the elution profile of antibody and HTRA1 (S328 A) complex. The dash lines indicate the calculated molar mass. FIG. 17A represents HC17 / LC21 and complex. FIG. 17B represents HC17 / LC21 conjugated with OG1802 only and in complex with HTRA1 (S328A).

[0043] FIGS. 18A-18C are graphs showing mass distribution of antibodies with mass photometry, HC40 / LC21 (FIG. 18A), HC41 / LC21 (FIG. 18B) and HTRAl-S328A (FIG. 18C), according to some non-limiting embodiments of the present disclosure. The Gaussian fitting is presented in the solid line. The mean peak value, width of the fitted peak and counts are shown in the graphs.

[0044] FIGS. 18D and 18E are graphs showing mass distribution of antibody and HTRA1 mixtures with mass photometry, according to some non-limiting embodiments of the present disclosure. Both HC40 / LC21 (FIG. 18D) and HC41 / LC21 (FIG. 18E) binding complexes present two major peaks corresponding to free antibody and free HTRA1 and antibody HTRA1 complexes. The mean peak value, width of the fitted peak and counts are shown in the graphs.

[0045] FIG. 19 shows amino acid sequences for human HTRA1, HTRA2, HTRA3 and HTRA4 proteins.

[0046] FIGS. 20A and 20B show sequence alignments for heavy chain and light chain variable region amino acid sequences, respectively, of non-limiting embodiments of the anti-HTRAl antibodies. CDRs are indicated within boxes.

[0047] FIG. 21 shows non-limiting examples of heavy chain and light chain variable region sequences of the present disclosure.

[0048] FIGs. 22A and 22B show non-limiting examples of heavy chain and light chain variable region sequences of the present disclosure. CDRs are underlined.

[0049] FIGs. 23 A and 23B show non-limiting examples of heavy chain and light chain variable region sequences of the present disclosure. CDRs are underlined.

[0050] FIGs. 24A and 24B show non-limiting examples of heavy chain and light chain variable region sequences of the present disclosure. CDRs are underlined.

[0051] FIGs. 25A and 25B show non-limiting examples of heavy chain and light chain sequences of the present disclosure. CDRs are underlined and constant regions are italicized.

[0052] FIG. 26A is a graph showing molecules HC17 / LC21, HC37 / LC21, HC41 / LC21 and aHTRAl_36 binding to the Loop A peptide, according to some non-limiting embodiments of the present disclosure. aHTRAl_37 serves as a positive control.

[0053] FIG. 26B is a graph showing molecules HC17 / LC21, HC37 / LC21, HC41 / LC21, aHTRAl_36 and aHTRAl_37 binding to HTRA1, according to some nonlimiting embodiments of the present disclosure.

[0054] FIG. 27A shows OG1786.

[0055] FIG. 27B shows OG1801.

[0056] FIG. 27C shows OG1802.

[0057] FIG. 28 A is a graph showing sequence alignment of HTRA1 protease domain (PD) in different species. The differential residues between HTRA1 in human and in other species were highlighted in grey. FIGS. 28B and 28C are a collection of graphs showing BIAcore kinetic analysis of molecules HC41 / LC21 and HC17 / LC21 binding to human, mouse, dog and rat HTRA1 PD domains, according to some non-limiting embodiments of the present disclosure. Binding data in the sensorgrams are presented in gray and kinetic fitting curves are in black.

[0058] FIG. 29 shows amino acid sequences for human, mouse, dog and rat HTRA1 protease domain (PD).DETAILED DESCRIPTION

[0059] Provided herein are antibodies (including antigen binding fragments thereof) that bind to HTRA1, e.g., human HTRA1. Also provided are conjugates of the antibodies that include an anti-HTRAl antibody covalently bonded to a polymer, such as aphosphorylcholine containing polymer. The antibodies and conjugates thereof of the present disclosure find use in treating an ocular disease, e.g., age-related macular degeneration (AMD).

[0060] Genome-wide association studies (GWAS) identified a locus at human chromosome 10q26 linked to risk of AMD where two genes ARMS2 and HTRA1 lie in proximity to each other. These studies suggest a correlation between disease progression and single-nucleotide polymorphisms (SNPs) at the promoter region of HTRA1, which resulted in its increased expression (Yang et al., 2006) (DeWan et al., 2006) (Fritsche et al., 2015).

[0061] It has been hypothesized that cleavage of certain ECM proteins contribute to extracellular debris accumulation that in turn sensitizes cells to inflammatory stimuli (Lin et al., 2018)(Beguier et al., 2020). Without being bound to theory, this mechanism may explain how genetic variations that increase expression of HTRA1 increase the risk of developing the dry form of the disease. HTRA1 has also been shown to induce expression of inflammatory cytokines and VEGF(Lu et al., 2019), and overexpression of HTRA1 in the retina of mouse models recapitulates key physiological markers of AMD (Jones et al., 2011); (Vierkotten, Muether, & Fauser, 2011). These data corroborate the observation that HTRA1 risk alleles show strong and nearly equal association with wet and dry forms of AMD, and therefore indicate that HTRA1 might be successfully targeted in both forms of the disease.Definitions

[0062] “HTRA1” as used herein refers to a HtrA serine protease. HTRA1 can refer to, without limitation, human HTRA1 (Gene ID: 5654), mouse HTRA1 (Gene ID: 56213), rat HTRA1 (Gene ID: 65164), canine HTRA1 (Gene ID: 477852), chicken HTRA1 (Gene ID: 100857572), bovine HTRA1 (Gene ID: 282326). In some embodiments, HTRA1 is human HTRA1 (“HuHTRAl”).

[0063] A “neovascular disorder” is a disorder or disease state characterized by altered, dysregulated or unregulated angiogenesis. Examples of neovascular disorders include neoplastic transformation (e.g. cancer) and ocular neovascular disorders including diabetic retinopathy and age-related macular degeneration.

[0064] An “ocular neovascular” disorder is a disorder characterized by altered, dysregulated or unregulated angiogenesis in the eye of a patient. Such disorders include optic disc neovascularization, iris neovascularization, retinal neovascularization, choroidalneovascul arization, corneal neovascularization, vitreal neovascularization, glaucoma, pannus, pterygium, macular edema, diabetic retinopathy, diabetic macular edema, vascular retinopathy, retinal degeneration, uveitis, inflammatory diseases of the retina, and proliferative vitreoretinopathy .

[0065] As used herein, “potency” with reference to an anti-HTRAl antibody denotes the ability to inhibit or the extent of inhibition of a HTRA1 activity (e.g., HTRA1 proteolytic activity) when the antibody is bound thereto.

[0066] The term antibody includes intact antibodies and binding fragments thereof. A binding fragment refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of binding fragments include Fv, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e g. scFv); and multispecific antibodies formed from antibody fragments. scFv antibodies are described in Houston JS. 1991. Methods in Enzymol. 203:46-96. In addition, antibody fragments comprise single chain polypeptides having the characteristics of a VH domain, namely being able to assemble together with a VL domain, or of a VL domain, namely being able to assemble together with a VH domain to a functional antigen binding site and thereby providing the antigen binding property of full length antibodies.

[0067] Specific binding of an antibody to its target antigen(s) means an affinity of at least 106, 107, 108, 109, or 1010M’1. Specific binding is detectab ly higher in magnitude and distinguishable from non-specific binding occurring to at least one unrelated target. Specific binding can be the result of formation of bonds between particular functional groups or particular spatial fit (e.g., lock and key type) whereas nonspecific binding is usually the result of van der Waals forces. Specific binding does not however necessarily imply that an antibody or fusion protein binds one and only one target.

[0068] A basic antibody structural unit is a tetramer of subunits. Each tetramer includes two identical pairs of polypeptide chains, each pair having one "light" (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. This variable region is initially expressed linked to a cleavable signal peptide. The variable region without the signal peptide is sometimes referred to as a mature variable region. Thus, for example, a light chain mature variable region means a light chain variableregion without the light chain signal peptide. However, reference to a variable region does not mean that a signal sequence is necessarily present; and in fact signal sequences are cleaved once the antibodies or fusion proteins have been expressed and secreted. A pair of heavy and light chain variable regions defines a binding region of an antibody. The carboxy-terminal portion of the light and heavy chains respectively defines light and heavy chain constant regions. The heavy chain constant region is primarily responsible for effector function. In IgG antibodies, the heavy chain constant region is divided into CHI, hinge, CH2, and CH3 regions. The CHI region binds to the light chain constant region by disulfide and noncovalent bonding. The hinge region provides flexibility between the binding and effector regions of an antibody and also provides sites for intermolecular disulfide bonding between the two heavy chain constant regions in a tetramer subunit. The CH2 and CH3 regions are the primary site of effector functions and FcR binding.

[0069] Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, and define the antibody's isotype as IgG, IgM, IgA, IgD and IgE, respectively. Within light and heavy chains, the variable and constant regions are joined by a "J" segment of about 12 or more amino acids, with the heavy chain also including a "D" segment of about 10 or more amino acids. (See generally, Fundamental Immunology (Paul, W., ed., 2nd ed. Raven Press, N.Y., 1989), Ch. 7) (incorporated by reference in its entirety for all purposes).

[0070] The mature variable regions of each light / heavy chain pair form the antibody binding site. Thus, an intact antibody has two binding sites, i.e., is divalent. In natural antibodies, the binding sites are the same. However, bispecific antibodies can be made in which the two binding sites are different (see, e.g., Songsivilai S, Lachmann PC. 1990. Bispecific antibody: a tool for diagnosis and treatment of disease. Clin Exp Immunol. 79:315- 321; Kostelny SA, Cole MS, Tso JY. 1992. Formation of bispecific antibody by the use of leucine zippers. J Immunol. 148: 1547-1553). The variable regions all exhibitthe same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs. The CDRs from the two chains of each pair are aligned by the framework regions, enabling binding to a specific epitope. From N-terminal to C-terminal, both light and heavy chains comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. For convenience, the variable heavy CDRscan be referred to as CDRHI , CDRH2 and CDRH3; the variable light chain CDRs can be referred to as CDRLI, CDRL2 and CDRL3. The assignment of amino acids to each domain is in accordance with the definitions of Kabat EA, et al. 1987 and 1991. Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD) or Chothia C, Lesk AM. 1987. Canonical Structures for the Hypervariable Regions of Immunoglobulins. J Mol Biol 196:901-917; Chothia C, et al. 1989. Conformations of Immunoglobulin Hypervariable Regions. Nature 342:877-883. Kabat also provides a widely used numbering convention (Kabat numbering) in which corresponding residues between different heavy chain variable regions or between different light chain variable regions are assigned the same number. Although Kabat numbering can be used for antibody constant regions, EU numbering is more commonly used, as is the case in this application. Although specific sequences are provided for exemplary antibodies disclosed herein, it will be appreciated that after expression of protein chains one to several amino acids at the amino or carboxy terminus of the light and / or heavy chain, particularly a heavy chain C-terminal lysine residue, may be missing or derivatized in a proportion or all of the molecules.

[0071] The term "epitope" refers to a site on an antigen to which an antibody or extracellular trap segment binds. An epitope on a protein can be formed from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of one or more proteins. Epitopes formed from contiguous amino acids (also known as linear epitopes) are typically retained on exposure to denaturing solvents whereas epitopes formed by tertiary folding (also known as conformational epitopes) are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation. Methods of determining spatial conformation of epitopes include, for example, x-ray crystallography and 2-dimensional nuclear magnetic resonance. See, e.g., Epitope Mapping Protocols, in Methods in Molecular Biology, Vol. 66, Glenn E. Morris, Ed. (1996).

[0072] Antibodies that recognize the same or overlapping epitopes can be identified in a simple immunoassay showing the ability of one antibody to compete with the binding of another antibody to a target antigen. The epitope of an antibody can also be defined by X-ray crystallography of the antibody (or Fab fragment) bound to its antigen to identify contact residues.

[0073] Alternatively, two antibodies have the same epitope if all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.

[0074] Competition between antibodies is determined by an assay in which an antibody under test inhibits specific binding of a reference antibody to a common antigen (see, e.g., Junghans et al., Cancer Res. 50: 1495, 1990). A test antibody competes with a reference antibody if an excess of a test antibody (e.g., at least 2x, 5x, lOx, 20x or lOOx) inhibits binding of the reference antibody by at least 50%. In some embodiments the test antibody inhibits binding of the reference antibody by 75%, 90%, or 99% as measured in a competitive binding assay. Antibodies identified by competition assay (competing antibodies) include antibodies binding to the same epitope as the reference antibody and antibodies binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference antibody for steric hindrance to occur.

[0075] The term "patient" includes human and other mammalian subjects that receive either prophylactic or therapeutic treatment.

[0076] For purposes of classifying amino acids substitutions as conservative or nonconservative, amino acids can be grouped as follows: Group I (hydrophobic side chains): met, ala, val, leu, ile; Group II (neutral hydrophilic side chains): cys, ser, thr, asn, gin; Group III (acidic side chains): asp, glu; Group IV (basic side chains): his, lys, arg; Group V (residues influencing chain orientation): gly, pro; and Group VI (aromatic side chains): trp, tyr, phe. Conservative substitutions can involve substitutions between amino acids in the same class. Non-conservative substitutions can constitute exchanging a member of one of these classes for a member of another.

[0077] Percentage sequence identities are determined with antibody sequences maximally aligned by the Kabat numbering convention for a variable region or EU numbering for a constant region. After alignment, if a subject antibody region (e.g., the entire mature variable region of a heavy or light chain) is being compared with the same region of a reference antibody, the percentage sequence identity between the subject and reference antibody regions is the number of positions occupied by the same amino acid in both the subject and reference antibody region divided by the total number of aligned positions of the two regions, with gapsnot counted, multiplied by 100 to convert to percentage. Sequence identities of other sequences can be determined by aligning sequences using algorithms, such as BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package Release 7.0, Genetics Computer Group, 575 Science Dr., Madison, WI, using default gap parameters, or by inspection, and the best alignment (i.e., resulting in the highest percentage of sequence similarity over a comparison window). Percentage of sequence identity is calculated by comparing two optimally aligned sequences over a window of comparison, determining the number of positions at which the identical residues occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity.

[0078] Compositions or methods "comprising" one or more recited elements may include other elements not specifically recited. For example, a composition that comprises antibody may contain the antibody alone or in combination with other ingredients.

[0079] The term "antibody-dependent cellular cytotoxicity", or ADCC, is a mechanism for inducing cell death that depends upon the interaction of antibody-coated target cells (i.e., cells with bound antibody) with immune cells possessing lytic activity (also referred to as effector cells). Such effector cells include natural killer cells, monocytes / macrophages and neutrophils. ADCC is triggered by interactions between the Fc region of an antibody bound to a cell and Fey receptors, particularly FcyRI and FcyRIII, on immune effector cells such as neutrophils, macrophages and natural killer cells. The target cell is eliminated by phagocytosis or lysis, depending on the type of mediating effector cell. Death of the antibody-coated target cell occurs as a result of effector cell activity.

[0080] The term opsonization also known as "antibody-dependent cellular phagocytosis", or ADCP, refers to the process by which antibody-coated cells are internalized, either in whole or in part, by phagocytic immune cells (e.g., macrophages, neutrophils and dendritic cells) that bind to an immunoglobulin Fc region.

[0081] The term "complement-dependent cytotoxicity" or CDC refers to a mechanism for inducing cell death in which an Fc effector domain(s) of a target-bound antibody activates a series of enzymatic reactions culminating in the formation of holes in the target cell membrane. Typically, antigen-antibody complexes such as those on antibody-coated target cells bind and activate complement component Clq which in turn activates the complement cascade leading to target cell death. Activation of complement may also result in deposition of complement components on the target cell surface that facilitate ADCC by binding complement receptors (e.g., CR3) on leukocytes.

[0082] A humanized antibody is a genetically engineered antibody in which the CDRs from a non-human "donor" antibody are grafted into human "acceptor" antibody sequences (see, e.g., Queen, US 5,530,101 and 5,585,089; Winter, US 5,225,539, Carter, US 6,407,213, Adair, US 5,859,205 6,881,557, Foote, US 6,881,557). The acceptor antibody sequences can be, for example, a mature human antibody sequence, a composite of such sequences, a consensus sequence of human antibody sequences, or a germLine region sequence. Thus, a humanized antibody is an antibody having some or all CDRs entirely or substantially from a donor antibody and variable region framework sequences and constant regions, if present, entirely or substantially from human antibody sequences. Similarly a humanized heavy chain has at least one, two and usually all three CDRs entirely or substantially from a donor antibody heavy chain, and a heavy chain variable region framework sequence and heavy chain constant region, if present, substantially from human heavy chain variable region framework and constant region sequences. Similarly a humanized light chain has at least one, two and usually all three CDRs entirely or substantially from a donor antibody light chain, and a light chain variable region framework sequence and light chain constant region, if present, substantially from human light chain variable region framework and constant region sequences. Other than nanobodies and dAbs, a humanized antibody comprises a humanized heavy chain and a humanized light chain. A CDR in a humanized antibody is substantially from a corresponding CDR in a non-human antibody when at least 85%, 90%, 95% or 100% of corresponding residues (as defined by Kabat) are identical between the respective CDRs. The variable region framework sequences of an antibody chain or the constant region of an antibody chain are substantially from a human variable region framework sequence or human constant region respectively when at least 85, 90, 95 or 100% of corresponding residues defined by Kabat are identical.

[0083] Although humanized antibodies often incorporate all six CDRs (which can be as defined by Kabat) from a mouse antibody, they can also be made with less than all CDRs (e.g., at least 3, 4, or 5 CDRs from a mouse antibody) (e.g., De Pascalis R, Iwahashi M, TamuraM, et al. 2002. Grafting “Abbreviated” Complementary-Determining Regions Containing Specificity-Determining Residues Essential for Ligand Contact to Engineer a Less Immunogenic Humanized Monoclonal Antibody. J Immunol. 169:3076-3084; Vajdos FF, Adams CW, Breece TN, Presta LG, de Vos AM, Sidhu, SS. 2002. Comprehensive functional maps of the antigen-binding site of an anti-ErbB2 antibody obtained with shotgun scanning mutagenesis. J Mol Biol. 320: 415-428; Iwahashi M, Milenic DE, Padlan EA, et al. 1999. CDR substitutions of a humanized monoclonal antibody (CC49): Contributions of individual CDRs to antigen binding and immunogenicity. Mol Immunol. 36: 1079-1091; Tamura M, Milenic DE, Iwahashi M, et al. 2000. Structural correlates of an anticarcinoma antibody: Identification of specificity-determining regions (SDRs) and development of a minimally immunogenic antibody variant by retention of SDRs only. J Immunol. 164: 1432-1441).

[0084] A chimeric antibody is an antibody in which the mature variable regions of light and heavy chains of a non-human antibody (e.g., a mouse) are combined with human light and heavy chain constant regions. Such antibodies substantially or entirely retain the binding specificity of the mouse antibody, and are about two-thirds human sequence.

[0085] A veneered antibody is a type of humanized antibody that retains some and usually all of the CDRs and some of the non-human variable region framework residues of a non-human antibody but replaces other variable region framework residues that may contribute to B- or T-cell epitopes, for example exposed residues (Padlan EA. 1991. A possible procedure for reducing the immunogenicity of antibody variable regions while preserving their ligandbinding properties. Mol Immunol. 28:489-98) with residues from the corresponding positions of a human antibody sequence. The result is an antibody in which the CDRs are entirely or substantially from a non-human antibody and the variable region frameworks of the non- human antibody are made more human-like by the substitutions. A human antibody can be isolated from a human, or otherwise result from expression of human immunoglobulin genes (e.g., in a transgenic mouse, in vitro or by phage display). Methods for producing human antibodies include the trioma method of Ostberg L, Pursch E. 1983. Human x (mouse x human) hybridomas stably producing human antibodies. Hybridoma 2:361-367; Ostberg, U.S. Patent No. 4,634,664; and Engleman et al., US Patent 4,634,666, use of transgenic mice including human immunoglobulin genes (see, e.g., Lonberg et al., W093 / 12227 (1993); US 5,877,397, US 5,874,299, US 5,814,318, US 5,789,650, US 5,770,429, US 5,661,016, US 5,633,425, US5,625,126, US 5,569,825, US 5,545,806, Nature 148, 1547-1553 (1994), Nature Biotechnology 14, 826 (1996), Kucherlapati, WO 91 / 10741 (1991) and phage display methods (see, .e.g. Dower et al., WO 91 / 17271 and McCafferty et al., WO 92 / 01047, US 5,877,218, US 5,871,907, US 5,858,657, US 5,837,242, US 5,733,743 and US 5,565,332.

[0086] For the purpose of this disclosure, “naturally occurring amino acids” found in proteins and polypeptides are L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamine, L-glutamic acid, L-glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and or L-valine. “Non-naturally occurring amino acids” found in proteins are any amino acid other than those recited as naturally occurring amino acids. Non-naturally occurring amino acids include, without limitation, the D isomers of the naturally occurring amino acids, and mixtures of D and L isomers of the naturally occurring amino acids. Other amino acids, such as N-alpha- methyl amino acids (e.g. sarcosine), 4-hydroxyproline, desmosine, isodesmosine, 5-hydroxylysine, epsilon-N-methyllysine, 3-methylhistidine, although found in naturally occurring proteins, are considered to be non-naturally occurring amino acids found in proteins for the purpose of this disclosure as they are generally introduced by means other than ribosomal translation of mRNA.

[0087] “Pharmaceutically acceptable excipient” refers to an excipient that can be included in compositions and that causes no significant adverse toxicological effect on the patient and is approved or approvable by the FDA for therapeutic use, particularly in humans. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose and the like.

[0088] Therapeutic proteins are administered in an effective regime meaning a dosage, route of administration and frequency of administration that delays the onset, reduces the severity, inhibits further deterioration, and / or ameliorates at least one sign or symptom of a disorder. If a patient is already suffering from a disorder, the regime can be referred to as a therapeutically effective regime. If the patient is at elevated risk of the disorder relative to the general population but is not yet experiencing symptoms, the regime can be referred to as a prophylactically effective regime. In some instances, therapeutic or prophylactic efficacy can be observed in an individual patient relative to historical controls or past experience in the same patient. In other instances, therapeutic or prophylactic efficacy can be demonstrated ina preclinical or clinical trial in a population of treated patients relative to a control population of untreated patients.

[0089] The “biological half-life” of a substance is a pharmacokinetic parameter which specifies the time required for one half of the substance to be removed from a tissue or an organism following introduction of the substance.

[0090] “BCVA” denotes Best Corrected Visual Acuity.

[0091] “OCT-A” denotes OCT-Angiography.

[0092] SD-OCT” denotes Spectral Domain Optical Coherence Tomography.

[0093] A “polymer” is a molecule composed of many repeating subunits. The subunits, also sometimes referred to as “monomers” can be the same or different. There are both natural and synthetic polymers. DNA, protein and complex carbohydrates are examples of natural polymers. Poly-styrene and poly-acrylamide are examples of synthetic polymers. A polymer composed of repeating units of a single monomer is called a homopolymer. A polymer composed of two or more monomers is called a copolymer or sometimes a heteropolymer. A copolymer in which certain monomer types are clustered together are sometimes called block copolymers. Polymers can be linear or branched. When the polymer is branched, polymer chains having a common origin are sometimes referred to as a polymer arm(s). As used herein, the term “biopolymer” denotes that a polymer has been linked to the protein of interest. The term can also be described as the “conjugated” form of the protein.

[0094] An “initiator” is a compound capable of serving as a substrate on which one or more polymerizations can take place using monomers or comonomers as described herein. The polymerization can be a conventional free radical polymerization or preferably a controlled / ”living” radical polymerization, such as Atom Transfer Radical Polymerization (ATRP), Reversible Addition-Fragmentation-Termination (RAFT) polymerization or nitroxide mediated polymerization (NMP). The polymerization can be a “pseudo” controlled polymerization, such as degenerative transfer. Initiators suitable for ATRP contain one or more labile bonds which can be homolytically cleaved to form an initiator fragment, I, being a radical capable of initiating a radical polymerization, and a radical scavenger, I’, which reacts with the radical of the growing polymer chain to reversibly terminate the polymerization. The radical scavenger F is typically a halogen, but can also be an organic moiety, such as a nitrile.In some embodiments of the present invention, the initiator contains one or more 2- bromoisobutyrate groups as sites for polymerization via ATRP.

[0095] A “chemical linker” refers to a chemical moiety that links two groups together, such as a half-life extending moiety and a protein. The linker can be cleavable or non-cleavable. Cleavable linkers can be hydrolysable, enzymatically cleavable, pH sensitive, photolabile, or disulfide linkers, among others. Other linkers include homobifunctional and heterobifunctional linkers. A “linking group” is a functional group capable of forming a covalent linkage consisting of one or more bonds to a bioactive agent. Non-limiting examples include those illustrated in Table 1 of WO2013059137 (incorporated by reference).

[0096] The term "reactive group" refers to a group that is capable of reacting with another chemical group to form a covalent bond, i.e. is covalently reactive under suitable reaction conditions, and generally represents a point of attachment for another substance. The reactive group is a moiety, such as maleimide or succinimidyl ester, is capable of chemically reacting with a functional group on a different moiety to form a covalent linkage. Reactive groups generally include nucleophiles, electrophiles and photoactivatable groups.

[0097] As used herein, “phosphorylcholine,” also denoted as “PC,” refers to the following:where * denotes the point of attachment. The phosphoryl choline is a zwitterionic group and includes salts (such as inner salts), and protonated and deprotonated forms thereof.

[0098] As used herein, “phosphorylcholine-based polymer” is a polymer that contains phosphorylcholine. “Zwitterion containing polymer” refers to a polymer that contains a zwitterion.

[0099] Poly(acryloyloxyethyl phosphorylcholine) containing polymer refers to a polymer containing 2-(acryloyloxy)ethyl-2-(trimethylammonium)ethyl phosphate as monomer.

[0100] Poly(methacryloyloxyethyl phosphoryl choline) containing polymer refers to a polymer containing 2-(methacryloyloxy)ethyl-2-(trimethylammonium)ethyl phosphate as monomer.

[0101] As used herein, “molecular weight” in the context of the polymer can be expressed as either a number average molecular weight, or a weight average molecular weight or a peak molecular weight. Unless otherwise indicated, all references to molecular weight herein refer to the peak molecular weight. These molecular weight determinations, number average (Mn), weight average (Mw) and peak (Mp), can be measured using size exclusion chromatography or other liquid chromatography techniques. Other methods for measuring molecular weight values can also be used, such as the use of end-group analysis or the measurement of colligative properties (e g., freezing-point depression, boiling-point elevation, or osmotic pressure) to determine number average molecular weight, or the use of light scattering techniques, ultracentrifugation or viscometry to determine weight average molecular weight. In a preferred embodiment of the present invention, the molecular weight is measured by SEC-MALS (size exclusion chromatography - multi angle light scattering). The polymeric reagents of the present disclosure are typically polydisperse (i.e., number average molecular weight and weight average molecular weight of the polymers are not equal). The Poly Dispersity Index (PDI) provides a measure for the dispersity of polymers in a mixture. PDI is given by the formula Mw / Mn. In this regard a homogenous protein will have a PDI of 1.0 (Mn is the same as Mw). Typically, the PDI for polymers will be above 1.0. Polymers in accordance with the present invention preferably have relatively low poly dispersity (PDI) values of, for example, less than about 1.5, as judged, for example, by SEC-MALS. In other embodiments, the polydispersities (PDI) are more preferably in the range of about 1.4 to about 1.2, still more preferably less than about 1.15, and still more preferably less than about 1.10, yet still more preferably less than about 1.05, and most preferably less than about 1.03.

[0102] As used herein, “protected,” “protected form,” “protecting group” and “protective group” refer to the presence of a group (i.e., the protecting group) that prevents or blocks reaction of a particular chemically reactive functional group in a molecule under certain reaction conditions. Protecting groups vary depending upon the type of chemically reactive group being protected as well as the reaction conditions to be employed and the presence of additional reactive or protecting groups in the molecule, if any. Suitable protecting groups include those such as found in the treatise by Greene et al., “Protective Groups In Organic Synthesis,” 3rd Edition, John Wiley and Sons, Inc., New York, 1999.

[0103] As used herein, “alkyl” refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated. For example, C1-C6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Other alkyl groups include, but are not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl can include any number of carbons, such as 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6 and 5-6 carbons.

[0104] The term “lower” referred to above and hereinafter in connection with organic radicals or compounds respectively defines a compound or radical which can be branched or unbranched with up to and including 7, preferably up to and including 4 and (as unbranched) one or two carbon atoms.

[0105] As used herein, “alkylene” refers to an alkyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene. For instance, a straight chain alkylene can be the bivalent radical of -(CH2)n, where n is 1, 2, 3, 4, 5 or 6. Alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene.

[0106] Substituents for the alkyl, alkenyl, alkylene, heteroalkyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl radicals can be one or more of a variety of groups selected from, but not limited to: -OR’, =0, =NR’,=N-0R’, -NR’R”, -SR’, -halogen, -SiR’R”R’”, -OC(O)R’, -C(O)R’, -CO2R’, -CONR’ R”, -OC(O)NR’R”, -NR”C(O)R’, -NR’-C(0)NR”R’”, -NR”C(O)2R’, -NR-C(NR’R”R’”>N R””, -NR-C(NR’R”)=NR’”, -S(O)R’, -S(O)2R’, -S(O)2NR’R”, -NRSO2R’, -CN and -NO2 in a number ranging from 1 to (2m’+l), where m’ is the total number of carbon atoms in such radical. Each of R’, R”, R’” and R”” independently refers to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When R’ and R” are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, -NR’R” is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl.

[0107] As used herein, “alkoxy” refers to alkyl group attached to an oxygen atom and forms radical -O-R, wherein R is alkyl. Alkoxy groups include, for example, methoxy,ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. The alkoxy groups can be further substituted with a variety of substituents described herein. For example, the alkoxy groups can be substituted with halogens to form a “halo-alkoxy” group.

[0108] As used herein, “carboxyalkyl” means an alkyl group (as defined herein) substituted with a carboxy group. The term “carboxycycloalkyl” means an cycloalkyl group (as defined herein) substituted with a carboxy group. The term alkoxyalkyl means an alkyl group (as defined herein) substituted with an alkoxy group. The term “carboxy” employed herein refers to carboxylic acids and their esters.

[0109] As used herein, “haloalkyl” refers to alkyl as defined above where some or all of the hydrogen atoms are substituted with halogen atoms. Halogen (halo) preferably represents chloro or fluoro, but may also be bromo or iodo. For example, haloalkyl includes trifluoromethyl, fluoromethyl, 1,2,3,4,5-pentafluoro-phenyl, etc. The term “perfluoro” defines a compound or radical which has all available hydrogens that are replaced with fluorine. For example, perfluorophenyl refers to 1,2,3,4,5-pentafluorophenyl, perfluoromethyl refers to 1,1,1 -trifluoromethyl, and perfluoromethoxy refers to 1,1,1 -trifluoromethoxy. Haloalkyl can also be referred to as halo- substitute alkyl, such as fluoro-substituted alkyl.

[0110] As used herein, “cycloalkyl” refers to a saturated mono- or multi- cyclic aliphatic ring system that contains from about 3 to 12, from 3 to 10, from 3 to 7, or from 3 to 6 carbon atoms. When cycloalkyl group is composed of two or more rings, the rings may be joined together with a fused ring or a spiro ring structure. When cycloalkyl group is composed of three or more rings, the rings may also join together forming a bridged ring structure. Monocyclic rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic and polycyclic rings include, for example, bicyclo[l. l.l]pentane, bicyclco[2.1.1]heptane, norbornane, decahydronaphthalene and adamantane. For example, C3-8 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and norbornane.[OHl] As used herein, “endocyclic” refers to an atom or group of atoms which comprise part of a cyclic ring structure.

[0112] As used herein, “exocyclic” refers to an atom or group of atoms which are attached but do not define the cyclic ring structure.

[0113] As used herein, “cyclic alkyl ether” refers to a 4 or 5 member cyclic alkyl group having 3 or 4 endocyclic carbon atoms and 1 endocyclic oxygen or sulfur atom (e.g., oxetane, thietane, tetrahydrofuran, tetrahydrothiophene); or a 6 to 7 member cyclic alkyl group having 1 or 2 endocyclic oxygen or sulfur atoms (e.g., tetrahydropyran, 1,3-di oxane,1.4-dioxane, tetrahydrothiopyran, 1,3-dithiane, 1,4-dithiane, 1,4-oxathiane).

[0114] As used herein, “alkenyl” refers to either a straight chain or branched hydrocarbon of 2 to 6 carbon atoms, having at least one double bond. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3 -pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3 -hexadienyl, 1,4-hexadienyl, 1,5 -hexadienyl,2.4-hexadienyl, or 1,3, 5 -hexatrienyl. Alkenyl groups can also have from 2 to 3, 2 to 4, 2 to 5, 3 to 4, 3 to 5, 3 to 6, 4 to 5, 4 to 6 and 5 to 6 carbons.

[0115] As used herein, “alkenylene” refers to an alkenyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moi eties linked to the alkenylene can be linked to the same atom or different atoms of the alkenylene. Alkenylene groups include, but are not limited to, ethenylene, propenylene, isopropenylene, butenylene, isobutenylene, sec-butenylene, pentenylene and hexenylene.

[0116] As used herein, “alkynyl” refers to either a straight chain or branched hydrocarbon of 2 to 6 carbon atoms, having at least one triple bond. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec-butynyl, butadiynyl, 1 -pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl,1.4-pentadiynyl, 1 -hexynyl, 2-hexynyl, 3 -hexynyl, 1,3 -hexadiynyl, 1,4-hexadiynyl,1.5-hexadiynyl, 2,4-hexadiynyl, or 1,3, 5 -hexatriynyl. Alkynyl groups can also have from 2 to 3, 2 to 4, 2 to 5, 3 to 4, 3 to 5, 3 to 6, 4 to 5, 4 to 6 and 5 to 6 carbons.

[0117] As used herein, “alkynylene” refers to an alkynyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moi eties linked to the alkynylene can be linked to the same atom or different atoms of the alkynylene. Alkynylene groups include, but are not limited to, ethynylene, propynylene, butynylene, sec-butynylene, pentynylene and hexynylene.

[0118] As used herein, “cycloalkylene” refers to a cycloalkyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moi etieslinked to the cycloalkylene can be linked to the same atom or different atoms of the cycloalkylene. Cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cyclooctylene.

[0119] As used herein, “heterocycloalkyl” refers to a ring system having from 3 ring members to about 20 ring members and from 1 to about 5 heteroatoms such as N, O and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. For example, heterocycle includes, but is not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, morpholino, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, piperidinyl, indolinyl, quinuclidinyl and l,4-dioxa-8-aza-spiro[4.5]dec-8-yl.

[0120] As used herein, “heterocycloalkylene” refers to a heterocyclalkyl group, as defined above, linking at least two other groups. The two moieties linked to the heterocycloalkylene can be linked to the same atom or different atoms of the heterocycloalkylene.

[0121] As used herein, “aryl” refers to a monocyclic or multicyclic (e.g., fused bicyclic, tricyclic or greater) aromatic ring assembly containing 6 to 16 carbon atoms. For example, aryl may be phenyl, benzyl or naphthyl, preferably phenyl. Aryl groups can be mono-, di- or tri -substituted by one, two or three radicals selected from alkyl, alkoxy, aryl, hydroxy, halogen, cyano, amino, amino-alkyl, trifluoromethyl, alkylenedioxy and oxy-C2-C3-alkylene; all of which are optionally further substituted, for instance as hereinbefore defined; or 1- or 2-naphthyl; or 1- or 2-phenanthrenyl. Alkylenedioxy is a divalent substitute attached to two adjacent carbon atoms of phenyl, e.g. methylenedioxy or ethylenedioxy. Oxy-C2-C3 -alkylene is also a divalent substituent attached to two adjacent carbon atoms of phenyl, e.g. oxyethylene or oxypropylene. An example for oxy- C2-C3-alkylene-phenyl is 2,3-dihydrobenzofuran-5-yl.

[0122] Preferred as aryl is naphthyl, phenyl or phenyl mono- or disubstituted by alkoxy, phenyl, halogen, alkyl or trifluoromethyl, especially phenyl or phenyl-mono- or disubstituted by alkoxy, halogen or trifluoromethyl, and in particular phenyl.

[0123] Examples of substituted phenyl groups as R are, e.g. 4-chlorophen-l-yl, 3,4-dichlorophen-l-yl, 4-methoxyphen-l-yl, 4-methylphen-l-yl, 4-aminomethylphen-l-yl, 4-methoxy ethylaminomethylphen- 1 -yl, 4-hydroxy ethylaminomethylphen- 1 -yl,4-hydroxyethyl-(methyl)-aminomethylphen-l-yl, 3-aminomethylphen-l-yl,4-N-acetylaminomethylphen-l-yl, 4-aminophen-l-yl, 3 -aminophen- 1-yl, 2-aminophen-l-yl, 4-phenyl-phen- 1 -yl, 4-(imidazol- 1 -yl)-phenyl, 4-(imidazol- 1 -ylmethyl)-phen- 1 -yl,4-(morpholin- 1 -yl)-phen- 1 -yl, 4-(morpholin- 1 -ylmethyl)-phen- 1 -yl,4-(2-methoxyethylaminomethyl)-phen- 1 -yl and 4-(pyrrolidin- 1 -ylmethyl)-phen- 1 -yl, 4-(thiophenyl)-phen-l-yl, 4-(3-thiophenyl)-phen-l-yl, 4-(4-methylpiperazin-l-yl)-phen-l-yl, and 4-(piperidinyl)-phenyl and 4-(pyridinyl)-phenyl optionally substituted in the heterocyclic ring.

[0124] As used herein, “arylene” refers to an aryl group, as defined above, linking at least two other groups. The two moieties linked to the arylene are linked to different atoms of the arylene. Arylene groups include, but are not limited to, phenylene.

[0125] As used herein, “arylene-oxy” refers to an arylene group, as defined above, where one of the moieties linked to the arylene is linked through an oxygen atom. Arylene-oxy groups include, but are not limited to, phenylene-oxy.

[0126] Similarly, substituents for the aryl and heteroaryl groups are varied and are selected from: -halogen, -OR’, -OC(O)R’, -NR’R”, -SR’, -R’, -CN, -NO2, -CO2R’, -CONR’R”, -C(O )R’, -OC(O)NR’R”, -NR”C(O)R’, -NR”C(O)2R’, -NR’-C(O)NR”R’”, -NH-C(NH2)=NH, -N R’C(NH2)=NH, -NH-C(NH2)=NR’, -S(O)R’, -S(O)2R’, -S(O)2NR’R”, -N3, -CH(Ph)2, perfluoro(Cl-C4)alkoxy, and perfluoro(Cl-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R’, R” and R’” are independently selected from hydrogen, (Cl-C8)alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (un substituted aryl)-(Cl-C4)alkyl, and (unsubstituted aryl)oxy-(Cl-C4)alkyl.

[0127] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH2)q-U-, wherein T and U are independently -NH-, -O-, -CH2- or a single bond, and q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR’- or a single bond, and r is an integer of from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms ofthe aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH2)s-X-(CH2)t-, where s and t are independently integers of from 0 to 3, and X is -O-, -NR’-, -S-, -S(O)-, -S(O)2-, or -S(0)2NR’-. The substituent R’ in -NR’- and -S(0)2NR’- is selected from hydrogen or unsubstituted (Cl-C6)alkyl.

[0128] As used herein, “heteroaryl” refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 4 of the ring atoms are a heteroatom each N, O or S. For example, heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, furanyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any other radicals substituted, especially mono- or di-substituted, by e.g. alkyl, nitro or halogen. Pyridyl represents 2-, 3- or 4-pyridyl, advantageously 2- or3-pyridyl. Thienyl represents 2- or 3-thienyl. Quinolinyl represents preferably 2-, 3- or4-quinolinyl. Isoquinolinyl represents preferably 1-, 3- or 4-isoquinolinyl. Benzopyranyl, benzothiopyranyl represents preferably 3 -benzopyranyl or 3 -benzothiopyranyl, respectively. Thiazolyl represents preferably 2- or 4-thiazolyl, and most preferred, 4-thiazolyl. Triazolyl is preferably 1-, 2- or 5-(l,2,4-triazolyl). Tetrazolyl is preferably 5-tetrazolyl.

[0129] Preferably, heteroaryl is pyridyl, indolyl, quinolinyl, pyrrolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, furanyl, benzothiazolyl, benzofuranyl, isoquinolinyl, benzothienyl, oxazolyl, indazolyl, or any of the radicals substituted, especially mono- or di-substituted.

[0130] The term “heteroalkyl” refers to an alkyl group having from 1 to 3 heteroatoms such as N, O and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. For example, heteroalkyl can include ethers, thioethers, alkyl-amines and alkyl -thiols.

[0131] The term “heteroalkylene” refers to a heteroalkyl group, as defined above, linking at least two other groups. The two moieties linked to the heteroalkylene can be linked to the same atom or different atoms of the heteroalkylene.

[0132] As used herein, “electrophile” refers to an ion or atom or collection of atoms, which may be ionic, having an electrophilic center, i.e., a center that is electron seeking, capable of reacting with a nucleophile. An electrophile (or electrophilic reagent) is a reagentthat forms a bond to its reaction partner (the nucleophile) by accepting both bonding electrons from that reaction partner.

[0133] As used herein, “nucleophile” refers to an ion or atom or collection of atoms, which may be ionic, having a nucleophilic center, i.e., a center that is seeking an electrophilic center or capable of reacting with an electrophile. A nucleophile (or nucleophilic reagent) is a reagent that forms a bond to its reaction partner (the electrophile) by donating both bonding electrons. A “nucleophilic group” refers to a nucleophile after it has reacted with a reactive group. Non limiting examples include amino, hydroxyl, alkoxy, haloalkoxy and the like.

[0134] As used herein, “maleimido” refers to a pyrrole-2,5-dione-l-yl group having the structure:which upon reaction with a sulfhydryl (e.g., a thio alkyl) forms an -S-maleimido group having the structuree point of attachment for the maleimido group and “^ indicates the point of attachment of the sulfur atom the thiol to the remainder of the original sulfhydryl bearing group.

[0135] As used herein, “linear” in reference to the geometry, architecture or overall structure of a polymer, refers to polymer having a single polymer arm.

[0136] As used herein, “branched,” in reference to the geometry, architecture or overall structure of a polymer, refers to a polymer having 2 or more polymer “arms” extending from a core structure contained within an initiator. The initiator may be employed in an atom transfer radical polymerization (ATRP) reaction. A branched polymer may possess 2 polymer chains (arms), 3 polymer arms, 4 polymer arms, 5 polymer arms, 6 polymer arms, 7 polymer arms, 8 polymer arms, 9 polymer arms or more. Each polymer arm extends from a polymer initiation site. Each polymer initiation site is capable of being a site for the growth of a polymerchain by the addition of monomers. For example and not by way of limitation, using ATRP, the site of polymer initiation on an initiator is typically an organic halide undergoing a reversible redox process catalyzed by a transition metal compound such as cuprous halide. Preferably, the halide is a bromine.

[0137] As used herein, “OG1786” is a 9-arm initiator used for polymer synthesis with the structure shown in FIG. 27A, which depicts that salt form of OG1786 with trifluor oracetic acid. OG1786 may be used in accordance with the present invention as other salts or as the free base.

[0138] As used herein, “OG1801” is an approximately (+ / - 15%) 750 kDa polymer (either by Mn or Mp) made using OG1786 as an initiator for ATRP synthesis using the monomer HEMA-PC. The structure of OG1801 is shown in FIG. 27B.

[0139] As used herein, “OG1802” is OG1801 with a maleimide functionality added, and it has the structure shown in FIG. 27C, wherein each of nl, n2, n3, n4, n5, n6, n7, n8 and n9 is an integer (positive) (from 0 up to about 3000) such that the total molecular weight of the polymer is (Mw) 750,000 ± 15% Daltons. When the term OG1802 is used to modify a protein term (such as an antibody), it designates that the protein is the conjugate protein.

[0140] Multi-angle light scattering (MALS) is a technique of analyzing macromolecules where the laser light impinges on the molecule, the oscillating electric field of the light induces an oscillating dipole within it. This oscillating dipole will re-radiate light and can be measured using a MALS detector such as Wyatt miniDawn TREOS. The intensity of the radiated light depends on the magnitude of the dipole induced in the macromolecule which in turn is proportional to the polarizability of the macromolecule, the larger the induced dipole, and hence, the greater the intensity of the scattered light. Therefore, in order to analyze the scattering from a solution of such macromolecules, one should know their polarizability relative to the surrounding medium (e.g., the solvent). This may be determined from a measurement of the change, A / / , of the solution's refractive index n with the molecular concentration change, Ac, by measuring the dn / dc (= n / c) value using a Wyatt Optilab T- rEX differential refractometer. Two molar weight parameters that MALS determination employ are number average molecular weight (Mn) and weight average molecular weight (Mw) where the polydispersity index (PDI) equals Mw divided by Mn. SEC also allowsanother average molecular weight determination of the peak molecular weight Mp which is defined as the molecular weight of the highest peak at the SEC.

[0141] The PDI is used as a measure of the broadness of a molecular weight distribution of a polymer and bioconjugate which is derived from conjugation of a discrete protein (e.g. aHTRAl_36, HC41 / LC21) to a polydisperse biopolymer (e.g., OG1802). For a protein sample, its poly dispersity is close to 1.0 due to the fact that it is a product of translation where every protein molecule in a solution is expected to have almost the same length and molar mass. In contrast, due to the polydisperse nature of the biopolymer where the various length of polymer chains are synthesized during the polymerization process, it is very important to determine the PDI of the sample as one of its quality attribute for narrow distribution of molecular weight.

[0142] Size exclusion chromatography (SEC) is a chromatography technique in which molecules in solution are separated by their size. Typically an aqueous solution is applied to transport the sample through the column which is packed with resins of various pore sizes. The resin is expected to be inert to the analyte when passing through the column and the analytes separate from each other based on their unique size and the pore size characteristics of the selected column.

[0143] Coupling the SEC with MALS or SEC / MALS provides accurate distribution of molar mass and size (root mean square radius) as opposed to relying on a set of SEC calibration standards. This type of arrangement has many advantages over traditional column calibration methods. Since the light scattering and concentration are measured for each eluting fraction, the molar mass and size can be determined independently of the elution position. This is particularly relevant for species with non-globular shaped macromolecules such as the biopolymers (e.g., OG1802) or bioconjugates (e.g., a conjugate of OG1802 with an anti-HTRAl antibody); such species typically do not elute in a manner that might be described by a set of column calibration standards.

[0144] In some embodiments, a SEC / MALS analysis includes a Waters HPLC system with Alliance 2695 solvent delivery module and Waters 2996 Photodiole Array Detector equipped with a Shodex SEC -HPLC column (7.8x300mm). This is connected online with a Wyatt miniDawn TREOS and Wyatt Optilab T-rEX differential refractometer. The Empower software from Waters can be used to control the Waters HPLC system and theASTRA V 6.1 .7.16 software from Wyatt can be used to acquire the MALS data from the Wyatt miniDawn TREOS, dn / dc data from the T-rEX detector and the mass recovery data using the A280 absorbance signal from the Waters 2996 Photodiole Array detector. SEC can be carried out at ImL / min in IxPBS pH 7.4, upon sample injection, the MALS and RI (or UV) signals can be analyzed by the ASTRA software for determination of absolute molar mass (Mp, Mw, Mn) and polydisperse index (PDI). In addition, the calculation also involves the input dn / dc values for polymer and protein as 0.142 and 0.183, respectively. In some embodiments, for bioconjugates dn / dc value, the dn / dc is calculated based on the weighted MW of the polymer and the protein to be about 0.148 using the formula below:Conjugate dn / dc = 0.142 x [ MW polymer / (MWpolymer+MWprotein)]+ 0.183 x [MW / rate / / / / (MWpolymer+MWprotein)] where MW polymer for OG1802 is 800 kDa and the MW protein for HC41 / LC21 is 146 kDa.

[0145] As used herein, “aHTRAl” and “anti-HTRAl antibody” are used interchangeably herein to refer to an antibody that binds to HTRA1, as provided herein.

[0146] The phrase “a” or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.

[0147] ‘About” means variation one might see in measurements taken among different instruments, samples, and sample preparations.ANTIBODIES, AND CONJUGATES THEREOF

[0148] Antibodies that bind HTRA1 and conjugates thereof are provided. Any reference to an antibody or anti-HTRAl antibody herein can include the antibody of an antibody conjugate or bioconjugate, as provided herein. In some embodiments, an anti- HTRAl antibody (or conjugate thereof) includes a heavy chain (and / or heavy chain variable region (VH)) and a light chain (and / or light chain variable region (VL)), wherein the heavy chain (or VH) has: a heavy chain complementarity determining region 1 (CDRHI) having an amino acid sequence of a CDRHI in any one of the heavy chain variable region (VH) sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, or with a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues thereof; a CDRH2 having an amino acidsequence of a CDRH2 in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, or with a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues thereof; and a CDRH3 having an amino acid sequence of a CDRH3 in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, or a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues thereof; and the light chain (or VL) has: a light chain complementarity determining region 1 (CDRLI) having an amino acid sequence of a CDRi.l in any one of the light chain variable region (VL) sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, or a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues thereof; a CDRL2 having an amino acid sequence of a CDRL2 in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, or a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues thereof; and a CDRL3 having an amino acid sequence of a CDRL3 in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, or a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues thereof. In some embodiments, the 3 VH CDR sequences are paired with the 3 VL CDR sequences according to any one of the paired arrangements of VH and VL sequences provided in FIG. 21 and Tables 0.4, 0.5, 0.7, 0.10, 0.11, 0.12, 1.2, 6.3, and 7.1. In some embodiments, the antibody (or conjugate thereof) includes a heavy chain variable region having 3 CDR sequences that each have an amino acid sequence based on a consensus sequence of the corresponding CDR from a sequence alignment of the VH sequences in one or more of Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, where each variable position is defined as one of the options in the alignment, and a light chain variable region having 3 CDR sequences that each have an amino acid sequence based on a consensus sequence of the corresponding CDR from a sequence alignment of the VL sequences in one or more of Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, where each variable position is defined as one of the options in thealignment. In any embodiment, each CDR can be specified according to the Kabat, Chothia or IMGT definition.

[0149] In some embodiments, the anti-HTRAl antibody light chain variable region includes at least one of the CDRHI, CDRH2, and CDRH3 sequences in any one of the VH sequences set forth in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a CDRHI, CDRH2, and CDRH3 sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to an amino acid sequence of a corresponding CDRHI, CDRH2, and CDRH3 set forth in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1. In some embodiments, the anti-HTRAl antibody light chain variable region includes at least one of the CDRLI, CDRL2, and CDRL3 sequences in any one of the VL sequences set forth in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2. In some embodiments, the anti-HTRAl antibody light chain variable region includes a CDRLI, CDRL2, and CDRL3 sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to an amino acid sequence of a corresponding CDRHI, CDRL2, and CDRL3 set forth in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2. In some embodiments, the 3 CDRH sequences are paired with the 3 CDRL sequences according to at least one of the paired arrangements of VH and VL sequences provided in FIG. 21 and Tables 0.4, 0.5, 0.7, 0.10, 0.11, 0.12, 1.2, 6.3, and 7.1. In any embodiment, each CDR can be specified according to the Kabat, Chothia or IMGT definition.

[0150] In some embodiments, an anti-HTRAl antibody (or conjugate thereof) includes a heavy chain (and / or heavy chain variable region (VH)) and a light chain (and / or light chain variable region (VL)), wherein the heavy chain (or VH) has: a heavy chain complementarity determining region 1 (CDRHI) having an amino acid sequence of a CDRHI in any one of the heavy chain variable region (VH) sequences in Table 0.1, or with a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no morethan 2, no more than 1) residues thereof; a CDRH2 having an amino acid sequence of a CDRH2 in any one of the VH sequences in Table 0.1, or with a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues thereof; and a CDRH3 having an amino acid sequence of a CDRH3 in any one of the VH sequences in Table 0.1, or a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues thereof; and the light chain (or VL) has: a light chain complementarity determining region 1 (CDRLI) having an amino acid sequence of a CDRLI in any one of the light chain variable region (VL) sequences in Table 0.1, or a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues thereof; a CDRL2 having an amino acid sequence of a CDRL2 in any one of the VL sequences in Table 0.1, or a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues thereof; and a CDRL3 having an amino acid sequence of a CDRL3 in any one of the VL sequences in Table 0.1, or a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues thereof. In some embodiments, the 3 CDRH sequences are paired with the 3 CDRL sequences according to any one of the paired arrangements of VH and VL sequences provided in Table 0.1. In some embodiments, the antibody (or conjugate thereof) includes a heavy chain variable region having 3 CDR sequences that each have an amino acid sequence based on a consensus sequence of the corresponding CDR from a sequence alignment of the VH sequences in one or more of Table 0.1, where each variable position is defined as one of the options in the alignment, and a light chain variable region having 3 CDR sequences that each have an amino acid sequence based on a consensus sequence of the corresponding CDR from a sequence alignment of the VL sequences in one or more of Table 0.1, where each variable position is defined as one of the options in the alignment. In any embodiment, each CDR can be specified according to the Kabat, Chothia or IMGT definition.Table 0.1

[0151] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) having the 3 CDRs in each of the VH and VL sequence of any one of the VH / VL pairings as shown in Table 0.1 is an antagonistic anti-HTRAl antibody (or conjugate thereof) that inhibitsHTRA1 function (e.g., protease activity). In some embodiments, an anti-HTRAl antibody (or conjugate thereof) derived from (e.g., through one or more rounds of affinity maturation) an anti-HTRAl antibody having the 3 CDRs in each of the VH and VL sequence of any one of the VH / VL pairings as shown in Table 0.1 is an antagonistic anti-HTRAl antibody (or conjugate thereof) that inhibits HTRA1 function (e.g., protease activity).

[0152] In some embodiments, the anti-HTRAl antibody heavy chain variable region includes any of the CDRul, CDRH2, and CDRH3 sequences in any one of the VH sequences set forth in Table 0.1. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a CDRul, CDRu2, and CDRu3 sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80- 100%, 85-99%, 90-97%, 95-100%, etc ), identical to an amino acid sequence of a corresponding CDRHI, CDRH2, and CDRH3 set forth in any one of the VH sequences in Table 0.1. In some embodiments, the anti-HTRAl antibody light chain variable region includes any of the CDRLI, CDRL2, and CDRL3 sequences in any one of the VL sequences set forth in Table 0.1. In some embodiments, the anti-HTRAl antibody light chain variable region includes a CDRLI , CDRL2, and CDRL3 sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90- 97%, 95-100%, etc ), identical to an amino acid sequence of a corresponding CDRul, CDRL2, and CDRL3 set forth in any one of the VL sequences in Table 0.1. In some embodiments, the 3 CDRH sequences are paired with the 3 CDRL sequences according to any one of the paired arrangements of VH and VL sequences provided in Table 0.1. In any embodiment, each CDR can be specified according to the Kabat, Chothia or IMGT definition.

[0153] In some embodiments, an anti-HTRAl antibody (or conjugate thereof) includes a heavy chain (and / or heavy chain variable region (VH)) and a light chain (and / or light chain variable region (VL)), wherein the heavy chain (or VH) has: a heavy chain complementarity determining region 1 (CDRHI ) having an amino acid sequence of a CDRHI in the heavy chain variable region (VH) sequence in aHTRAl_36 (SEQ ID NO: 43), or with a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues thereof; a CDRu2 having an amino acid sequence ofa CDRH2 in the VH sequence in aHTRAl_36 (SEQ ID NO: 43), or with a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues thereof; and a CDRH3 having an amino acid sequence of a CDRH3 in the VH sequence in aHTRAl_36 (SEQ ID NO: 43), or a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues thereof; and the light chain (or VL) has: a light chain complementarity determining region 1 (CDRLI) having an amino acid sequence of a CDRLI in the light chain variable region (VL) sequence in aHTRAl_36 (SEQ ID NO: 307), or a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues thereof; a CDRL2 having an amino acid sequence of a CDRL2 in the VL sequence in aHTRAl_36 (SEQ ID NO: 307), or a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues thereof; and a CDRL3 having an amino acid sequence of a CDRL3 in the VL sequence in aHTRAl_36 (SEQ ID NO: 307), or a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues thereof. In any embodiment, each CDR can be specified according to the Kabat, Chothia or IMGT definition. In some embodiments, the anti-HTRAl antibody (or conjugate thereof) is an antagonistic anti-HTRAl antibody (or conjugate thereof) that inhibits HTRA1 function (e.g., protease activity).

[0154] In some embodiments, the anti-HTRAl antibody heavy chain variable region includes the CDRul, CDRu2, and CDRH3 sequences in the VH sequence of aHTRAl_36 (SEQ ID NO: 43). In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a CDRHI, CDRH2, and CDRH3 sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80- 100%, 85-99%, 90-97%, 95-100%, etc.), identical to an amino acid sequence of a corresponding CDRul, CDRu2, and CDRu3 in the VH sequence of aHTRAl_36 (SEQ ID NO: 43). In some embodiments, the anti-HTRAl antibody light chain variable region includes the CDRLI , CDRL2, and CDRL3 in the VL sequence of aHTRAl_36 (SEQ ID NO: 307). In some embodiments, the anti-HTRAl antibody light chain variable region includes a CDRLI, CDRL2, and CDRL3 sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range definedby any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to an amino acid sequence of a corresponding CDRHI, CDRL2, and CDRL3 in the VL sequence of aHTRAl 36 (SEQ ID NO: 307). In any embodiment, each CDR can be specified according to the Kabat, Chothia or IMGT definition.

[0155] In some embodiments, the antibody (or conjugate thereof) includes a heavy chain variable region having 3 CDR sequences that each have an amino acid sequence based on a consensus sequence of the corresponding CDR from a sequence alignment of the VH sequences as shown in Fig. 20B, and a light chain variable region having 3 CDR sequences that each have an amino acid sequence based on a consensus sequence of the corresponding CDR from a sequence alignment of the VL sequences as shown in Fig. 20A. In any embodiment, each CDR can be specified according to the Kabat, Chothia or IMGT definition.

[0156] In some embodiments, the anti-HTRAl antibody heavy chain variable region includes any of the CDRHI, CDRH2, and CDRH3 sequences set forth in Table 0.2. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a CDRHI, CDRH2, and CDRH3 sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to a corresponding CDRnl, CDRn2, and CDRH3 sequence set forth in Table 0.2. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a CDRHI, CDRH2, and CDRH3 sequence of a corresponding CDRHI, CDRH2, and CDRH3 sequence set forth in Table 0.2 with a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues in each of the CDRHI, CDRH2, and CDRH3 sequences. In some embodiments, the CDR sequences are as defined by Kabat, Chothia or IMGT.Table 0.2

[0157] In some embodiments, the anti-HTRAl antibody light chain variable region includes any of the CDRLI, CDRL2, and CDRL3 sequences set forth in Table 0.3. In some embodiments, the anti-HTRAl antibody light chain variable region includes a CDRLI, CDRL2, and CDRL3 sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to a corresponding CDRHI, CDRL2, and CDRL3 sequence set forth in Table 0.3. In some embodiments, the anti-HTRAl antibody light chain variable region includes a CDRLI , CDRL2, and CDRL3 sequence of a corresponding CDRLI, CDRL2, and CDRL3 sequence set forth in Table 0.3 with a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues in each of the CDRLI, CDRL2, and CDRL3 sequences. In some embodiments, the CDR sequences are as defined by Kabat, Chothia or IMGT.Table 0.3

[0158] In some embodiments, the anti-HTRAl antibody heavy chain variable region includes any of the CDRHI, CDRH2, and CDRH3 sequences set forth in Table 0.2, and the anti-HTRAl antibody light chain variable region includes any of the CDRLI, CDRL2, and CDRL3 sequences set forth in Table 0.3. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a CDRHI, CDRH2, and CDRH3 sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to a corresponding CDRHI , CDRH2, and CDRH3 sequence set forth in Table 0.2, and the anti-HTRAl antibody light chain variable region includes a CDR sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95- 100%, etc.), identical to a corresponding CDRLI, CDRL2, and CDRL3 sequence set forth in Table 0.3. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a CDRHI, CDRH2, and CDRH3 sequence of a corresponding CDRHI, CDRH2, and CDRH3 sequence set forth in Table 0.2 with a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no more than 1) residues in each of the CDRHI, CDRH2, and CDRH3 sequences, and the anti-HTRAl antibody light chain variable region includes a CDRLI, CDRL2, and CDRL3 sequence of a corresponding CDRLI , CDRL2, and CDRL3 sequence set forth in Table 0.3 with a variation (e.g., substitution, deletion) at no more than 5 (e.g., no more than 4, no more than 3, no more than 2, no morethan 1) residues in each of the CDRLI , CDRL2, and CDRL3 sequences. In some embodiments, the CDRHI, CDRH2, CDRH3, CDRLI, CDRL2, and CDRL3 sequences are as defined by Kabat, Chothia or IMGT. In some embodiments, an anti-HTRAl antibody (or conjugate thereof) having a heavy chain variable region that includes any of the CDRHI , CDRH2, and CDRH3 sequences set forth in Table 0.2 (or variants thereof), and a light chain variable region that includes any of the CDRLI, CDRL2, and CDRL3 sequences set forth in Table 0.3 (or variants thereof) is an antagonistic anti-HTRAl antibody (or conjugate thereof) that inhibits HTRA1 function (e.g., protease activity).

[0159] In some embodiments, the anti-HTRAl antibody heavy chain variable region includes CDRHI : FYHVH (SEQ ID NO:830), CDRH2: SIYTSGYTEYASALES (SEQ ID NO:831), and CDRH3 : EGLQRVGVLDA (SEQ ID NO:834) or EGLQRVGVFDA (SEQ ID NO:832) or EGLQRVGVMDA (SEQ ID NO:833), and the anti-HTRAl antibody light chain variable region includes CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO: 841), and CDRL3 : QQATYFPYT (SEQ ID NO: 839). In some embodiments, the anti-HTRAl antibody heavy chain variable region includes CDRHI : GFSLTFYH (SEQ ID NO: SEQ ID NO:825), CDRH2: IYTSGYT (SEQ ID NO:826), and CDRH3: AREGLQRVGVFDA (SEQ ID NO: 827) or AREGLQRVGVMDA (SEQ ID NO:828) or AREGLQRVGVLDA (SEQ ID NO:829), and the anti-HTRAl antibody light chain variable region comprises CDRLI : QSLLDEAGETY (SEQ ID NO:837), CDRL2: EV (SEQ ID NO:838), and CDRL3 : QQATYFPYT (SEQ ID NO:839). In some embodiments, the anti-HTRAl antibody heavy chain variable region includes CDRHI : GFSLTFY (SEQ ID NO: SEQ ID NO: 835), CDRH2: YTSGY (SEQ ID NO: 836), and CDRH3 : EGLQRVGVLDA (SEQ ID NO:834) or EGLQRVGVFDA (SEQ ID NO 832) or EGLQRVGVMDA (SEQ ID NO:833), and the anti-HTRAl antibody light chain variable region comprises CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO:841), and CDRL3 : QQATYFPYT (SEQ ID NO:839). In some embodiments, the anti-HTRAl antibody heavy chain variable region includes CDRHI : FYHVH (SEQ ID NO: 830), CDRH2: SIYTSGYTEYASALES (SEQ ID NO:831), and CDRH3 : EGLQRVGVFDA (SEQ ID NO:832), and the anti-HTRAl antibody light chain variable region includes CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO:841), and CDRL3 : QQATYFPYT (SEQ ID NO:839). In some embodiments, the anti-HTRAl antibodyheavy chain variable region includes CDRHI : FYHVH (SEQ ID NO:830), CDRH2: SIYTSGYTEYASALES (SEQ ID NO:831), and CDRH3 : EGLQRVGVLDA (SEQ ID NO:834), and the anti-HTRAl antibody light chain variable region includes CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO:841), and CDRL3 : QQATYFPYT (SEQ ID NO:839). In some embodiments, the anti-HTRAl antibody heavy chain variable region includes CDRHI : FYHVH (SEQ ID NO:830), CDRH2: SIYTSGYTEYASALES (SEQ ID NO:831), and CDRH3: EGLQRVGVMDA (SEQ ID NO:833), and the anti-HTRAl antibody light chain variable region includes CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRi 2: EVSLLES (SEQ ID NO:841), and CDRL3 : QQATYFPYT (SEQ ID NO:839). In some embodiments, the anti-HTRAl antibody heavy chain variable region includes CDRHI : GFSLTFYH (SEQ ID NO:825), CDRH2: IYTSGYT (SEQ ID NO:826), and CDRH3 : AREGLQRVGVFDA (SEQ ID NO:827), and the anti-HTRAl antibody light chain variable region comprises CDRLI : QSLLDEAGETY (SEQ ID NO:837), CDRL2: EV (SEQ ID NO:838), and CDRL3 : QQATYFPYT (SEQ ID NO:839). In some embodiments, the anti-HTRAl antibody heavy chain variable region includes CDRHI : GFSLTFYH (SEQ ID NO:825), CDRH2: IYTSGYT (SEQ ID NO 826), and CDRH3 : AREGLQRVGVMDA (SEQ ID NO: 828), and the anti-HTRAl antibody light chain variable region comprises CDRLI : QSLLDEAGETY (SEQ ID NO:837), CDRL2: EV (SEQ ID NO:838), and CDRL3 : QQATYFPYT (SEQ ID NO:839). In some embodiments, the anti- HTRAl antibody heavy chain variable region includes CDRHI : GFSLTFYH (SEQ ID NO 825), CDRH2: IYTSGYT (SEQ ID NO: 826), and CDRH3 : AREGLQRVGVLDA (SEQ ID NO:829), and the anti-HTRAl antibody light chain variable region comprises CDRLI : QSLLDEAGETY (SEQ ID NO:837), CDRL2: EV (SEQ ID NO:838), and CDRL3 : QQATYFPYT (SEQ ID NO:839). In some embodiments, the anti-HTRAl antibody heavy chain variable region includes CDRHI : GFSLTFY (SEQ ID NO:835), CDRH2: YTSGY (SEQ ID NO:836), and CDRH3 : EGLQRVGVLDA (SEQ ID NO:834), and the anti-HTRAl antibody light chain variable region comprises CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO:841), and CDRL3: QQATYFPYT (SEQ ID NO:839). In some embodiments, the anti-HTRAl antibody heavy chain variable region includes CDRHI : GFSLTFY (SEQ ID NO:835), CDRH2: YTSGY (SEQ ID NO:836), and CDRH3: EGLQRVGVFDA (SEQ ID NO:832), and the anti-HTRAl antibody light chainvariable region comprises CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO: 841), and CDRL3 : QQATYFPYT (SEQ ID NO: 839). In some embodiments, the anti-HTRAl antibody heavy chain variable region includes CDRHI : GFSLTFY (SEQ ID NO: 835), CDRH2: YTSGY (SEQ ID NO: 836), and CDRH3 : EGLQRVGVMDA (SEQ ID NO:833), and the anti-HTRAl antibody light chain variable region comprises CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO:841), and CDRL3 : QQATYFPYT (SEQ ID NO:839). In some embodiments, the anti-HTRAl antibody (or conjugate thereof) is an antagonistic anti-HTRAl antibody (or conjugate thereof) that inhibits HTRA1 function (e.g., protease activity).

[0160] In some embodiments, the anti-HTRAl antibody heavy chain variable region includes CDRHI : GFSLTSYHVH (SEQ ID NO:538), CDRH2: VIWTSGNTEYN SALES (SEQ ID NO:539), and CDRH3 : AREGLRRVGVMDA (SEQ ID NO:540), and the anti-HTRAl antibody light chain variable region includes CDRLI : RSSQSLLDSDGDTYLN (SEQ ID NO:541), CDRL2: SVSNLES (SEQ ID NO:542), and CDRL3 : MQATHAPYT (SEQ ID NO:543). In some embodiments, the anti-HTRAl antibody (or conjugate thereof) is an antagonistic anti-HTRAl antibody (or conjugate thereof) that inhibits HTRA1 function (e.g., protease activity).

[0161] In some embodiments, an anti-HTRAl antibody (or conjugate thereof) of the present disclosure includes a VH having an amino acid sequence of at least one of the VH sequences provided in Figs. 21, 22A, 23A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7,7.12, 7.17, and 8.1. In some embodiments, an anti-HTRAl antibody of the present disclosure includes a VH having an amino acid sequence at least about 80% identical to any one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7,7.12, 7.17, and 8.1. In some embodiments, an anti-HTRAl antibody of the present disclosure includes a VH having an amino acid sequence at least about 90% identical to any one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7,7.12, 7.17, and 8.1. In some embodiments, an anti-HTRAl antibody of the present disclosure includes a VH having an amino acid sequence at least about 95% identical to any one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7,7.12, 7.17, and 8.1. In some embodiments, an anti-HTRAl antibody of the present disclosure includes a VH having an amino acid sequence at least about 97% identical to any one of theVH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1 .2, 6.3, 6.5, 7.1, 7.4, 7.7,7.12, 7.17, and 8.1. In some embodiments, any variation (e.g., substitution, deletion) within the amino acid sequence of the VH of the anti-HTRAl antibody from any one of the VH sequences provided in Figs. 21, 22A, 23A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7,7.12, 7.17, and 8.1 is in no more than 5, 4, 3, 2, or 1 residue of a CDR of the VH sequence. In some embodiments, any variation within the amino acid sequence of the VH of the anti- HTRAl antibody from a VH sequence provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1 is not within a CDR of the VH sequence. In some embodiments, an anti-HTRAl antibody of the present disclosure includes a VH having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100% identical to any one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, where any variation (e.g., substitution, deletion) within the amino acid sequence of the VH of the anti-HTRAl antibody from any one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1 is in no more than 5, 4, 3, 2, or 1 residue of a CDR of the VH sequence. In some embodiments, an anti-HTRAl antibody of the present disclosure includes a VH having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100% identical to any one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, where any sequence variation from the VH sequence provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12,7.17, and 8.1 is not within a CDR of the VH sequence.

[0162] In some embodiments, an anti-HTRAl antibody (or conjugate thereof) of the present disclosure includes a VL having an amino acid sequence of at least one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13,7.18, and 8.2. In some embodiments, an anti-HTRAl antibody of the present disclosure includes a VL having an amino acid sequence at least about 80% identical to any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8,7.13, 7.18, and 8.2. In some embodiments, an anti-HTRAl antibody of the present disclosure includes a VL having an amino acid sequence at least about 90% identical to any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8,7.13, 7.18, and 8.2. In some embodiments, an anti-HTRAl antibody of the present disclosure includes a VL having an amino acid sequence at least about 95% identical to any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8,7.13, 7.18, and 8.2. In some embodiments, an anti-HTRAl antibody of the present disclosure includes a VL having an amino acid sequence at least about 97% identical to any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8,7.13, 7.18, and 8.2. In some embodiments, any variation (e.g., substitution, deletion) within the amino acid sequence of the VL of the anti-HTRAl antibody from any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2 is in no more than 5, 4, 3, 2, or 1 residue of a CDR of the VL sequence. In some embodiments, any variation within the amino acid sequence of the VL of the anti-HTRAl antibody from a VL sequence provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2 is not within a CDR of the VL sequence. In some embodiments, an anti-HTRAl antibody of the present disclosure includes a VL having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100% identical to any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, where any variation (e.g., substitution, deletion) within the amino acid sequence of the VL of the anti- HTRAl antibody from any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2 is in no more than 5, 4, 3, 2, or 1 residue of a CDR of the VL sequence. In some embodiments, an anti-HTRAl antibody of the present disclosure includes a VL having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100% identical to any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, where any sequence variation from the VL sequence provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2 is not within a CDR of the VL sequence.

[0163] In some embodiments, an anti-HTRAl antibody (or conjugate thereof) of the present disclosure includes a VH having an amino acid sequence of at least one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, and a VL having an amino acid sequence of at least one ofthe VL sequencesprovided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and8.2. In some embodiments, an anti-HTRAl antibody (or conjugate thereof) of the present disclosure includes a VH having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95- 100%, etc.), identical to any one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, and a VL having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2. In some embodiments, an anti-HTRAl antibody (or conjugate thereof) of the present disclosure includes a VH having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90- 97%, 95-100%, etc.), identical to any one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, where any variation (e.g., substitution, deletion) within the amino acid sequence of the VH of the anti-HTRAl antibody from any one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2,6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1 is in no more than 5, 4, 3, 2, or 1 residue of a CDR of the VH sequence, and a VL having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95- 100%, etc.), identical to any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, where any sequence variation from the VL sequence provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2 is not within a CDR of the VL sequence. In some embodiments, an anti-HTRAl antibody (or conjugate thereof) of the present disclosure includes a VH having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of theVH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1 .2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, where any sequence variation from the VH sequence provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1 is not within a CDR of the VH sequence, and a VL having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90- 97%, 95-100%, etc.), identical to any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, where any sequence variation from the VL sequence provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2 is not within a CDR of the VL sequence. In some embodiments, the VH and VL sequences of the anti-HTRAl antibody (or conjugate thereof) are paired according to at least one of the paired arrangements provided in FIG. 21 and Tables 0.1, 0.4, 0.5, 0.7, 0.10, 0.11, 0.12, 1.2, 6.3, and 7.1.

[0164] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) includes a heavy chain variable region having at least an amino acid sequence of a consensus sequence from a sequence alignment of the VH sequences in one or more of Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, where each variable position is defined as one of the options in the alignment, and a light chain variable region having at least an amino acid sequence of a consensus sequence from a sequence alignment of the VL sequences in one or more of Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, where each variable position is defined as one of the options in the alignment.

[0165] In some embodiments, the antibody (or conjugate thereof) includes at least one of the pairings of VH and VL as shown in Fig. 21. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 80% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Fig. 21. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 90% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Fig. 21. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 95% identical to a corresponding VH and VL sequenceof one of the sequence pairs shown in Fig. 21 . In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 97% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Fig. 21. In some embodiments, the antibody (or conjugate thereof) includes a VH and VL each having CDRs of the corresponding CDRs in at least one of the pairings of VH and VL as shown in Fig. 21.

[0166] In some embodiments, the antibody (or conjugate thereof) includes at least one of the pairings of VH and VL as shown in Table 0.1. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 80% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.1. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 90% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.1. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 95% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.1. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 97% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.1. In some embodiments, the antibody (or conjugate thereof) includes a VH and VL each having CDRs of the corresponding CDRs in at least one of the pairings of VH and VL as shown in Table 0.1. In some embodiments, the anti-HTRAl antibody having a VH / VL pairing as shown in Table 0.1 is an antagonistic anti-HTRAl antibody that inhibits HTRA1 function (e.g., protease activity). In some embodiments, the anti-HTRAl antibody (or conjugate thereof) having a VH / VL pairing as shown in Table 0.1 is an antagonistic anti- HTRAl antibody (or conjugate thereof) that inhibits HTRA1 function (e.g., protease activity). In some embodiments, an anti-HTRAl antibody (or conjugate thereof) derived from (e.g., through one or more rounds of affinity maturation) an anti-HTRAl antibody having a VH / VL pairing as shown in Table 0.1 is an antagonistic anti-HTRAl antibody (or conjugate thereof) that inhibits HTRA1 function (e.g., protease activity).

[0167] In some embodiments, the antibody (or conjugate thereof) includes at least one of the pairings of VH and VL as shown in Table 0.4 (where the HC# corresponds to a VHsequence as provided in Fig. 22A or Table 6.5, and the LC# corresponds to a VL sequence as provided in Fig. 22B or Table 6.6). In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 80% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.4. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 90% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.4. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 95% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.4. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 97% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.4. In some embodiments, the antibody (or conjugate thereof) includes a VH and VL each having CDRs of the corresponding CDRs in at least one of the pairings of VH and VL as shown in Table 0.4.Table 0.4

[0168] In some embodiments, the antibody (or conjugate thereof) includes at least one of the pairings of VH and VL as shown in Table 0.5. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 80% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.5. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 90% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.5. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 95% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.5. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 97% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.5. In some embodiments, the antibody (or conjugate thereof) includes a VH and VL each having CDRs of the corresponding CDRs in at least one of the pairings of VH and VL as shown in Table 0.5.Table 0.5

[0169] In some embodiments, the antibody includes at least one VH point mutation, one VL point mutation, or both as provided in Table 0.6. In some embodiments, the antibody includes at least two VH point mutations, at least one VL point mutation, or both as provided in Table 0.6. In some embodiments, the antibody includes at least one VH point mutation, at least two VL point mutations, or both as provided in Table 0.6. In some embodiments, the antibody includes at least two VH point mutations, at least two VL point mutations, or both as provided in Table 0.6. In some embodiments, the antibody includes 1, 2, 3, 4, 5, 6, or 7 VH point mutations, as provided in Table 0.6. In some embodiments, the antibody includes 1, 2, 3, 4, 5, 6, 7, 8, or 9 VL point mutations, as provided in Table 0.6. In some embodiments, the antibody includes 1, 2, 3, 4, 5, 6, or 7 VH point mutations, 1, 2, 3, 4, 5, 6, 7, 8, or 9 VL point mutations, or the respective number of point mutations in both VH and VL, as provided in Table 0.6. In some embodiments, the VH point mutations provided in Table 0.6 are relative to SEQ ID NO: 43. In some embodiments, the VL point mutations provided in Table 0.6 are relative to SEQ ID NO: 307.Table 0.6

[0170] In some embodiments, the antibody (or conjugate thereof) includes at least one of the pairings of VH and VL as shown in Table 0.7 (where the HC# corresponds to a VH sequence as provided in Fig. 22A or 23A, and the LC# corresponds to a VL sequence as provided in Fig. 22B or 23B). In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 80% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.7. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 90% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.7. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 95% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.7. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 97% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.7. In some embodiments, the antibody (or conjugate thereof) includes a VH and VL each having CDRs of the corresponding CDRs in at least one of the pairings of VH and VL as shown in Table 0.7.Table 0.7

[0171] In some embodiments, the antibody (or conjugate thereof) of the present disclosure includes at least one, at least two, at least three, at least four, at least five, or any six of the CDRs shown in Tables 0.8 and 0.9. In some embodiments, the antibody (or conjugate thereof) includes at least one, at least two, at least three, at least four, at least five, or any six of the CDRs shown in Tables 0.8 and 0.9 with no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 point mutation per CDR. In some embodiments, the antibody (or conjugate thereof) of the present disclosure includes a combination of CDRs selected from any combination of the CDRs shown in Table 0.8, with no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 point mutation per CDR, and includes a combination of CDRs selected from any combination of the CDRs shown in Table 0.9, with no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 point mutation per CDR. In some embodiments, the antibody (or conjugate thereof) includes one or more CDRs that is a Kabat, Chothia, or IMGT option or subpart of the corresponding CDR of Tables 0.8 or 0.9.Table 0.8Table 0.9

[0172] In some embodiments, the antibody (or conjugate thereof) includes at least one of the pairings of VH and VL as shown in Table 0.10 (where the HC# corresponds to a VH sequence as provided in Fig. 22A, 23 A, or 24A, and the LC# corresponds to a VL sequence as provided in Fig. 22B, 23B, or 24B). In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 80% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.10. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 90% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.10. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 95% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.10. In some embodiments the antibody (or conjugate thereof) includes at least a VH / VL pairing where each VH and VL sequence is at least about 97% identical to a corresponding VH and VL sequence of one of the sequence pairs shown in Table 0.10. In some embodiments, the antibody (or conjugate thereof) includes a VH and VL each having CDRs of the corresponding CDRs in at least one of the pairings of VH and VL as shown in Table 0.10.Table 0.10

[0173] In some embodiments, an anti-HTRAl antibody (or conjugate thereof) of the present disclosure includes a VH having an amino acid sequence of SEQ ID NO:725, and a VL having an amino acid sequence of SEQ ID NO:748. In some embodiments, the anti- HTRAl antibody (or conjugate thereof) includes a VH having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80- 100%, 85-99%, 90-97%, 95-100%, etc.), identical to SEQ ID NO:725, and a VL having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to SEQ ID NO: 748. In some embodiments, any variation within the amino acid sequence of the VH of the anti-HTRAl antibody from SEQ ID NO:725 is not within a CDR of the VH sequence. In some embodiments, any variation within the amino acid sequence of the VL of the anti-HTRAl antibody from SEQ ID NO:748 is not within a CDR of the VL sequence.

[0174] In some embodiments, an anti-HTRAl antibody (or conjugate thereof) of the present disclosure includes a VH having an amino acid sequence of SEQ ID NO:746, anda VL having an amino acid sequence of SEQ ID NO:748. In some embodiments, the anti- HTRA1 antibody (or conjugate thereof) includes a VH having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80- 100%, 85-99%, 90-97%, 95-100%, etc.), identical to SEQ ID NO:746, and a VL having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%>, at least about 97%o, or about 100%, or a percentage in a range defined by any two of the preceding values, identical to SEQ ID NO: 748. In some embodiments, any variation within the amino acid sequence of the VH of the anti-HTRAl antibody from SEQ ID NO:746 is not within a CDR of the VH sequence. In some embodiments, any variation within the amino acid sequence of the VL of the anti-HTRAl antibody from SEQ ID NO:748 is not within a CDR of the VL sequence.

[0175] In some embodiments, an anti-HTRAl antibody (or conjugate thereof) of the present disclosure includes a VH having an amino acid sequence of SEQ ID NO:745, and a VL having an amino acid sequence of SEQ ID NO:748. In some embodiments, the anti- HTRAl antibody (or conjugate thereof) includes a VH having an amino acid sequence at least about 80%o, at least about 85%>, at least about 90%, at least about 95%, at least about 97%>, or about 100%o, or a percentage in a range defined by any two of the preceding values (e.g., 80- 100%, 85-99%o, 90-97%o, 95-100%), etc.), identical to SEQ ID NO:745, and a VL having an amino acid sequence at least about 80%, at least about 85%, at least about 90%>, at least about 95%o, at least about 97%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%), 85-99%, 90-97%o, 95-100%o, etc.), identical to SEQ ID NO:748. In some embodiments, any variation within the amino acid sequence of the VH of the anti-HTRAl antibody from SEQ ID NO:745 is not within a CDR of the VH sequence. In some embodiments, any variation within the amino acid sequence of the VL of the anti-HTRAl antibody from SEQ ID NO:748 is not within a CDR of the VL sequence.

[0176] In some embodiments, an anti-HTRAl antibody (or conjugate thereof) of the present disclosure includes a VH having an amino acid sequence of SEQ ID NO:742, and a VL having an amino acid sequence of SEQ ID NO:748. In some embodiments, the anti- HTRAl antibody (or conjugate thereof) includes a VH having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%>, orabout 100%, or a percentage in a range defined by any two of the preceding values (e g., 80- 100%, 85-99%, 90-97%, 95-100%, etc.), identical to SEQ ID NO:742, and a VL having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to SEQ ID NO:748. In some embodiments, any variation within the amino acid sequence of the VH of the anti-HTRAl antibody from SEQ ID NO:742 is not within a CDR of the VH sequence. In some embodiments, any variation within the amino acid sequence of the VL of the anti-HTRAl antibody from SEQ ID NO:748 is not within a CDR of the VL sequence.

[0177] In some embodiments, an anti-HTRAl antibody (or conjugate thereof) of the present disclosure includes a VH having an amino acid sequence of SEQ ID NO:744, and a VL having an amino acid sequence of SEQ ID NO:748. In some embodiments, the anti- HTRAl antibody (or conjugate thereof) includes a VH having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80- 100%, 85-99%, 90-97%, 95-100%, etc.), identical to SEQ ID NO:744, and a VL having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to SEQ ID NO:748. In some embodiments, any variation within the amino acid sequence of the VH of the anti-HTRAl antibody from SEQ ID NO:744 is not within a CDR of the VH sequence. In some embodiments, any variation within the amino acid sequence of the VL of the anti-HTRAl antibody from SEQ ID NO:748 is not within a CDR of the VL sequence.

[0178] In some embodiments, an anti-HTRAl antibody (or conjugate thereof) of the present disclosure includes a VH having an amino acid sequence of SEQ ID NO:563, and a VL having an amino acid sequence of SEQ ID NO:569. In some embodiments, the anti- HTRAl antibody (or conjugate thereof) includes a VH having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80- 100%, 85-99%, 90-97%, 95-100%, etc.), identical to SEQ ID NO:563, and a VL having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about95%, at least about 97%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to SEQ ID NO:569. In some embodiments, any variation within the amino acid sequence of the VH of the anti-HTRAl antibody from SEQ ID NO: 563 is not within a CDR of the VH sequence. In some embodiments, any variation within the amino acid sequence of the VL of the anti-HTRAl antibody from SEQ ID NO:569 is not within a CDR of the VL sequence.

[0179] In any embodiment herein, reference to “the anti-HTRAl antibody” contemplates the antibody portion of a conjugate of the anti-HTRAl antibody, as provided herein.

[0180] An anti-HTRAl antibody of the present disclosure (or a conjugate thereof) binds to HTRA1 from any suitable species. In some embodiments, the antibody (or conjugate thereof) binds to human HTRA1. In some embodiments, the antibody (or conjugate thereof) binds to human HTRA1 having the amino acid sequence of SEQ ID NO: 1, or a portion thereof.

[0181] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) binds to the loop A peptide of HTRA1. In some embodiments, the anti-HTRAl antibody (or conjugate thereof) binds to a loop A peptide of HTRA1, where the loop A peptide includes the amino acid sequence of FRKLPFSKREVPV (SEQ ID NO:851). In some embodiments, the anti-HTRAl antibody (or conjugate thereof) binds to a loop A peptide of HTRA1, where the loop A peptide has the amino acid sequence of FRKLPFSKREVPV (SEQ ID NO:851). Binding to the loop A peptide (or lack thereof) can be determined using any suitable option, e.g., by ELISA.

[0182] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) that binds to the loop A peptide of HTRA1 includes a heavy chain variable region having any of the CDRHI, CDRH2, and CDRH3 sequences in any one of the VH sequences set forth in Table 0. 11. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a CDRHI, CDRH2, and CDRH3 sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95- 100%, etc.), identical to an amino acid sequence of a corresponding CDRHI, CDRH2, and CDRH3 set forth in any one of the VH sequences in Table 0.11. In some embodiments, the anti-HTRAl antibody (or conjugate thereof) that binds to the loop A peptide of HTRA1includes a light chain variable region having any of the CDRLI , CDRL2, and CDRL3 sequences in any one of the VL sequences set forth in Table 0.11. In some embodiments, the anti-HTRAl antibody light chain variable region includes a CDRLI, CDRL2, and CDRL3 sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to an amino acid sequence of a corresponding CDRLI, CDRL2, and CDRL3 set forth in any one of the VL sequences in Table 0.11. In some embodiments, the 3 CDRH sequences are paired with the 3 CDRL sequences according to at least one of the paired arrangements of VH and VL sequences provided in Table 0.11. In any embodiment, each CDR can be specified according to the Kabat, Chothia or IMGT definition.Table 0.11

[0183] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) that binds to the loop A peptide of HTRA1 includes a heavy chain variable region having at least one of the VH sequences set forth in Table 0.11. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a VH sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VH sequences in Table 0.11. In some embodiments, any variation (e.g., substitution, deletion) within the amino acid sequenceof the VH of the anti-HTRAl antibody from any one of the VH sequences provided in Table 0.11 is in no more than 5, 4, 3, 2, or 1 residue of a CDR of the VH sequence. In some embodiments, any variation within the amino acid sequence of the VH of the anti-HTRAl antibody from a VH sequence provided in Table 0.11 is not within a CDR of the VH sequence. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a VH sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VH sequences in Table 0.11, where any variation (e.g., substitution, deletion) within the amino acid sequence of the VH of the anti-HTRAl antibody from any one of the VH sequences provided in Table 0.11 is in no more than 5, 4, 3, 2, or 1 residue of a CDR of the VH sequence. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a VH sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VH sequences in Table 0.11, where any variation within the amino acid sequence of the VH of the anti-HTRAl antibody from a VH sequence provided in Table 0.11 is not within a CDR of the VH sequence.

[0184] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) that binds to the loop A peptide of HTRA1 includes a light chain variable region having at least one of the VL sequences set forth in Table 0.11. In some embodiments, the anti-HTRAl antibody light chain variable region includes a VL sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VL sequences in Table 0.11. In some embodiments, any variation (e.g., substitution, deletion) within the amino acid sequence of the VL of the anti-HTRAl antibody from any one of the VL sequences provided in Table 0.11 is in no more than 5, 4, 3, 2, or 1 residue of a CDR of the VL sequence. In some embodiments, any variation within the amino acid sequence of the VL of the anti-HTRAl antibody from a VL sequence provided in Table 0.11 is not within a CDR of the VL sequence. In some embodiments, the anti-HTRAl antibody light chain variable region includes a VLsequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VL sequences in Table 0.11, where any variation (e.g., substitution, deletion) within the amino acid sequence of the VL of the anti-HTRAl antibody from any one of the VL sequences provided in Table 0.11 is in no more than 5, 4, 3, 2, or 1 residue of a CDR of the VL sequence. In some embodiments, the anti-HTRAl antibody light chain variable region includes a VL sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VL sequences in Table 0.11, where any variation within the amino acid sequence of the VL of the anti-HTRAl antibody from a VL sequence provided in Table 0.11 is not within a CDR of the VL sequence.

[0185] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) that binds to the loop A peptide of HTRA1 includes a heavy chain variable region having at least one of the VH sequences set forth in Table 0.11, and a light chain variable region having at least one of the VL sequences set forth in Table 0.11. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a VH sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VH sequences in Table 0.11, and the anti-HTRAl antibody light chain variable region includes a VL sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VL sequences in Table 0.11. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a VH sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95- 100%, etc.), identical to any one of the VH sequences in Table 0.11, where any variation (e.g., substitution, deletion) within the amino acid sequence of the VH of the anti-HTRAl antibodyfrom any one of the VH sequences provided in Table 0.11 is in no more than 5, 4, 3, 2, or 1 residue of, or is not within, a CDR of the VH sequence, and the anti-HTRAl antibody light chain variable region includes a VL sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90- 97%, 95-100%, etc.), identical to any one of the VL sequences in Table 0.11, where any variation (e.g., substitution, deletion) within the amino acid sequence of the VL of the anti- HTRAl antibody from any one of the VL sequences provided in Table 0.11 is in no more than 5, 4, 3, 2, or 1 residue of, or is not within, a CDR of the VL sequence. In some embodiments, the VH and VL sequences of the anti-HTRAl antibody (or conjugate thereof) are paired according to any one of the paired arrangements provided in Table 0.11.

[0186] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) does not bind to the loop A peptide of HTRA1. In some embodiments, the anti-HTRAl antibody (or conjugate thereof) does not bind to the loop A peptide of HTRA1, where the loop A peptide includes the amino acid sequence of FRKLPFSKREVPV (SEQ ID NO:851). In some embodiments, the anti-HTRAl antibody (or conjugate thereof) does not bind to the loop A peptide of HTRA1, where the loop A peptide has the amino acid sequence of FRKLPFSKREVPV (SEQ ID NO:851). In some embodiments, the anti-HTRAl antibody (or conjugate thereof) does not require the loop A peptide of HTRA1 or binding to HTRA1, where the loop A peptide has the amino acid sequence of FRKLPFSKREVPV (SEQ ID NO:851). Binding to the loop A peptide (or lack thereof) can be determined using any suitable option, e.g., by ELISA.

[0187] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) that does not bind to the loop A peptide of HTRA1 includes a heavy chain variable region having any of the CDRHI , CDRH2, and CDRH3 sequences in any one of the VH sequences set forth in Table 0.12. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a CDRHI, CDRH2, and CDRH3 sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to an amino acid sequence of a corresponding CDRHI, CDRH2, and CDRH3 set forth in any one of the VH sequences in Table 0.12. In someembodiments, the anti-HTRAl antibody (or conjugate thereof) that does not bind to the loop A peptide of HTRA1 includes a light chain variable region having any of the CDRLI, CDRL2, and CDRL3 sequences in any one of the VL sequences set forth in Table 0.12. In some embodiments, the anti-HTRAl antibody light chain variable region includes a CDRLI, CDRL2, and CDRL3 sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to an amino acid sequence of a corresponding CDRHI, CDRL2, and CDRL3 set forth in any one of the VL sequences in Table 0.12. In some embodiments, the 3 CDRu sequences are paired with the 3 CDRL sequences according to any one of the paired arrangements of VH and VL sequences provided in Table 0 0.12. In any embodiment, each CDR can be specified according to the Kabat, Chothia or IMGT definition.Table 0.12

[0188] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) that does not bind to the loop A peptide of HTRA1 includes a heavy chain variable region having at least one of the VH sequences set forth in Table 0.12. In some embodiments, the anti- HTRAl antibody heavy chain variable region includes a VH sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80- 100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VH sequences in Table 0.12. In some embodiments, any variation (e g., substitution, deletion) within the amino acid sequence of the VH of the anti-HTRAl antibody from any one of the VH sequences provided in Table 0 0.12 is in no more than 5, 4, 3, 2, or 1 residue of a CDR of the VH sequence. In some embodiments, any variation within the amino acid sequence of the VH of the anti- HTRAl antibody from a VH sequence provided in Table 0.12 is not within a CDR of the VH sequence. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a VH sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VH sequences in Table 0.12, where any variation (e.g., substitution, deletion) within the amino acid sequence of the VH of the anti-HTRAl antibody from any one of the VH sequences provided in Table 0.12 is in no more than 5, 4, 3, 2, or 1 residue of a CDR of the VH sequence. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a VH sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VH sequences in Table 0.12, where any variation within the amino acid sequence of the VH of the anti-HTRAl antibody from a VH sequence provided in Table 0.12 is not within a CDR of the VH sequence.

[0189] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) that does not bind to the loop A peptide of HTRA1 includes a light chain variable region having at least one of the VL sequences set forth in Table 0.12. In some embodiments, the anti-HTRAl antibody light chain variable region includes a VL sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VL sequences in Table 0.12. In some embodiments, any variation (e.g., substitution, deletion) within the amino acid sequence of the VL of the anti-HTRAl antibody from any one of the VL sequences provided in Table 0.12 is in no more than 5, 4, 3, 2, or 1 residue of a CDR of the VL sequence. In some embodiments, any variation within the amino acid sequence of the VL of the anti-HTRAl antibody from a VL sequence provided in Table 0.12 is not within a CDR of the VL sequence. In some embodiments, the anti-HTRAl antibody light chain variable region includes a VL sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VL sequences in Table 0.12, where any variation (e.g., substitution, deletion) within the amino acid sequence of the VL of the anti-HTRAl antibody from any one of the VL sequences provided in Table 0.12 is in no more than 5, 4, 3, 2, or 1 residue of a CDR of the VL sequence. In some embodiments, the anti-HTRAl antibody light chain variable region includes a VL sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VL sequences in Table 0.12, where any variation within the amino acid sequence of the VL of the anti-HTRAl antibody from a VL sequence provided in Table 0.12 is not within a CDR of the VL sequence.

[0190] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) that does not bind to the loop A peptide of HTRA1 includes a heavy chain variable region having at least one of the VH sequences set forth in Table 0.12, and a light chain variable region having at least one of the VL sequences set forth in Table 0.12. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a VH sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VH sequences in Table 0.12, and the anti-HTRAl antibody light chain variable region includes a VL sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VL sequences in Tables 0.12. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a VH sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95- 100%, etc.), identical to any one of the VH sequences in Table 0.12, where any variation (e.g., substitution, deletion) within the amino acid sequence of the VH of the anti-HTRAl antibody from any one of the VH sequences provided in Table 0.12 is in no more than 5, 4, 3, 2, or 1 residue of, or is not within, a CDR of the VH sequence, and the anti-HTRAl antibody light chain variable region includes a VL sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90- 97%, 95-100%, etc.), identical to any one of the VL sequences in Table 0.12, where any variation (e.g., substitution, deletion) within the amino acid sequence of the VL of the anti- HTRAl antibody from any one of the VL sequences provided in Table 0.12 is in no more than 5, 4, 3, 2, or 1 residue of, or is not within, a CDR of the VL sequence. In some embodiments, the VH and VL sequences of the anti-HTRAl antibody (or conjugate thereof) are paired according to any one of the paired arrangements provided in Table 0.12.

[0191] An anti-HTRAl antibody (or a conjugate thereof) of the present disclosure can bind to HTRA1 with a high affinity. In some embodiments, the anti-HTRAl antibody binds to HTRA1 with a binding affinity (KD) of about 1.0 x 10'9M or less, about 1.0 x IO10M or less, about 5.0 x 10'11M or less, about 2.0 x 10'11M or less, about 1.0 x 10'11M or less, about 5.0 x IO’12M or less, about 2.0 x 10'12M or less, or about 1.0 x 10'12M or less, or with a binding affinity in a range defined by any two of the preceding values (e.g., 1.0 x 10'9- 1.0 x IO’12M, 1.0 x IO’10- 1.0 x IO’12M, 5.0 x 10’11- 5.0 x IO’12M, 1.0 x 10’11- 1.0 x 10’12M, 1.0 x 10'10- 1.0 x 10’11M, etc.), e g., as determined by kinetic analysis.

[0192] In some embodiment, the anti-HTRAl antibody (or conjugate thereof) binds to a HTRA1 monomer or a trimer. In some embodiment, the anti-HTRAl antibody weakly binds to a HTRA1 monomer. In some embodiments, the anti-HTRAl antibody (or conjugate thereof) selectively binds to a HTRA1 trimer over a HTRA1 monomer. In someembodiments, the anti-HTRAl antibody (or conjugate thereof) binds to a HTRA1 trimer with a higher affinity than to a HTRA1 monomer. In some embodiments, the anti-HTRAl antibody binds to a HTRA1 trimer with an affinity that is two times or more, 3 times or more, 5 times or more, 10 times or more, 20 times or more, 50 times or more, 100 times or more, 1,000 times or more, 10,000 times or more, or 100,000 times or more, or a fold difference defined by any two of the preceding values (e.g., 2-100,000 times, 3-100,000 times, 10-10,000 times, 20-1,000 times, 2-10 times, 2-50 times, 5-100 times, etc.), stronger (e.g., with a lower KD) than to a HTRA1 monomer. The relative affinity can be determined using any suitable method, e.g., a kinetic analysis.

[0193] An anti-HTRAl antibody (or a conjugate thereof) binds to HTRA1 with any suitable stoichiometry of antibody to HTRA1. In some embodiments, the anti-HTRAl antibody (or conjugate thereof) binds to a HTRA1 trimer with a stoichiometry of at least about 0.3: 1, at least about 0.7: 1, at least about 0.9: 1, or at least about 1: 1 of anti-HTRAl antibody to HTRA1 trimer. In some embodiments, the anti-HTRAl antibody (or conjugate thereof) binds to a HTRA1 trimer with a stoichiometry of at most about 6: 1, at most about 3: 1, at most about 1.5: 1, at most about 1.1 :1, or at most about 1 : 1 of anti-HTRAl antibody to HTRA1 trimer. In some embodiments, the anti-HTRAl antibody (or conjugate thereof) binds to a HTRA1 trimer with a stoichiometry in a range of about 0.3:1 to about 6: 1, about 0.7: 1 to about 3:1, about 0.7:1 to about 1.5:1, or about 0.9: 1 to about 1.1 :1, of anti-HTRAl antibody to HTRA1 trimer. In some embodiments, the anti-HTRAl antibody (or conjugate thereof) binds to a HTRA1 trimer with a stoichiometry of about 1 :1. The stoichiometry of binding can be determined using any suitable option, e.g., size exclusion chromatography.

[0194] An anti-HTRAl antibody (or a conjugate thereof) of the present disclosure can specifically bind HTRA1. In some embodiments, the anti-HTRAl antibody (or conjugate thereof) does not bind to one or more of HTRA2, HTRA3, HTRA4, e.g., as determined by kinetic analysis. In some embodiments, the anti-HTRAl antibody binds to HTRA1 with a higher affinity than to HTRA2, HTRA3, and / or HTRA4, e.g., as determined by kinetic analysis. In some embodiments, the anti-HTRAl antibody binds uniquely to HTRA1 (e.g., binds to HTRA1 and does not bind to HTRA2, HTRA3 and HTRA4), e.g., as determined by kinetic analysis. In some embodiments, HTRA1 has the amino acid sequence of SEQ ID NO: 1 or 756, or a fragment thereof, or the amino acid sequence of SEQ ID NO:756 without the signalpeptide (e.g., as shown underlined in Fig 19) or fragment thereof. In some embodiments, HTRA2 has the amino acid sequence of SEQ ID NO:757, or a fragment thereof, or the amino acid sequence of SEQ ID NO:757 without the signal peptide (e.g., as shown underlined in Fig. 19) or fragment thereof. In some embodiments, HTRA3 has the amino acid sequence of SEQ ID NO:5 or 758, or a fragment thereof, or the amino acid sequence of SEQ ID NO:758 without the signal peptide (e.g., as shown underlined in Fig 19) or fragment thereof. In some embodiments, HTRA4 has the amino acid sequence or a fragment of SEQ ID NO:759, or a fragment thereof, or the amino acid sequence of SEQ ID NO:759 without the signal peptide (e.g., as shown underlined in Fig. 19) or fragment thereof.

[0195] In some embodiments, the anti-HTRAl antibody (e.g., antagonistic anti- HTRA1 antibody) or conjugate thereof inhibits an enzymatic activity, e.g., protease activity, of HTRA1 when the antibody is bound thereto. In some embodiments, the anti-HTRAl antibody (or conjugate thereof) inhibits the protease activity of HTRA1. In some embodiments, the anti-HTRAl antibody (or conjugate thereof) inhibits HTRA1 protease activity by at least 10%, at least 20%, 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 about 100%, or by a percentage within a range defined by any two of the preceding values (e.g., 10-100%, 20-100%, 30-80%, 40- 80%, 50-90%, 85-99%, etc.). In some embodiments, percentage inhibition of HTRA1 protease activity is relative to a suitable control (e.g., a blank solution, a non-specific antibody, etc.). In some embodiments, the anti-HTRAl antibody (or conjugate thereof) inhibits the protease activity of HTRA1 with an IC50 of 1 x 10’9M or less, 5 x 10'10M or less, 2 x 10'10M or less, 1 x IO10M or less, 5 x 1011M or less, 2 x 1011M or less, 1 x 1011M or less, 5 x 1012M or less, 2 x IO’12M or less, or 1 x 10'12M or less, or with an IC50 in a range defined by any two of the preceding values (e.g., 1 x 10’9-1 x 10'12M, 5 x 10'10-1 x 10'12M, 2 x 10'10-2 x 10'12M, 1 x IO’10-2 x IO’12M, 1 x 10’11-5 x IO’12M, etc.).

[0196] In some embodiments, the anti-HTRAl antibody that inhibits or neutralizes HTRA1 function (e.g., antagonistic anti-HTRAl antibody) includes at least one of the VH / VL pairing as shown in Table 0.1. In some embodiments, the anti-HTRAl antibody that inhibits or neutralizes HTRA1 function (e.g., antagonistic anti-HTRAl antibody) includes at least the 3 CDRs of each of the VH and VL sequences in any one of the VH / VL pairing as shown in Table 0.1. In some embodiments, the anti-HTRAl antibody is derived from one or moreantagonistic anti-HTRAl antibodies as provided herein (e.g., by affinity maturation). In some embodiments, the anti-HTRAl antibody that inhibits or neutralizes HTRA1 function (e.g., antagonistic anti-HTRAl antibody) is derived from one or more parental antagonistic anti- HTRAl antibodies as provided herein (e.g., by affinity maturation).

[0197] In some embodiments, the anti-HTRAl antibody that inhibits or neutralizes HTRA1 function (e.g., antagonistic anti-HTRAl antibody) includes at least one of the following VH / VL pairing: HC4 / LC1, HC1 / LC1, HC7 / LC1, HC4 / LC3, HC4 / LC4, HC1 / LC3, HC7 / LC4, HC17 / LC21, HC37 / LC21, HC39 / LC21, HC40 / LC21, HC41 / LC21 (with reference to Figs. 22A, 22B, 24A, 24B). In some embodiments, the anti-HTRAl antibody that inhibits or neutralizes HTRA1 function (e.g., antagonistic anti-HTRAl antibody) includes a VH and VL amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to the corresponding VH and VL sequences in any one of the following VH / VL pairing: HC4 / LC1, HC1 / LC1, HC7 / LC1, HC4 / LC3, HC4 / LC4, HC1 / LC3, HC7 / LC4, HC17 / LC21, HC37 / LC21, HC39 / LC21, HC40 / LC21, HC41 / LC21 (with reference to Figs. 22A, 22B, 24A, 24B). In some embodiments, the anti-HTRAl antibody that inhibits or neutralizes HTRA1 function (e.g., antagonistic anti-HTRAl antibody) includes at least the 3 CDRs of each of the VH and VL sequences in any one of the following VH / VL pairing: HC4 / LC1, HC1 / LC1, HC7 / LC1, HC4 / LC3, HC4 / LC4, HC1 / LC3, HC7 / LC4, HC17 / LC21, HC37 / LC21, HC39 / LC21, HC40 / LC21, HC41 / LC21 (with reference to Figs. 22A, 22B, 24A, 24B).

[0198] In some embodiments, the anti-HTRAl antibody (e.g., antagonistic anti- HTRAl antibody) or conjugate thereof neutralizes (or reduces or inhibits) HTRA1 cleavage activity. In some embodiments, the anti-HTRAl antibody (or conjugate thereof) reduces HTRA1 cleavage activity by at least 10%, at least 20%, 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 about 100%, or by a percentage within a range defined by any two of the preceding values (e.g., 10-100%, 20- 100%, 30-80%, 40-80%, 50-90%, 85-99%, etc.). In some embodiments, the percentage reduction in HTRA1 cleavage activity is relative to a suitable control (e.g., a blank solution, a non-specific antibody, etc.). In some embodiments, the anti-HTRAl antibody (e.g.,antagonistic anti-HTRAl antibody) or conjugate thereof neutralizes (or reduces or inhibits) HTRA1 serine protease activity. In some embodiments, the anti-HTRAl antibody (or conjugate thereof) reduces HTRA1 serine protease activity by at least 10%, at least 20%, 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 about 100%, or by a percentage within a range defined by any two of the preceding values (e.g., 10-100%, 20-100%, 30-80%, 40-80%, 50-90%, 85-99%, etc.). In some embodiments, the percentage reduction in HTRA1 serine protease activity is relative to a suitable control (e.g., a blank solution, a non-specific antibody, etc.).

[0199] In some embodiments, an anti-HTRAl antibody (or conjugate thereof) that inhibits or neutralizes HTRA1 function (e.g., antagonistic anti-HTRAl antibody), and does not bind to the loop A peptide of HTRA1 includes a heavy chain variable region having at least one of the VH sequences of HC17, HC39, HC41 (with reference to Fig. 24A), and a light chain variable region having the VL sequence of LC21 (with reference to Fig. 24B). In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a VH sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VH sequences of HC17, HC39, HC41, and the anti-HTRAl antibody light chain variable region includes a VL sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to the VL sequences of LC21. In some embodiments, the anti-HTRAl antibody heavy chain variable region includes a VH sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the VH sequences of HC17, HC39, HC41, where any variation (e.g., substitution, deletion) within the amino acid sequence of the VH of the anti-HTRAl antibody from any one of the VH sequences of HC17, HC39, HC41 is in no more than 5, 4, 3, 2, or 1 residue of, or is not within, a CDR of the VH sequence, and the anti- HTRAl antibody light chain variable region includes a VL sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%,or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80- 100%, 85-99%, 90-97%, 95-100%, etc.), identical to the VL sequences of LC21, where any variation (e.g., substitution, deletion) within the amino acid sequence of the VL of the anti- HTRA1 antibody from the VL sequences of LC21 is in no more than 5, 4, 3, 2, or 1 residue of, or is not within, a CDR of the VL sequence.

[0200] Inhibition of HTRA1 enzymatic activity (e.g., serine protease activity) or cleavage activity can be measured using any suitable option. In some embodiments, inhibition of HTRA1 enzymatic activity by an anti-HTRAl antibody or conjugate thereof of the present disclosure is measured using an H2-Opt assay, as provided herein. In some embodiments, the substrate for the H2-Opt assay has the amino acid sequence Mca-Ile-Arg-Arg-VaLSer-Tyr- Ser-Phe-Lys(Dnp)-Lys-OH (SEQ ID NO:750), where Mca is 7-methoxycoumarin-4-acetic acid and Dnp is N-dinitrophenyldiaminopropionic acid. In some embodiments, the anti- HTRAl antibody or conjugate thereof inhibits casein digestion by HTRA1 when the antibody is bound thereto. In some embodiments, inhibition of HTRA1 enzymatic activity by an anti- HTRAl antibody or conjugate thereof of the present disclosure is measured using a casein digestion assay, as provided herein.

[0201] In some embodiments, the HTRA1 neutralizing activity of the antibody is not substantially affected by the presence of a polymer covalently bonded to the antibody, as provided herein. In some embodiments, the antibody conjugate inhibits the enzymatic activity, e g., protease activity, of HTRA1 when the antibody conjugate is bound thereto as well as the antibody does when the unconjugated antibody is bound to HTRA1. In some embodiments, the antibody conjugate retains at least 20% HTRA1 neutralizing activity relative to unconjugated antibody. In some embodiments, the antibody conjugate retains at least 50% HTRA1 neutralizing activity relative to unconjugated antibody. In some embodiments, the antibody conjugate retains at least 90% HTRA1 neutralizing activity relative to unconjugated antibody. In some embodiments, the antibody conjugate retains at least 95% HTRA1 neutralizing activity relative to unconjugated antibody. In some embodiments, the antibody conjugate retains about 100% HTRA1 neutralizing activity relative to unconjugated antibody.

[0202] In some embodiments, the HTRA1 neutralizing activity of the antibody is not substantially affected by exposure to changes in pH, e.g., low pH. In some embodiments, the anti-HTRAl antibody substantially retains HTRA1 neutralizing activity after being treatedwith a lower pH, such as a pH of about 6.5 or lower, about 6.0 or lower, about 5.5 or lower, about 5.0 or lower, about 4.5 of lower, about 4.0 or lower, about 3.7 or lower, about 3.5 or lower, or about 3.4, and / or a pH of about 3.0 or higher, about 3.2 or higher, about 3.3 or higher, or a pH in a range defined by any two of the preceding values (e.g., pH 3.0-6.5, pH 3.0-5.5, pH 3.2-4.5, pH 3.0-4.0, pH 3.2-3.7). In some embodiments, the anti-HTRAl antibody substantially retains HTRA1 neutralizing activity after being treated with a lower pH (e.g., about pH 3.4) for about 30 minute or more, about 1 hour or more, about 1.5 hours or more, about 2 hours or more, about 2.5 hours or more, about 3 hours of more, about 3.5 hours or more, about 4 hours or more, and / or for about 6 hours or less, about 5.5 hours or less, about 5 hours or less, or about 4.5 hours or less, or by time interval in a range defined by any two of the preceding values (e.g., 0.5-6 hours, 1-5.5 hours, 2-5 hours, 2.5-4.5 hours, 1.5-4.5 hours, etc ). In some embodiments, at least about 50%, about 60%, about 70%, about 80%, about 85%, about 90%, about 95% or more, or a percentage in a range defined by any two of the preceding values (e.g., 50-95%, 60-90%, 70-85%, 70-95%, etc.) of the HTRA1 neutralizing activity of the anti-HTRAl antibody is retained after being treated with a lower pH (e.g., about pH 3.4).

[0203] An anti-HTRAl antibody of the present disclosure can be generated using any suitable option. Provided herein is an antibody that binds to HTRA1, e.g., human HTRA1, generated by immunizing a host animal, e.g., a mouse or rat, with a human HTRA1 protein, e g., with a human HTRA1 protease domain. In some embodiments, the antibody that binds to HTRA1, e.g., human HTRA1, of the present disclosure is generated by at least screening / selecting clones (e.g., clonal antibody-secreting cell lineages) from the immunized animal based on binding characteristics of the antibodies produced by the clones to a human HTRA1 N-terminal truncation (HTRA1 PD / PDZ), HTRA1 loop A, and / or HTRA3. In some embodiments, an antibody that binds to HTRA1, e.g., human HTRA1, of the present disclosure is obtained by at least screening / selecting for a clone that binds to a human HTRA1 N-terminal truncation (HTRA1 PD / PDZ) and / or binds to or does not bind to a HTRA1 loop A and / or does not bind HTRA3. An anti-HTRAl antibody of the present disclosure can be obtained by at least screening / selecting antibodies produced by clones from the immunized animals based on one or more of the following properties:1. Binding to human HTRA1 (e.g., a human HTRA1 N-terminal truncation (HTRA1 PD / PDZ));2. Inhibition of HTRA1 proteolytic activity;3. Binding affinity for HTRA1 loop A;4. Binding affinity for HTRA3 ;5. Relative binding affinity to trimeric HTRA1 and monomeric HTRA1;6. Stoichiometry of binding to HTRA1.

[0204] In some embodiments, an anti-HTRAl antibody of the present disclosure is obtained by at least further carrying out affinity maturation of antibodies identified by screening or selecting for clones, as provided herein.

[0205] In some embodiments, the anti-HTRAl antibody is a humanized antibody. In some embodiments, the anti-HTRAl antibody includes at least a humanized antibody. In some embodiments, an antibody conjugate of the present disclosure includes an anti-HTRAl antibody that is humanized. In some embodiments, the anti-HTRAl antibody includes a heavy chain variable domain including a framework region (HFR) 1, HFR2, HFR3, and HFR4 each having an amino acid sequence as set forth in Table 0.13, or with a variation (e.g., substitution, deletion) at no more than 6 (e.g., no more than 5, no more than 4, no more than 3, no more than 2, no more than 1) residues in each of the HFR1, HFR2, HFR3, and HFR4. In some embodiments, the anti-HTRAl antibody includes a light chain variable domain including a framework region (LFR) 1, LFR2, LFR3, and LFR4 each having an amino acid sequence as set forth in Table 0.13, with a variation (e.g., substitution, deletion) at no more than 6 (e.g., no more than 5, no more than 4, no more than 3, no more than 2, no more than 1) residues in each of the LFR1, LFR2, LFR3, and LFR4.Table 0.13

[0206] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) includes a light chain and a heavy chain where the heavy chain has an Fc region. In some embodiments, the anti-HTRAl heavy chain isotype is IgGl. In some embodiments, the IgGl constant region has one or more mutations relative to a native IgGl constant region to modulate effector function. In some embodiments, the effector function mutations are one or more of the following: (EU numbering) E233X, L234X, L235X, G236X, G237X, A327X, A330X, and P33 IX wherein X is any natural or unnatural amino acid. In some embodiments, the effector function mutations are one or more of the following: (EU numbering) L234X, L235X, and G237X, wherein X is any natural or unnatural amino acid. In some embodiments, the mutations are selected from the group consisting of (EU numbering): E233P, L234V, L234A, L235A, G237A, A327G, A330S, and P331 S. In some embodiments, the mutations are selected from the group consisting of (EU numbering): L234A, L235A, and G237A. In some embodiments, antibody conjugate has the following mutations (EU numbering): L234A, L235A, and G237A.

[0207] Alternatively, the IgG domain can be IgG2, IgG3 or IgG4 or a composite in which a constant regions is formed from more than one of these isotypes (e.g., CHI region from IgG2 or IgG4, hinge, CH2 and CH3 regions from IgGl). Such domains can contain mutations to reduce and / or modulate effector function at one or more of the EU position mentioned for IgGl . Human IgG2 and IgG4 have reduced effector functions relative to human IgGl and IgG3.

[0208] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) includes a heavy chain variable region having framework regions (e.g., HFR1, HFR2, HFR3, HFR4) each independently having an amino acid sequence at least 80%, e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95- 100%, etc.), identical to the corresponding framework regions of SEQ ID NOs:544-547. In some embodiments, the anti-HTRAl antibody (or conjugate thereof) includes a heavy chainhaving constant regions (e.g., CHI , CH2, CH3, FC), each independently having an amino acid sequence at least 80%, e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.) identical to the corresponding constant regions of SEQ ID NO:536.

[0209] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) includes a light chain variable region having framework regions (e.g., LFR1, LFR2, LFR3, LFR4) each independently having an amino acid sequence at least 80%, e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95- 100%, etc.) identical to the corresponding framework regions of SEQ ID NOs:548-551. In some embodiments, the anti-HTRAl antibody (or conjugate thereof) includes a light chain having a constant region having an amino acid sequence at least 80%, e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or about 100%, or a percentage in a range defined by any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95- 100%, etc.) identical to the constant region of SEQ ID NO:537.

[0210] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) includes a non-native cysteine residue outside a variable region of the antibody. In some embodiments, the cysteine is in the Fc region and the anti-HTRAl antibody is an immunoglobulin G (IgG). In some embodiments, the anti-HTRAl antibody has a cysteine outside a variable region of the antibody covalently bonded to a phosphorylcholine containing polymer, where the cysteine has been added via recombinant DNA technology (e.g., is nonnative). In some embodiments, cysteine residue is in the anti-HTRAl heavy chain and is Q347C (EU numbering) or L443C (EU numbering). In some embodiments, the cysteine residue is L443C (EU numbering). In some embodiments, “added by recombinant DNA technology” means that the cysteine residue replaces a non-cysteine amino acid that occurs in the same position in a known or existing antibody or in a consensus antibody sequence or a native sequence. Thus, for example where the antibody is an IgGl and the heavy chain possess a leucine at EU position 443, the leucine is replaced via recombinant DNA technology with a cysteine (L443C, EU numbering). Correspondingly, the native IgGl sequence at EU position347 is Q (glutamine) and the Q is replaced with cysteine via recombinant DNA technology to yield Q347C.

[0211] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) includes a heavy chain constant region (HC) having an amino acid sequence of SEQ ID NO 536 (as provided in Table 0.14), and the anti-HTRAl antibody includes a light chain constant region (LC) having an amino acid sequence of SEQ ID NO:537 (as provided in Table 0.14). In some embodiments, the anti-HTRAl antibody (or conjugate thereof) includes a heavy chain constant region (HC) having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined any two of the preceding values (e.g., 80-100%, 85-99%, 90- 97%, 95-100%, etc.), identical to SEQ ID NO: 536 (as provided in Table 0.14). In some embodiments, the anti-HTRAl antibody includes a light chain constant region (LC) having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to SEQ ID NO:537 (as provided in Table 0.14). In some embodiments, the anti-HTRAl antibody (or conjugate thereof) includes a heavy chain constant region (HC) having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to SEQ ID NO:536 (as provided in Table 0.14), and the anti-HTRAl antibody includes a light chain constant region (LC) having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to SEQ ID NO:537 (as provided in Table 0.14).Table 0.14

[0212] In some embodiments, the anti-HTRAl antibody (or conjugate thereof) includes a heavy chain having an amino acid sequence as provided in any one of SEQ ID NOs: 819-823 (Fig. 25 A), and a light chain having an amino acid sequence as provided in SEQ ID NO:824 (Fig. 25B). In some embodiments, the anti-HTRAl antibody (or conjugate thereof) includes a heavy chain having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined any two of the preceding values (e g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the heavy chain sequences as provided in any one of SEQ ID NOs:819-823 (Fig. 25A), and a light chain having an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to any one of the heavy chain sequences as provided in SEQ ID NO: 824 (Fig. 25B).

[0213] Also provided are antibody conjugates that includes: any one of the anti- HTRAl antibodies as disclosed herein; and a polymer covalently bonded to the antibody at a non-native cysteine outside a variable region of the antibody. In some embodiments, the polymer is a phosphorylcholine containing polymer. In some embodiments, the polymer is bonded to a single cysteine in the antibody. In some embodiments, the antibody is conjugated with a poly(acryloyloxyethyl phosphorylcholine) containing polymer, such as a polymer of acrylic acid containing at least one acryloyloxyethyl phosphorylcholine monomer such as 2- methacryloyloxyethyl phosphorylcholine (i.e., 2-methacryloyl-2'-trimethylammonium ethyl phosphate).

[0214] In some embodiments, the polymer is a water-soluble polymer, which refers to a polymer that is soluble in water. A solution of a water-soluble polymer may transmit at least about 75%, more preferably at least about 95% of light, transmitted by the same solutionafter filtering. On a weight basis, a water-soluble polymer or segment thereof may be at least about 35%, at least about 50%, about 70%, about 85%, about 95% or 100% (by weight of dry polymer) soluble in water.

[0215] In some embodiments, the polymer has at least 2 or 3 or more arms. In some embodiments, the polymer has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 arms. In some embodiments, the polymer has 3, 6 or 9 arms. In some embodiments, the polymer has 9 arms. In some embodiments, the polymer peak molecular weight is between 300,000 and 1,750,000 Da. In some embodiments, the polymer has a peak molecular weight between 500,000 and 1,000,000 Da. In some embodiments, the polymer has a peak molecular weight between 600,000 to 800,000 Da.

[0216] In some embodiments, the polymer has a peak molecular weight between 300,000 and 1,750,000 Daltons as measured by size exclusion chromatography - multi angle light scattering (hereinafter “SEC-MALS”). In some embodiments, the polymer has a peak molecular weight between 500,000 and 1,000,000 Daltons as measured by SEC-MALS. In some embodiments, the polymer has a peak molecular weight between 600,000 to 800,000 Daltons as measured by SEC-MALS.

[0217] In accordance with another aspect of the present invention, provided are methods for synthesizing zwitterionic polymer-trap-antibody fusion conjugates, the conjugate having one or more functional agents and one or more polymer arms wherein each of the polymer arms has one or more monomer units wherein at least one of the units has a zwitterion. For example, such a method can have the steps of: providing an initiator having one or more sites for monomer polymerization and a first linker having an amine group wherein the initiator is a trifluoro acetic acid salt; providing one or more monomers suitable for polymerization wherein at least one of the monomers is zwitterionic; reacting the monomers with the initiator to form one or more polymer arms each corresponding to the sites for monomer polymerization to provide an initiator-polymer conjugate having the first linker with the amine group; providing a second linker having at least second and third reactive groups; coupling one of the second and third reactive groups of the second linker to the amine group of the first linker of the initiator-polymer conjugate to provide a linker-initiator-polymer conjugate having one or more reactive groups that were not used in the coupling step; and coupling one or morefunctional agents to one or more of the unreacted reactive groups of the 1 inker-ini ti at or- polymer moiety to provide the polymer-functional agent conjugate.

[0218] In some embodiments, the conjugation group (e.g. maleimide) is added after polymer synthesis. This is sometimes referred to as a “snap-on strategy” or “universal polymer strategy”. See, e.g., U.S. Patent Application No. 14 / 916,180 (published as U.S. Patent Application Publication No. 20160199501), hereby incorporated by reference in its entirety. In some embodiments, a single initiator moiety can be used for large scale polymer synthesis. Thus, conditions can be developed for scaled up optimal polymer synthesis. Such polymers can then be adapted to various types of functional agents by “snapping-on” various types of linkers. For example, if it is desired to conjugate a larger functional agent to a polymer of the present invention such as an antibody of even a Fab fragment, a longer linker sequence can be snapped on to the polymer. In contrast, smaller functional agents may call for relatively shorter linker sequences.

[0219] In some embodiments of the methods, the initiator has about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 sites for polymer initiation. In some embodiments, the initiator has about 3, about 6, or about 9 sites for polymer initiation.

[0220] In accordance with another aspect of the present invention, a second linker has second, third, fourth, fifth, and sixth reactive groups. More preferably, a second linker has just second and third reactive groups.

[0221] In accordance with an aspect of the present disclosure, each polymer arm has from about 20 to about 2000 monomer units. Preferably, each arm has from about 100 to 500 monomer units or from about 500 to 1000 monomer units or from about 1000 to 1500 monomer units or from about 1500 to 2000 monomer units.

[0222] In accordance with an aspect of the present disclosure, the peak molecular weight of the polymer-functional agent conjugate is about 100,000 to 1,500,000 Da. Preferably, the peak molecular weight of the polymer-functional agent conjugate is about 200,000 to about 300,000 Da, about 400,000 to about 600,000 Da or about 650,000 to about 850,000 Da.

[0223] In accordance with another aspect of the present disclosure, the first linker is preferably alkyl, substituted alkyl, alkylene, alkoxy, carboxyalkyl, haloalkyl, cycloalkyl, cyclic alkyl ether, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkylene, heterocycloalkyl,heterocycloalkylene, aryl, arylene, arylene-oxy, heteroaryl, amino, amido or any combination thereof. More preferably, the first linker has the formula:Formula (1) wherein m is 1 to 10. In some embodiments, the first linker has the above formula (Formula (1)) and m is 4.

[0224] In some embodiments, the initiator preferably includes a structure selected from group consisting ofFormula (4)wherein X is selected from the group consisting of NCS, F, Cl, Br and T. More preferably, X in Formula (2), Formula (3) and / or Formula (4) is Br.

[0225] In some embodiments, the monomer is selected from the group consisting ofFormula (5)Formula (6)Formula (7)Formula (8), andFormula (9) wherein R7 is H or Cl -6 alkyl and t is 1 to 6.

[0226] More preferably, the monomer is selected from the group consisting of 2- (methacryloyloxyethyl)-2’ -(trimethylammonium ethyl) phosphate (HEMA-PC) and 2- (acryloyl oxy ethyl)-2’ -(trimethylammoniumethyl) phosphate.

[0227] Most preferably, the monomer is 2-(methacryloyloxyethyl)-2’- (trimethylammoniumethyl) phosphate.

[0228] The second linker moiety preferably comprises an activated ester having the structureFormula (10) wherein R8 is selected from the group consisting ofFormula (11) wherein p is 1 to 12.

[0229] In more preferred embodiments of the present invention, the polymer has 9 arms, m is 2-4, R9 isFormula (11) wherein p is 4 to 15. Still more preferably, m is 4 and p is 12.

[0230] In some embodiments, the radically polymerizable monomer isFormula (12) wherein R1 is H or Cl -6 alkyl, R2, R3, R4 are the same or different and are H or Cl- 4alkyl and X and Y are the same or different and are integers from 1-6. In some embodiments, Rl, R2, R3 and R4 are each methyl and X and Y are each 2 in Formula (12).

[0231] In some embodiments, the radically polymerizable monomer isFormula (13) wherein Rl is H or Cl-6alkyl, R2 and R3 are the same or different and are H or Cl- 4alkyl, R4 is PO4-, SO3- or CO2- and X and Y are the same or different and are integers from1-6. In some embodiments, Rl , R2 and R3 are methyl, R4 is PO4- and X and Y are each 2 inFormula (13).

[0232] In some embodiments, the monomer isFormula (14) wherein R1 is H or Cl-6alkyl, R2, R3 and R4 are the same or different and are H or Cl-4alkyl, R5 is PO4-, SO3- or CO2- and X and Y are the same or different and are integers from 1-6. In some embodiments, Rl, R2, R3 and R4 are methyl, R5 is PO4- and X and Y are 2 in Formula (14).

[0233] When a polymer is to be conjugated via a cysteine (or other specified residue), the polymer can be linked directly or indirectly to the residue (e.g., with an intervening initiator, and or spacer or the like).

[0234] In some embodiments, the phosphorylcholine containing polymer comprises 2-(methacryloyloxyethyl)-2'-(trimethylammonium)ethyl phosphate (MPC) monomers as set forth below:Formula (15) such that the polymer comprises the following repeating units:Formula (16) where n is an integer from 1 to 3000 and the wavy lines indicate the points of attachment between monomer units in the polymer.

[0235] In some embodiments, the polymer has three or more arms, or is synthesized with an initiator comprising 3 or more polymer initiation sites. In some embodiments, the polymer has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 arms, oris synthesized with an initiator comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 polymer initiation sites. More preferably, the polymer has 3, 6, or 9 arms, or is synthesized with an initiator comprising 3, 6, or 9 polymer initiation sites.In some embodiments, the polymer has 9 arms, or is synthesized with an initiator comprising 9 polymer initiation sites.

[0236] In some embodiments, the polymer of the antibody conjugate has a molecular weight between about 300,000 and about 1,750,000 Da (SEC-MALs). In some embodiments, the polymer has a molecular weight between about 500,000 and about 1,000,000 Da. In some embodiments, the polymer has a molecular weight of between about 600,000 to about 900,000 Da. In some embodiments, the polymer has a molecular weight of between about 750,000 to about 850,000 Da. In some embodiments, the polymer has a molecular weight of between about 800,000 to about 850,000 Da. In some embodiments, the polymer has a molecular weight of between about 750,000 to about 800,000 Da.

[0237] In some embodiments, any of the antibodies described herein can be further conjugated to a polymer to form a bioconjugate or antibody conjugate. The molecular weight of the bioconjugate or antibody conjugate (in total, SEC-MALs) can be between about 350,000 and 2,000,000 Daltons, for example, between about 450,000 and 1,900,000 Daltons, between about 550,000 and 1,800,000 Daltons, between about 650,000 and 1,700,000 Daltons, between about 750,000 and 1,600,000 Daltons, between about 850,000 and 1,500,000 Daltons, between about 900,000 and 1,400,000 Daltons, between about 950,000 and 1,300,000 Daltons, between about 900,000 and 1,000,000 Daltons, between about 1,000,000 and 1,300,000 Daltons, between about 850,000 and 1,300,000 Daltons, between about 850,000 and 1,000,000 Daltons, and between about 1,000,000 and 1,200,000 Daltons.

[0238] In some embodiments, the antibody conjugate is purified. In some embodiments, the polymer is aspect of the antibody conjugate is polydisperse, i.e. the polymer PDI is not 1.0. In some embodiments, the PDI is less than 1.5. In some embodiments, the PDI is less than 1.4. In some embodiments, the PDI is less than 1.3. In some embodiments the PDI is less than 1.2. In some embodiments the PDI is less than 1.1.

[0239] Also provided herein is an antibody conjugate comprising an anti-HTRAl immunoglobulin G (IgG) bonded to a polymer, which polymer comprises MPC monomers, wherein the anti-HTRAl antibody heavy chain comprises: a heavy chain variable region (VH) comprising an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined any two of the preceding values (e g., 80-100%, 85-99%, 90-97%, 95-100%, etc ), identical to anyone of SEQ ID NOs: 725, 742, 744, 745, 746, C-terminally fused to a heavy chain constant region (HC) comprising an amino acid sequence of SEQ ID NO: 536, wherein the polymer is bonded to C326 of SEQ ID NO:536 (as provided in Table 0.14), and wherein the anti-HTRAl antibody light chain comprises: a light chain variable region (VL) comprising an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined any two of the preceding values (e.g., 80-100%, 85-99%, 90-97%, 95-100%, etc.), identical to SEQ ID NO: 748, C-terminally fused to a light chain constant region (LC) comprising an amino acid sequence of SEQ ID NO:537 (as provided in Table 0.14).

[0240] In some embodiments, the antibody conjugate has an anti-HTRAl immunoglobulin G (IgG) bonded to a polymer, which polymer comprises MPC monomers, wherein the sequence of the anti-HTRAl heavy chain includes a VH sequence of at least one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, or a sequence at least 80% identical thereto, and the sequence of the anti-HTRAl light chain includes a VL sequence of at least one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and8.2, or a sequence at least 80% identical thereto, and wherein the antibody is bonded only at C443 (EU numbering) to the polymer. In some embodiments, the antibody conjugate has an anti-HTRAl immunoglobulin G (IgG) bonded to a polymer, which polymer comprises MPC monomers, wherein the sequence of the anti-HTRAl heavy chain includes a VH sequence at least 85% to any one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, and the sequence of the anti-HTRAl light chain includes a VL sequence at least 85% to any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, and wherein the antibody is bonded only at C443 (EU numbering) to the polymer. In some embodiments, the antibody conjugate has an anti-HTRAl immunoglobulin G (IgG) bonded to a polymer, which polymer comprises MPC monomers, wherein the sequence of the anti-HTRAl heavy chain includes a VH sequence at least 90% to any one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, and the sequence of the anti-HTRAl light chain includes a VL sequence at least 90% to any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13,7.18, and 8.2, and wherein the antibody is bonded only at C443 (EU numbering) to the polymer. In some embodiments, the antibody conjugate has an anti-HTRAl immunoglobulin G (IgG) bonded to a polymer, which polymer comprises MPC monomers, wherein the sequence of the anti-HTRAl heavy chain includes a VH sequence at least 95% to any one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, and the sequence of the anti-HTRAl light chain includes a VL sequence at least 95% to any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, and wherein the antibody is bonded only at C443 (EU numbering) to the polymer. In some embodiments, the antibody conjugate has an anti-HTRAl immunoglobulin G (IgG) bonded to a polymer, which polymer comprises MPC monomers, wherein the sequence of the anti-HTRAl heavy chain includes a VH sequence at least 97% to any one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, and the sequence of the anti-HTRAl light chain includes a VL sequence at least 97% to any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, and wherein the antibody is bonded only at C443 (EU numbering) to the polymer. In some embodiments, the VH and VL sequences of the antibody conjugate are paired according to any one of the paired arrangements provided in FIG. 21 and Tables 0.1, 0.4, 0.5, 0.7, 0.10, 0.11, 0.12, 1.2, 6.3, and 7.1. In some embodiments, the polymer has 9 arms and has a molecular weight of between about 600,000 to about 1,000,000 Da.

[0241] In some embodiments, the antibody conjugate has an anti-HTRAl immunoglobulin G (IgG) bonded to a polymer, which polymer comprises MPC monomers, wherein the sequence of the anti-HTRAl heavy chain includes a VH sequence of at least one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1,7.4, 7.7, 7.12, 7.17, and 8.1, or a sequence at least 80% identical thereto, where any sequence variation from the VH sequence provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3,6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1 is not within a CDR of the VH sequence, and the sequence of the anti-HTRAl light chain includes a VL sequence of at least one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, or a sequence at least 80% identical thereto, where any sequence variation from the VL sequence provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13,7.18, and 8.2 is not within a CDR of the VL sequence, and wherein the antibody is bonded only at C443 (EU numbering) to the polymer. In some embodiments, the antibody conjugate has an anti-HTRAl immunoglobulin G (IgG) bonded to a polymer, which polymer comprises MPC monomers, wherein the sequence of the anti-HTRAl heavy chain includes a VH sequence at least 85% to any one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, where any sequence variation from the VH sequence provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1 is not within a CDR of the VH sequence, and the sequence of the anti-HTRAl light chain includes a VL sequence at least 85% to any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and8.2, where any sequence variation from the VL sequence provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2 is not within a CDR of the VL sequence, and wherein the antibody is bonded only at C443 (EU numbering) to the polymer. In some embodiments, the antibody conjugate has an anti-HTRAl immunoglobulin G (IgG) bonded to a polymer, which polymer comprises MPC monomers, wherein the sequence of the anti-HTRAl heavy chain includes a VH sequence at least 90% to any one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and8.1, where any sequence variation from the VH sequence provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1 is not within a CDR of the VH sequence, and the sequence of the anti-HTRAl light chain includes a VL sequence at least 90% to any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2,6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, where any sequence variation from the VL sequence provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2 is not within a CDR of the VL sequence, and wherein the antibody is bonded only at C443 (EU numbering) to the polymer. In some embodiments, the antibody conjugate has an anti- HTRAl immunoglobulin G (IgG) bonded to a polymer, which polymer comprises MPC monomers, wherein the sequence of the anti-HTRAl heavy chain includes a VH sequence at least 95% to any one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, where any sequence variation from the VH sequence provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1 is not within a CDR of the VH sequence, and the sequence of the anti-HTRAllight chain includes a VL sequence at least 95% to any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, where any sequence variation from the VL sequence provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2 is not within a CDR of the VL sequence, and wherein the antibody is bonded only at C443 (EU numbering) to the polymer. In some embodiments, the antibody conjugate has an anti-HTRAl immunoglobulin G (IgG) bonded to a polymer, which polymer comprises MPC monomers, wherein the sequence of the anti- HTRAl heavy chain includes a VH sequence at least 97% to any one of the VH sequences provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, where any sequence variation from the VH sequence provided in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1 is not within a CDR of the VH sequence, and the sequence of the anti-HTRAl light chain includes a VL sequence at least 97% to any one of the VL sequences provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, where any sequence variation from the VL sequence provided in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2 is not within a CDR of the VL sequence, and wherein the antibody is bonded only at C443 (EU numbering) to the polymer. In some embodiments, the VH and VL of the antibody conjugate include CDRs of the corresponding CDRs in are paired according to at least one of the paired arrangements provided in FIG. 21 and Tables 0.1, 0.4, 0.5, 0.7, 0.10, 0.11, 0.12, 1.2, 6.3, and 7.1. In some embodiments, the polymer has 9 arms and has a molecular weight of between about 600,000 to about 1,000,000 Da.

[0242] In some embodiments, the antibody conjugate has the structure of Formula (I):Formula (I) wherein: each heavy chain of the anti-HTRAl antibody is denoted by the letter H, and each light chain of the anti-HTRAl antibody is denoted by the letter L; the polymer is bonded to the anti-HTRAl antibody through the sulfhydryl of C443 (EU numbering), which bond isdepicted on one of the heavy chains; PC is, where the curvy line indicates the point of attachment to the rest of the polymer; wherein X is a) -OR where R is - H, Methyl, ethyl, propyl, isopropyl, b) H, or c) any halogen, including -Br, -Cl, or -I; and either i) nl, n2, n3, n4, n5, n6, n7, n8 and n9 are the same or different and are integers from 0 to 3000; or ii) nl, n2, n3, n4, n5, n6, n7, n8 and n9 are the same or different such that the sum of nl, n2, n3, n4, n5, n6, n7, n8 and n9 is 2500 plus or minus 15%. In some embodiments, thesum of nl, n2, n3, n4, n5, n6, n7, n8 and n9 is about 1500 to about 3500 plus or minus about 10% to about 20%. In some embodiments, X is -OR, where R is a sugar, an aminoalkyl, monosubstituted, poly-substituted or unsubstituted variants of the following residues: saturated Ci - C24 alkyl, unsaturated C2 -C24 alkenyl or C2 -C24 alkynyl, acyl, acyloxy, alkyloxycarbonyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, arylalkoxy carbonyl, alkoxy carbonylacyl, amino, aminocarbonyl, aminocarboyloxy, nitro, azido, phenyl, hydroxy, alkylthio, arylthio, oxysulfonyl, carboxy, cyano, and halogenated alkyl including polyhalogenated alkyl, — CO— O— R7, carbonyl — CCO— R7, — CO— NRsR9, — (CH2)n- -COOR7, — CO— (CH) n-COOR?, — (CH2) n-NR8R9, ester, alkoxycarbonyl, aryloxycarbonyl, wherein n is an integer from 1 to 6, wherein each R7, Rs and R9 is separately selected from the group consisting of a hydrogen atom, halogen atom, mono-substituted, poly-substituted or unsubstituted variants of the following residues: saturated Ci- C24 alkyl, unsaturated C2 -C24 alkenyl or C2- C24 alkynyl, acyl, acyloxy, alkyloxycarbonyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, arylalkoxy carbonyl, alkoxy carbonylacyl, amino, aminocarbonyl, aminocarboyloxy, nitro, azido, phenyl, hydroxy, alkylthio, arylthio, oxysulfonyl, carboxy, cyano, and halogenated alkyl including poly halogenated alkyl, a 5-membered ring, and a 6-membered ring.

[0243] In some embodiments, the antibody conjugate has the structure of Formula(II):Formula (II) wherein:“n.” is an integer from 1 to 50 and “n.i” is an integer from 1 to 50; each heavy chain of the anti-HTRAl antibody is denoted by the letter H, and each light chain of the anti-HTRAl antibody is denoted by the letter L; the polymer is bonded to the anti- HTRAl antibody through the sulfhydryl of C443 (EU numbering), which bond is depicted onone of the heavy chains; PC is, where the curvy line indicates the point of attachment to the rest of the polymer; wherein X is a) -OR where R is -H, Methyl, ethyl, propyl, isopropyl, b) H, or c) any halogen, including -Br, -Cl, or -I; and either i) nl , n2, n3, n4, n5, n6, n7, n8 and n9 are the same or different and are integers from 0 to 3000; or ii)nl, n2, n3, n4, n5, n6, n7, n8 and n9 are the same or different such that the sum of nl , n2, n3, n4, n5, n6, n7, n8 and n9 is 2500 plus or minus 15%. In some embodiments, the sum of nl, n2, n3, n4, n5, n6, n7, n8 and n9 is about 1500 to about 3500 plus or minus about 10% to about 20%.

[0244] In some embodiments, the polymers disclosed herein can comprise one or more of the following: a zwitterion, a phosphoryl choline, or a PEG linker bridging a center of a polymer branching point to the maleimide functional group. In some embodiments, any of the polymers provided herein can be added to a protein via the methods provided herein.

[0245] In some embodiments, the half-life of the anti-HTRAl antibodies is extended by attachment of a “half-life (“half life”) extending moieties” or “half-life (“half life”) extending groups”. Half-life extending moieties include peptides and proteins which can be expressed in frame with the biological drug of issue (or conjugated chemically depending on the situation) and various polymers which can be attached or conjugated to one or more amino acid side chain or end functionalities such as -SH, -OH, -COOH, -CONH2, -NH2, or one or more N- and / or O-glycan structures. Half-life extending moieties generally act to increase the in vivo circulatory half-life of biologic drugs.

[0246] Suitable peptide / protein half-life extending moieties include, without limitation, Fc fusion, human serum albumin (HAS) fusion, carboxy terminal peptide (CTP) fusion, genetic fusion of non-exact repeat peptide sequence (XTEN) fusion, elastin like peptide (ELPylation) (MCpherson DT, Morrow C, Minehan DS, et al. Production and purification of a recombinant elastomeric polypeptide, G-(VPGVG)19-VPGV, from Escheriachia coli, human transferrin fusion, proline-alanine-serine (PASylation), homo-amino acid polymer (HAPylation) and gelatin like protein (GLK) fusion.

[0247] Examples of polymer half-life extending moieties include polyethylene glycol (PEG), branched PEG, PolyPEG® (Warwick Effect Polymers; Coventry, UK), polysialic acid (PSA), starch, hydroxylethyl starch (HES), hydroxyalkyl starch (HAS), carbohydrate, polysaccharides, pullulane, chitosan, hyaluronic acid, chondroitin sulfate, dermatan sulfate, dextran, carboxymethyl-dextran, polyalkylene oxide (PAO), polyalkylene glycol (PAG), polypropylene glycol (PPG), polyoxazoline, polyacryloylmorpholine, polyvinyl alcohol (PVA), polycarboxylate, polyvinylpyrrolidone, polyphosphazene, polyoxazoline, polyethylene-co-maleic acid anyhydride, polystyrene-co-maleic acid anhydride, poly(l-hydroxymethyethylene hydroxymethylformal) (PHF), a zwitterionic polymer, a phosphorylcholine containing polymer and a polymer comprising MPC, Poly (Glyx-Sery), Hyaluronic acid (HA), Heparosan polymers (HEP), Fleximers, Dextran, and Poly-sialic acids (PSA).

[0248] In one embodiment a half-life extending moiety can be conjugated to an antibody via free amino groups of the protein using N-hydroxysuccinimide (NHS) esters. Reagents targeting conjugation to amine groups can randomly react to c-amine group of lysines, a-amine group of N-terminal amino acids, and 5-amine group of histidines.

[0249] In some embodiments, a half-life extending moiety is coupled to one or more free SH groups using any appropriate thiol -reactive chemistry including, without limitation, maleimide chemistry, or the coupling of polymer hydrazides or polymer amines to carbohydrate moieties of the antibody after prior oxidation. In some embodiments maleimide coupling is used. In some embodiments, coupling occurs at cysteines naturally present or introduced via genetic engineering.

[0250] In some embodiments, a polymer is covalently attached to a cysteine residue introduced into anti-HTRAl antibodies by site directed mutagenesis, or to a non-native cysteine. In some embodiments, the cysteine residue is employed in the Fc portion of the antibody. In some embodiments, the non-native cysteine residue is in the Fc portion of the antibody. In some embodiments, the sites to introduce cysteine residues into an Fc region are provided in WO 2013 / 093809, US 7,521,541, WO 2008 / 020827, US 8,008,453, US 8,455,622 and US2012 / 0213705, incorporated herein by reference for all purposes. In some embodiments, the cysteine mutations are Q347C (EU numbering) and L443C referring to the human IgG heavy chain by EU numbering.

[0251] In some embodiments, conjugates of antibody and high MW polymers serving as half-life extenders are provided. In some embodiments, a conjugate comprises an antibody that is coupled to a zwitterionic polymer wherein the polymer is formed from one or more monomer units and wherein at least one monomer unit has a zwitterionic group is provided. In some embodiments, the zwitterionic group is phosphorylcholine.

[0252] In some embodiments, one of the monomer units is HEMA-PC. In some embodiments, a polymer is synthesized from a single monomer which is HEMA-PC.

[0253] In some embodiments, some antibody conjugates have 2, 3, or more polymer arms wherein the monomer is HEMA-PC. In some embodiments, the conjugates have 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 polymer arms wherein the monomer is HEMA-PC. In some embodiments, the conjugates have 3, 6 or 9 arms. In some embodiments, the conjugate has 9 arms.

[0254] In some embodiments, polymer-antibody conjugates have a polymer portion with a molecular weight of between 100,000 and 1,500,000 Da. In some embodiments, the conjugate has a polymer portion with a molecular weight between 500,000 and 1,000,000 Da. In some embodiments, the conjugate has a polymer portion with a molecular weight between 600,000 to 800,000 Da. In some embodiments, the conjugate has a polymer portion with a molecular weight between 600,000 and 850,000 Da and has 9 arms. When a molecular weight is given for an antibody conjugated to a polymer, the molecular weight will be the addition of the molecular weight of the protein, including any carbohydrate moi eties associated therewith, and the molecular weight of the polymer.

[0255] In some embodiments, an anti-HTRAl antibody has a HEMA-PC polymer which has a molecular weight measured by Mw of between about 100 kDa and 1650 kDa is provided. In some embodiments, the molecular weight of the polymer as measured by Mw is between about 500 kDa and 1000 kDa. In some embodiments, the molecular weight of the polymer as measured by Mw is between about 600 kDa to about 900 kDa. In some embodiments, the polymer molecular weight as measured by Mw is 750 kDa plus or minus 15%.

[0256] In some embodiments, the antibody conjugate has an anti-HTRAl immunoglobulin G (IgG) bonded to a polymer, which polymer comprises MPC monomers, where the sequence of the anti-HTRAl heavy chain variable region (VH) includes at least one of the VH sequences as set forth in SEQ ID NOs:725, 742, 744, 745, 746, where the VH is C- terminally fused to a heavy chain constant region (HC) that includes the amino acid sequence of SEQ ID NO:536, where the polymer is bonded to C326 of SEQ ID NO:536 (as provided in Table 0.14), and the sequence of the anti-HTRAl light chain variable region includes at least one of the VL sequences as set forth in SEQ ID NO:748, where the VL is C-terminally fused to a light chain constant region (LC) comprising an amino acid sequence of SEQ ID NO:537. In some embodiments, the antibody conjugate has an anti-HTRAl immunoglobulin G (IgG)bonded to a polymer, which polymer comprises MPC monomers, where the sequence of the anti-HTRAl heavy chain variable region (VH) includes an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined any two of the preceding values (e.g., 80-100%, 85- 99%, 90-97%, 95-100%, etc.), identical to at least one of the VH sequences as set forth in SEQ ID NOs: 725, 742, 744, 745, 746, where the VH is C-terminally fused to a heavy chain constant region (HC) that includes the amino acid sequence of SEQ ID NO:536, where the polymer is bonded to C326 of SEQ ID NO:536 (as provided in Table 0.14), and the sequence of the anti- HTRAl light chain variable region includes an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or about 100%, or a percentage in a range defined any two of the preceding values (e.g., 80-100%, 85-99%, 90- 97%, 95-100%, etc.), identical to at least one of the VL sequences as set forth in SEQ ID NO:748, where the VL is C-terminally fused to a light chain constant region (LC) comprising an amino acid sequence of SEQ ID NO:537. In some embodiments, the polymer has 9 arms and has a molecular weight of between about 600,000 to about 1,000,000 Da.

[0257] In some embodiments, the antibody conjugate has an anti-HTRAl immunoglobulin G (IgG) bonded to a polymer, which polymer comprises MPC monomers, where the sequence of the anti-HTRAl heavy chain includes at least one of SEQ ID NOs: 819- 823, where the polymer is bonded to C445 of the at least one of SEQ ID NOs: 819-823, and the sequence of the anti-HTRAl light chain includes SEQ ID NO:824. In some embodiments, the polymer has 9 arms and has a molecular weight of between about 600,000 to about 1,000,000 Da.COMPOSITIONS

[0258] Also provided are pharmaceutical compositions that contain an antibody or antibody conjugate of the present disclosure. In some embodiments, the antibody conjugate is present in a liquid formulation. In some embodiments, the antibody conjugate is combined with a pharmaceutically acceptable carrier.

[0259] Therapeutic formulations of the anti-HTRAl antibodies and anti-HTRAl antibody conjugates used in accordance with the present invention are prepared for storage by mixing an antibody (or conjugate thereof) having the desired degree of purity with optionalpharmaceutically acceptable carriers, excipients or stabilizers, in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and may comprise buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

[0260] Liposomes containing the anti-HTRAl antibody and / or anti-HTRAl antibody conjugate are prepared by methods known in the art. Liposomes with enhanced circulation time are known in the art. Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through fdters of defined pore size to yield liposomes with the desired diameter.

[0261] The active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.

[0262] Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g. fdms, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (forexample, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and 7 ethyl -L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3 -hydroxybutyric acid.

[0263] The formulations to be used for in vivo administration must be sterile. This is readily accomplished by, for example, fdtration through sterile filtration membranes. Therapeutic anti-HTRAl antibody and / or antibody conjugate compositions are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle. In some embodiments, the antibody and / or antibody conjugate compositions are placed into a syringe to provide a prefilled syringe.

[0264] In some embodiments, the composition is a pyrogen-free composition which is substantially free of endotoxins and / or related pyrogenic substances. In some embodiments, the endotoxin and pyrogen levels in the composition are less than 10 EU / mg, or less than 5 EU / mg, or less than 1 EU / mg, or less than 0.1 EU / mg, or less than 0.01 EU / mg, or less than 0.001 EU / mg. In some embodiments, the compositions or methods provided herein allow for 0. lEU / eye / inj ection. In some embodiments, the compositions or methods provided herein allow for 0.05EU / eye / inj ection. In some embodiments, the compositions or methods provided herein allow for 0.02EU / eye / inj ection. In some embodiments, the compositions or methods provided herein allow for O.OlEU / eye / injection.

[0265] The compositions according to the present invention may be in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.

[0266] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to thesepreformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[0267] Suitable surface-active agents include, in particular, non-ionic agents, such as Polysorbate or polyoxyethylenesorbitans (e g. Tween™ 20, 40, 60, 80 or 85) and other sorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Compositions with a surface-active agent will conveniently comprise between 0.01%, and 5% surface-active agent, and can be between 0.01 and 0.02% or 0.1 and 2.5% (polysorbate 20 or 80). It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary.

[0268] Suitable emulsions may be prepared using commercially available fat emulsions, such as INTRALIPID™, LIPOSYN™, INFONUTROL™, LIPOFUNDIN™ and LIPIPHYSAN™. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g. egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion can comprise fat droplets between 0.1 and 1.0 pm, particularly 0.1 and 0.5 pm, and have a pH in the range of 5.5 to 8.0.

[0269] The emulsion compositions can be those prepared by mixing an anti- HTRA1 antibody with Intralipid™ or the components thereof (soybean oil, egg phospholipids, glycerol and water).

[0270] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.POLYNUCLEOTIDES, VECTORS, AND HOST CELLS

[0271] Also provided herein are polynucleotides encoding any of the antibodies, including antibody fragments and modified antibodies described herein. Also provided is a method of making any of the polynucleotides described herein. Polynucleotides can be made and expressed by procedures known in the art. Accordingly, provided herein are polynucleotides or compositions, including pharmaceutical compositions, comprising polynucleotides, encoding any of the anti-HTRAl antibodies provided herein.

[0272] Polynucleotides complementary to any such sequences are also contemplated. Polynucleotides may be single-stranded (coding or antisense) or doublestranded, and may be DNA (genomic, cDNA or synthetic) or RNA molecules. RNA molecules include HnRNA molecules, which contain introns and correspond to a DNA molecule in a one- to-one manner, and mRNA molecules, which do not contain introns. Additional coding or non-coding sequences may, but need not, be present within a polynucleotide of the present invention, and a polynucleotide may, but need not, be linked to other molecules and / or support materials.

[0273] Polynucleotides may comprise a native sequence (i.e., an endogenous sequence that encodes an antibody or a fragment thereof) or may comprise a variant of such asequence. Polynucleotide variants contain one or more substitutions, additions, deletions and / or insertions such that the immunoreactivity of the encoded polypeptide is not diminished, relative to a native immunoreactive molecule. The effect on the immunoreactivity of the encoded polypeptide may generally be assessed as described herein. In some embodiments, variants exhibit at least about 70% identity, more preferably, at least about 80% identity, yet more preferably, at least about 90% identity, and most preferably, at least about 95% identity to a polynucleotide sequence that encodes a native antibody or a fragment thereof.

[0274] Two polynucleotide or polypeptide sequences are said to be "identical" if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. A "comparison window" as used herein, refers to a segment of at least about 20 contiguous positions, usually 30 to about 75, or 40 to about 50, in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.

[0275] Optimal alignment of sequences for comparison may be conducted using the MegAlign® program in the Lasergene® suite of bioinformatics software (DNASTAR®, Inc., Madison, WI), using default parameters.

[0276] In some embodiments, the "percentage of sequence identity" is determined by comparing two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e. the window size) and multiplying the results by 100 to yield the percentage of sequence identity.

[0277] It will be appreciated by those of ordinary skill in the art that, as a result of the degeneracy of the genetic code, there are many nucleotide sequences that encode apolypeptide as described herein. Some of these polynucleotides bear minimal homology to the nucleotide sequence of any native gene. Nonetheless, polynucleotides that vary due to differences in codon usage are specifically contemplated by the present disclosure. Further, alleles of the genes comprising the polynucleotide sequences provided herein are within the scope of the present disclosure. Alleles are endogenous genes that are altered as a result of one or more mutations, such as deletions, additions and / or substitutions of nucleotides. The resulting mRNA and protein may, but need not, have an altered structure or function. Alleles may be identified using standard techniques (such as hybridization, amplification and / or database sequence comparison).

[0278] The polynucleotides of this disclosure can be obtained using chemical synthesis, recombinant methods, or PCR. Any suitable option for chemical polynucleotide synthesis, such as a commercial DNA synthesizer, can be used to produce the sequences provided herein.

[0279] For preparing polynucleotides using recombinant methods, a polynucleotide comprising a desired sequence can be inserted into a suitable vector, and the vector in turn can be introduced into a suitable host cell for replication and amplification, as further discussed herein. Polynucleotides may be inserted into host cells by any means known in the art. Cells are transformed by introducing an exogenous polynucleotide by direct uptake, endocytosis, transfection, F-mating or electroporation. Once introduced, the exogenous polynucleotide can be maintained within the cell as a non-integrated vector (such as a plasmid) or integrated into the host cell genome. The polynucleotide so amplified can be isolated from the host cell by methods well known within the art.

[0280] Alternatively, PCR allows reproduction of DNA sequences.

[0281] RNA can be obtained by using the isolated DNA in an appropriate vector and inserting it into a suitable host cell. When the cell replicates and the DNA is transcribed into RNA, the RNA can then be isolated using any suitable option.

[0282] Suitable cloning vectors may be constructed according to standard techniques, or may be selected from a large number of cloning vectors available in the art. While the cloning vector selected may vary according to the host cell intended to be used, useful cloning vectors will generally have the ability to self-replicate, may possess a single target for a particular restriction endonuclease, and / or may carry genes for a marker that canbe used in selecting clones containing the vector. Suitable examples include, without limitation, plasmids and bacterial viruses, e.g., pUC18, pUC19, Bluescript (e.g., pBS SK+) and its derivatives, mpl8, mpl9, pBR322, pMB9, ColEl, pCRl, RP4, phage DNAs, and shuttle vectors such as pSA3 and pAT28.

[0283] Expression vectors are further provided. Expression vectors generally are replicable polynucleotide constructs that contain a polynucleotide according to the present disclosure. It is implied that an expression vector must be replicable in the host cells either as episomes or as an integral part of the chromosomal DNA. Suitable expression vectors include but are not limited to plasmids, viral vectors, including adenoviruses, adeno-associated viruses, retroviruses, cosmids, and expression vector(s). Vector components may generally include, but are not limited to, one or more of the following: a signal sequence; an origin of replication; one or more marker genes; suitable transcriptional controlling elements (such as promoters, enhancers and terminator). For expression (i.e., translation), one or more translational controlling elements are also usually required, such as ribosome binding sites, translation initiation sites, and stop codons.

[0284] The vectors containing the polynucleotides of interest can be introduced into the host cell by any of a number of appropriate means, including electroporation, transfection employing calcium chloride, rubidium chloride, calcium phosphate, DEAE- dextran, or other substances; microprojectile bombardment; lipofection; and infection (e.g., where the vector is an infectious agent such as vaccinia virus). The choice of introducing vectors or polynucleotides will often depend on features of the host cell.

[0285] The present disclosure also provides host cells comprising any of the polynucleotides described herein. Any host cells capable of over-expressing heterologous DNAs can be used for the purpose of isolating the genes encoding the antibody, polypeptide or protein of interest. Non-limiting examples of mammalian host cells include but not limited to COS, HeLa, HEK293, and CHO cells. Suitable non-mammalian host cells include prokaryotes (such as E. coli or B. subtillis) and yeast (such as S. cerevisae, S. pombe or K. lactis). Preferably, the host cells express the cDNAs at a level of about 5 fold higher, more preferably, 10 fold higher, even more preferably, 20 fold higher than that of the corresponding endogenous antibody or protein of interest, if present, in the host cells. In some embodiments,screening the host cells for a specific binding to HTRA1 is effected by an immunoassay or FACS. A cell overexpressing the antibody or protein of interest can be identified.

[0286] In some embodiments, an expression vector can be used to direct expression of any of the anti-HTRAl antibodies provided herein.METHODS OF MAKING AN ANTIBODY AND CONJUGATES THEREOF

[0287] Also provided herein are methods of making an antibody of the present disclosure. In some embodiments, a screening method can include immunizing a host animal, e.g., a mouse or rat, with human HTRA1, or a portion thereof. In some embodiments, the host animal is immunized with at least the human HTRA1 protease domain. In some embodiments, the host animal is immunized with the human HTRA1 protease domain having at least an amino acid sequence of SEQ ID NO:2. In some embodiments, the screening method includes screening clones of antibody-producing cells (e.g., B cells) obtained from the immunized host animal based on one or more functional properties of the antibodies produced by the clones. In some embodiments, the one or more functional properties include one or more of: binding to human HTRA1 (e g., a human HTRA1 N-terminal truncation (HTRA1 PD / PDZ)); inhibition of HTRA1 proteolytic activity; binding affinity for HTRA1 loop A; binding affinity for HTRA3; relative binding affinity to trimeric HTRA1 and monomeric HTRA1; and stoichiometry of binding to HTRA1.

[0288] In some embodiments, clones are screened based on binding to human HTRA1, such as a human HTRA1 N-terminal truncation (HTRA1 PD / PDZ). In some embodiments, the human HTRA1 N-terminal truncation (HTRA1 PD / PDZ) has at least an amino acid sequence of SEQ ID NO: 3. In some embodiments, one or more clones that produce antibodies that bind to human HTRA1 are selected. Binding to human HTRA1 can be measured using any suitable option, e.g., using a kinetic assay. In some embodiments, one or more clones that produce antibodies that have a binding affinity of about 10'7M or less, about 1 O’8M or less, about 10'9M or less, about IO'10M or less, about 10'11M or less, about 10'12M or less, or a binding affinity in a range defined by any two of the preceding values (e.g., 10'7- 10'12M, 1 O'8- 1 O'12M, 1 O'9- 1 O'11M, etc.), are selected.

[0289] In some embodiments, clones are screened based on inhibition of HTRA1 proteolytic activity. In some embodiments, inhibition of HTRA1 proteolytic activity isdetermined using an optimized substrate (H2-Opt) to measure proteolytic activity. In some embodiments, the optimized substrate has at least an amino acid sequence Mca-Ile-Arg-Arg- Val-Ser-Tyr-Ser-Phe-Lys(Dnp)-Lys-OH (SEQ ID NO:750). In some embodiments, inhibition of HTRA1 proteolytic activity is determined using casein, e.g., ^-casein, as a substrate. In some embodiments, one or more clones that produce antibodies that inhibit HTRA1 proteolytic activity are selected. In some embodiments, one or more clones that produce antibodies that inhibit HTRA1 proteolytic with an IC50 of about 10'8M or less, about 10'9M or less, about 10’10M or less, about 10'11M or less, or an IC50 in a range defined by any two of the preceding values (e.g., 10‘8-l O’11M, I O‘9-1O'" M, 1 O'9- 1 O’10M, etc.), are selected.

[0290] In some embodiments, clones are screened based on binding affinity for HTRA1 loop A. In some embodiments, the HTRA1 loop A has at least an amino acid sequence of SEQ ID NO:4. In some embodiments, one or more clones that produce antibodies that bind to HTRA1 loop A are selected. In some embodiments, one or more clones that produce antibodies that do not bind HTRA1 loop A are selected. Binding to HTRA1 loop A, or lack thereof, can be determined using any suitable option, e.g., by ELISA.

[0291] In some embodiments, clones are screened based on binding affinity for HTRA3. In some embodiments, the HTRA3 has at least an amino acid sequence of SEQ ID NO: 5. In some embodiments, one or more clones that produce antibodies that do not bind to HTRA3 are selected. Lack of binding to HTRA3 can be determined using any suitable option, e g., by ELISA.

[0292] In some embodiments, clones are screened based on relative binding affinity to trimeric HTRA1 and monomeric HTRA1. In some embodiments, the trimeric HTRA1 includes HTRA1 having at least an amino acid sequence of SEQ ID NOB. In some embodiments, the monomeric HTRA1 includes HTRA1 having at least an amino acid sequence of SEQ ID NO:7. In some embodiments, one or more clones that produce antibodies that preferentially bind trimeric HTRA1 over monomeric HTRA1 are selected. In some embodiments, one or more clones that produce antibodies that bind trimeric HTRA1 and do not bind monomeric HTRA1 are selected. Binding to trimeric or monomeric HTRA is HTRA1 can be measured using any suitable option, e.g., using a kinetic assay.

[0293] In some embodiments, clones are screened based on stoichiometry of binding to HTRA1. In some embodiments, the HTRA1 includes HTRA1 having at least an-I l l-amino acid sequence of SEQ ID N0 3. In some embodiments, one or more clones that produce antibodies that bind to HTRA1 with a stoichiometry of about 0.3:1, about 0.7:1, about 1 :1, about 2: 1, about 3 : 1, or greater are selected. The stoichiometry of binding can be determined using any suitable option, e.g., size exclusion chromatography.

[0294] In some embodiments, the screening method of the present disclosure includes carrying out one or more rounds of affinity maturation on one or more of the anti- HTRA1 antibodies. Any suitable option for affinity maturation can be used. In some embodiments, affinity maturation includes generating a library, e.g., a phage library, of heavy chain and light chain CDR variants of a parental heavy chain and light chain variable region pair, and selecting for variants that bind a suitable target over one or more rounds. In some embodiments, selecting for target binding is carried out with increasing stringency over subsequent rounds, e.g., by reducing target concentration, increasing washing steps, increasing washing time, etc. In some embodiments, the binding target is an HTRA1 protein. In some embodiments, the binding target is a HTRA1 N-terminal truncation (HTRA1 PD / PDZ). In some embodiments, the desired target has at least an amino acid sequence of SEQ ID NO:3.

[0295] In some embodiments, affinity maturation includes depleting the library for non-specific binders. In some embodiments, depleting the library for non-specific binders includes contacting the variants with HTRA3 to remove non-specific binders. In some embodiments, the HTRA3 includes at least an amino acid sequence of SEQ ID NO: 5.

[0296] Also provided are methods of producing an anti-HTRAl antibody, including: culturing a cell line that recombinantly produces an anti-HTRAl antibody as provided herein, under conditions wherein the antibody is produced; and recovering the antibody. In some embodiments, the cell line comprises a nucleic acid encoding a heavy chain comprising at least one of the heavy chain variable region (VH) amino acid sequences shown in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1; and a nucleic acid encoding a light chain comprising at least one of the light chain variable region (VL) amino acid sequences shown in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, under conditions wherein an antibody comprising the heavy chain and the light chain is produced; and recovering the antibody. In some embodiments, the heavy and light chains of the antibody are encoded on separate vectors. In some embodiments, the heavy and light chains of the antibody are encoded on the same vector.

[0297] The anti-HTRAl antibodies can be produced by recombinant expression including (i) the production of recombinant DNA by genetic engineering, (ii) introducing recombinant DNA into prokaryotic or eukaryotic cells by, for example and without limitation, transfection, electroporation or microinjection, (iii) cultivating the transformed cells, (iv) expressing antibody, e.g. constitutively or on induction, and (v) isolating the antibody, e.g. from the culture medium or by harvesting the transformed cells, in order to (vi) obtain purified antibody.

[0298] The anti-HTRAl antibodies can be produced by expression in a suitable prokaryotic or eukaryotic host system characterized by producing a pharmacologically acceptable antibody molecule. Examples of eukaryotic cells are mammalian cells, such as CHO, COS, HEK 293, BHK, SK-Hip, and HepG2. Other suitable expression systems are prokaryotic (e g., E. coli with pET / BL21 expression system), yeast (Saccharomyces cerevisiae and / or Pichia pastoris systems), and insect cells.

[0299] A wide variety of vectors can be used for the preparation of the antibodies disclosed herein and are selected from eukaryotic and prokaryotic expression vectors. Examples of vectors for prokaryotic expression include plasmids such as, and without limitation, preset, pet, and pad, wherein the promoters used in prokaryotic expression vectors include one or more of, and without limitation, lac, trc, trp, recA, or araBAD. Examples of vectors for eukaryotic expression include: (i) for expression in yeast, vectors such as, and without limitation, pAO, pPIC, pYES, or pMET, using promoters such as, and without limitation, A0X1, GAP, GALI, or AUG1; (ii) for expression in insect cells, vectors such as and without limitation, pMT, pAc5, pIB, pMIB, or pBAC, using promoters such as and without limitation PH, plO, MT, Ac5, OpIE2, gp64, or polh, and (iii) for expression in mammalian cells, vectors such as, and without limitation, pSVL, pCMV, pRc / RSV, pcDNA3, or pBPV, and vectors derived from, in one aspect, viral systems such as and without limitation vaccinia virus, adeno-associated viruses, herpes viruses, or retroviruses, using promoters such as and without limitation CMV, SV40, EF-1, UbC, RSV, ADV, BPV, and beta-actin.

[0300] Also provided are methods of making an antibody conjugate of the present disclosure. In some embodiments, the method includes conjugating an anti-HTRAl antibody as provided herein to a polymer, e.g., a phosphorylcholine containing polymer, wherein the anti-HTRAl antibody comprises a non-native cysteine residue outside a variable region of theantibody. In some embodiments, the polymer comprises or consists of a phosphorylcholine containing polymer. In some embodiments, the phosphorylcholine containing polymer comprises a sulfhydryl specific reacting group selected from the group consisting of a maleimide, a vinylsulfone, an orthopyridyl-disulfide, and an iodoacetamide. In some embodiments, the sulfhydryl specific reacting group on the phosphorylcholine containing polymer reacts with the non-native cysteine residue on the anti-HTRAl antibody to make the antibody conjugate.

[0301] In some embodiments, the anti-HTRAl antibody is an immunoglobulin G (IgG) and the cysteine is in the Fc region of the antibody. In some embodiments, the anti- HTRAl antibody comprises a light chain and a heavy chain, wherein the anti-HTRAl antibody heavy chain variable region comprises CDRHI : FYHVH (SEQ ID NO:830), CDRH2: SIYTSGYTEYASALES (SEQ ID NO:831), and CDRH3 : EGLQRVGVLDA (SEQ ID NO 834) or EGLQRVGVFDA (SEQ ID NO:832) or EGLQRVGVMDA (SEQ ID NO:833), and the anti-HTRAl antibody light chain variable region comprises CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO:841), and CDRL3 : QQATYFPYT (SEQ ID NO:839). In some embodiments, the anti-HTRAl antibody heavy chain isotype is IgGl . In some embodiments, the anti-HTRAl antibody has one or more mutations relative to an IgGl constant region to modulate effector function, as provided herein. In some embodiments, the anti-HTRAl antibody heavy chain comprises a heavy chain variable region (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NOs: 725, 742, 744, 745, 746, and the anti-HTRAl antibody light chain comprises a light chain variable region (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO:748.

[0302] In some embodiments, the non-native cysteine residue is selected from the group consisting of Q347C (EU numbering) and L443C (EU numbering).

[0303] In some embodiments, the sulfhydryl specific reacting group is maleimide.

[0304] In some embodiments, the polymer is selected from the group consisting of polyethylene glycol (PEG), branched PEG, PolyPEG® (Warwick Effect Polymers; Coventry, UK), polysialic acid (PSA), starch, hydroxylethyl starch (HES), hydroxyalkyl starch (HAS), carbohydrate, polysaccharides, pullulane, chitosan, hyaluronic acid, chondroitin sulfate, dermatan sulfate, dextran, carboxymethyl-dextran, polyalkylene oxide (PAO), polyalkylene glycol (PAG), polypropylene glycol (PPG), polyoxazoline, polyacryloylmorpholine, polyvinylalcohol (PVA), polycarboxylate, polyvinylpyrrolidone, polyphosphazene, polyoxazoline, polyethylene-co-maleic acid anyhydride, polystyrene-co-maleic acid anhydride, poly(l- hydroxymethyethylene hydroxymethylformal) (PHF), a zwitterionic polymer, a phosphorylcholine containing polymer and a polymer comprising 2-methacryloyloxy-2’- ethyltrimethylammoniumphosphate (MPC). In some embodiments, the polymer is a half-life extending moiety.

[0305] In some embodiments, the polymer is a zwitterionic polymer. In some embodiments, the zwitterion is phosphorylcholine, i.e. a phosphorylcholine containing polymer. In some embodiments, the polymer is composed of MPC units.

[0306] In some embodiments, the polymer, e.g., MPC polymer, has three or more arms. In some embodiments, the polymer, e.g., MPC polymer, has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more arms. In some embodiments, the polymer, e g., MPC polymer, has 3, 6, or 9 arms. In some embodiments, the polymer, e g., MPC polymer, has 9 arms. In some embodiments, the polymer is synthesized with an initiator comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more polymerization initiation sites. In some embodiments, the polymer has three or more arms or is synthesized with an initiator comprising 3 or more polymerization initiation sites. In some embodiments, the polymer is synthesized with an initiator comprising 9 polymerization initiation sites.

[0307] In some embodiments, the polymer, e.g., MPC polymer, has a molecular weight between about 300,000 and 1,750,000 Da. In some embodiments, the polymer, e.g., MPC polymer, has a molecular weight between about 500,000 and 1,000,000 Da, or between about 600,000 and 1,000,000 Da, or between about 600,000 to 900,000 Da, or between about 600,000 to 850,000 Da.

[0308] In some embodiments, the method of making the antibody conjugate has an additional step of contacting the antibody with a thiol reductant under conditions that produce a reduced cysteine sulfhydryl group. In some embodiments, to free the newly added cysteine from the disulfide adduct, the protein after purification is treated with a reducing agent, e.g., dithiothreitol. In some embodiments, all native (e.g., inter and intra) Cys-Cys disulfides are reformed.

[0309] To reform native inter and intra-chain disulfide residues, after reduction to remove the cysteine disulfide adducts, the therapeutic protein is exposed to oxidizingconditions and / or oxidizing agents for a prescribed period of time, e.g., overnight. In some embodiments, ambient air exposure overnight can be used to achieve reformation of the native disulfide bonds. In some embodiments, an oxidizing agent is employed to restore the native disulfides. In some embodiments, the oxidizing agent is selected from the group consisting of aqueous CuSCh and dehydroascorbic acid (DHAA). In some embodiments, the oxidizing agent is DHAA. In some embodiments, the range of DHAA used is in the range of 5-30 equivalents. In some embodiments, the range is 10-20 equivalents. In some embodiments, the range is 15 equivalents.

[0310] In some embodiments, the thiol reductant is selected from the group consisting of: Tris[2-carboxyehtyl]phosphine hydrochloride (TCEP), dithiothreitol (DTT), di thioerythritol (DTE), sodium borohydride (NaBHi), sodium cyanoborohydride (NaCNBH3), P-mercaptoethanol (BME), 3,3',3''-Phosphanetriyltris(benzenesulfonic acid) trisodium (TPPTS), cysteine hydrochloride and cysteine. In some embodiments, the thiol reductant is TCEP.

[0311] In some embodiments, the thiol reductant concentration is between 1 and 100 fold molar excess relative to the therapeutic protein concentration. In some embodiments, the thiol reductant concentration is between 20 to 50 fold molar excess relative to the therapeutic protein concentration. In some embodiments, the thiol reductant is removed following incubation with the therapeutic protein prior to oxidation of the therapeutic protein.

[0312] In some embodiments, the method includes a further step of purifying the antibody conjugate after conjugation. In some embodiments, the antibody conjugate is purified using a technique selected from the group consisting of ion exchange chromatography, hydrophobic interaction chromatography, size exclusion chromatography, and affinity chromatography or combinations thereof.

[0313] In some embodiments, the antibody conjugate retains at least 20% biological activity relative to unconjugated antibody. In some embodiments, the antibody conjugate retains at least 50% biological activity relative to unconjugated antibody. In some embodiments, the antibody conjugate retains at least 90% biological activity relative to native antibody. In some embodiments, the antibody conjugate retains at least 95% biological activity relative to native antibody. In some embodiments, the antibody conjugate retains about 100% biological activity relative to native antibody.

[0314] In some embodiments, the antibody conjugate has an increased half-life relative to unconjugated antibody. In some embodiments, the antibody conjugate has at least a 1.5 fold increase in half-life relative to unconjugated antibody. In some embodiments, the antibody conjugate has at least a 5 fold increase in half-life relative to unconjugated antibody.

[0315] In some embodiments, the polymer is made from an initiator suitable for ATRP having one or more polymerization initiation sites. In some embodiments, the polymer initiation site has a 2-bromoisobutyrate site. In some embodiments, the initiator has 3 or more polymerization initiation sites. In some embodiments, the initiator has 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more polymerization initiation sites. In some embodiments, the initiator has 3, 6 or 9 polymerization initiation sites. In some embodiments, the initiator has 9 polymerization initiation sites. In some embodiments, the initiator is OG1786.METHODS OF USING AN ANTIBODY OR CONJUGATE THEREOF

[0316] The antibodies, conjugates thereof, and pharmaceutical compositions containing the same find use in many applications where antibody binding to HTRA1 and / or inhibition of HTRA1 enzymatic activity is desired. Provided herein is a method for treatment or prophylaxis of an ocular disease in subject in need thereof using an antibody or antibody conjugate of the present disclosure. In some embodiments, an antibody or antibody conjugate of the present disclosure finds use in the treatment or prophylaxis of a disorder, e.g., an ocular disease, related to HTRA1, e.g., HTRA1 activity. The treatment or prophylaxis method can include administering an therapeutically effective dose of any antibody conjugate or antibody of the present disclosure to a subject in need thereof. In some embodiments, the disease can be age-related macular degeneration (AMD). In some embodiments, the disease can be wet AMD. In some embodiments, the disease can be dry AMD.

[0317] In some embodiments, the ocular disease is selected from one or more of the group consisting of diabetic retinopathy, age-related macular degeneration (AMD) (e.g., early, intermediate, or advanced AMD), retinopathy of prematurity (ROP), dry AMD, geographic atrophy, wet AMD, polypoidal choroidal vasculopathy, and HTRA1 -associated disorders. In some embodiments, the ocular disease is diabetic retinopathy.

[0318] In some embodiments, the ocular disease is an HTRA-1 -associated disorder. In some embodiments, the ocular disease is dry AMD or geographic atrophy. In some embodiments, the dry AMD comprises early, intermediate or advanced dry AMD.

[0319] The anti-HTRAl antibody (or conjugate thereof) can be administered to a subject via any suitable route. It should be apparent to a person skilled in the art that the examples described herein are not intended to be limiting but to be illustrative of the techniques available. Accordingly, in some embodiments, the anti-HTRAl antibody (or conjugate thereof) is administered to a subject in accord with known methods, such as intravenous administration, e.g., as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerebrospinal, transdermal, subcutaneous, intra-articular, sublingually, intrasynovial, via insufflation, intrathecal, oral, inhalation or topical routes. Administration can be systemic, e g., intravenous administration, or localized. Commercially available nebulizers for liquid formulations, including jet nebulizers and ultrasonic nebulizers are useful for administration. Liquid formulations can be directly nebulized and lyophilized powder can be nebulized after reconstitution. Alternatively, anti-HTRAl antibody (or conjugate thereof) can be aerosolized using a fluorocarbon formulation and a metered dose inhaler, or inhaled as a lyophilized and milled powder.

[0320] In some embodiments, the anti-HTRAl antibodies, anti-HTRAl antibody conjugates, and pharmaceutical compositions disclosed herein are used for prophylaxis or treatment of an ocular disease or condition. So used, the conjugates are typically formulated for and administered by ocular, intraocular, and / or intravitreal injection, and / or juxtascleral injection, and / or subtenon injection, and / or suprachoroidal injection and / or topical administration in the form of eye drops and / or ointment. Such anti-HTRAl antibodies, anti- HTRAl antibody conjugates, and compositions can be delivered by any suitable option, e g. intravitreally as a device and / or a depot that allows for slow release of the compound into the vitreous. In one non-limiting example, a device may be in the form of a minimum and / or a matrix and / or a passive diffusion system and / or encapsulated cells that release the compound for a prolonged period of time. In therapy or as a prophylactic, the active agent may be administered to an individual as an injectable composition, for example as a sterile aqueous dispersion, preferably isotonic or substantially isotonic.

[0321] Formulations for ocular, intraocular or intravitreal administration can be prepared by methods and using ingredients known in the art. Proper penetration into the eye is desirable for efficient treatment. Unlike diseases of the front of the eye, where drugs can be delivered topically, retinal diseases merit a more site-specific approach. Eye drops and ointments rarely penetrate the back of the eye, and the blood-ocular barrier hinders penetration of systemically administered drugs into ocular tissue. In some embodiments, the method of choice for drug delivery to treat retinal disease, such as AMD, is direct intravitreal injection. In some embodiments, intravitreal injections are repeated at intervals which depend on the patient's condition, and the properties and half-life of the drug delivered.

[0322] For administration to mammals, and particularly humans, it is expected that the dosage of the active agent is from 0.01 mg / kg body weight, to typically around 1 mg / kg, for systemic administrations. For ocular diseases that require local administration (for example, intravitreal, suprachoroidal, peri-ocular etc), dosage is typically 0.1 mg / eye / dose to 10 mg / eye / dose or more. In some embodiments, the dosage is 100 ul / dose / eye. In some embodiments, a needle can be used to administer the dosage. The needle can be, for example, a 30 gauge !4 inch needle or a ’A inch needle that is 27G or 29G. The physician can determine the actual dosage most suitable for an individual which depends on factors including the age, weight, sex and response of the individual, the disease or disorder being treated and the age and condition of the individual being treated. The above dosages are exemplary of the average case. There can, of course, be instances where higher or lower dosages are merited.

[0323] This dosage may be repeated as often as appropriate (e.g., weekly, fortnightly, monthly, quarterly). If side effects develop the amount and / or frequency of the dosage can be reduced, in accordance with normal clinical practice. In one embodiment, the pharmaceutical composition may be administered once every one to thirty days. In some embodiments, the antibody or antibody conjugate is administered no more frequently than once a month. In some embodiments, the antibody or conjugate thereof is administered two times per month or weekly. In some embodiments, the antibody or conjugate thereof is administered once every two months, once every three months, once every four months, once every five months, once every six months, once every seven months, once every eight months, once every nine months, once every ten months, once every eleven months, or once every twelve months.

[0324] The anti-HTRAl antibodies of the present disclosure may be employed by expression of such polypeptides in vivo in a patient, i.e., gene therapy. There are two major approaches to getting the nucleic acid (optionally contained in a vector) into the patient's cells: in vivo and ex vivo. For in vivo delivery the nucleic acid is injected directly into the patient, usually at the sites where the therapeutic protein is required, i.e., where biological activity of the therapeutic protein is needed. For ex vivo treatment, the patient's cells are removed, the nucleic acid is introduced into these isolated cells, and the modified cells are administered to the patient either directly or, for example, encapsulated within porous membranes that are implanted into the patient. There are a variety of techniques available for introducing nucleic acids into viable cells. The techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro, or transferred in vivo in the cells of the intended host. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, transduction, cell fusion, DEAE-dextran, the calcium phosphate precipitation method, etc. Transduction involves the association of a replication-defective, recombinant viral (preferably retroviral) particle with a cellular receptor, followed by introduction of the nucleic acids contained by the particle into the cell. A commonly used vector for ex vivo delivery of the gene is a retrovirus.

[0325] In some embodiments, in vivo nucleic acid transfer techniques include transfection with viral or non-viral vectors (such as adenovirus, lentivirus, Herpes simplex I virus, or adeno-associated virus (AAV)) and lipid-based systems (useful lipids for lipid- mediated transfer of the gene are, for example, DOTMA, DOPE, and DC-Chol). The most preferred vectors for use in gene therapy are viruses, most preferably adenoviruses, AAV, lentiviruses, or retroviruses. A viral vector such as a retroviral vector includes at least one transcriptional promoter / enhancer or locus-defining element(s), or other elements that control gene expression by other means such as alternate splicing, nuclear RNA export, or post- translational modification of messenger. In addition, a viral vector such as a retroviral vector includes a nucleic acid molecule that, when transcribed in the presence of a gene encoding the therapeutic protein, is operably linked thereto and acts as a translation initiation sequence. Such vector constructs also include a packaging signal, long terminal repeats (LTRs) or portions thereof, and positive and negative strand primer binding sites appropriate to the virus used (if these are not already present in the viral vector). In addition, such vector typicallyincludes a signal sequence for secretion of the PRO polypeptide from a host cell in which it is placed. Preferably the signal sequence for this purpose is a mammalian signal sequence, most preferably the native signal sequence for the therapeutic protein. Optionally, the vector construct may also include a signal that directs polyadenylation, as well as one or more restriction sites and a translation termination sequence. By way of example, such vectors will typically include a 5' LTR, a tRNA binding site, a packaging signal, an origin of second-strand DNA synthesis, and a 3' LTR or a portion thereof. Other vectors can be used that are non- viral, such as cationic lipids, polylysine, and dendrimers.

[0326] In some embodiments, it is desirable to provide the nucleic acid source with an agent that targets the target cells, such as an antibody specific for a cell-surface membrane protein or the target cell, a ligand for a receptor on the target cell, etc. Where liposomes are employed, proteins that bind to a cell-surface membrane protein associated with endocytosis may be used for targeting and / or to facilitate uptake, e.g., capsid proteins or fragments thereof tropic for a particular cell type, antibodies for proteins that undergo internalization in cycling, and proteins that target intracellular localization and enhance intracellular half-life. Any suitable technique of receptor-mediated endocytosis can be used.

[0327] Any suitable gene therapy and methods for making retroviral particles and structural proteins can be used.

[0328] In accordance some aspects, a method for treatment or prophylaxis of an ocular disease in a mammal is presented in which a nucleic acid molecule that encodes an anti- HTRA1 antibody is administered.KITS

[0329] Also provided are kits comprising any or all of the antibodies, antibody conjugates or pharmaceutical compositions and formulations described herein. Kits of the present disclosure include one or more containers comprising an anti-HTRAl antibody or conjugate described herein and instructions for use in accordance with any of the methods of the present disclosure. In some embodiments, these instructions comprise a description of administration of the anti-HTRAl antibody or conjugate for the therapeutic treatments disclosed herein. In some embodiments, kits are provided for producing a single-dose administration unit. In certain embodiments, the kit can contain both a first container havinga dried protein and a second container having an aqueous formulation. In certain embodiments, kits containing single and multi-chambered pre-filled syringes (e.g., liquid syringes and lyosyringes) are included.

[0330] In some embodiments, the antibody is a human antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the instructions relating to the use of an anti- HTRA1 antibody or conjugate include information as to dosage, dosing schedule, and route of administration for the intended treatment. The containers may be unit doses, bulk packages (e.g., multi -dose packages) or sub-unit doses. Instructions supplied in the kits of the invention are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.

[0331] In some embodiments, the kits are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. Also contemplated are packages for use in combination with a specific device, such as prefilled syringe, an inhaler, nasal administration device (e.g., an atomizer) or an infusion device such as a minipump. In some embodiments, the kit has a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The container may also have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is an anti-HTRAl antibody or conjugate. The container may further comprise a second pharmaceutically active agent.

[0332] In some embodiments, the kits provide additional components such as buffers and interpretive information. In some embodiments, the kits can include an additional syringe and needle used for back fill of the dosing syringe. Normally, the kit comprises a container and a label or package insert(s) on or associated with the container.

[0333] Additional non-limiting embodiments are provided in the following numbered arrangements.1. An antibody conjugate comprising (1) an anti-HTRAl antibody and (2) a phosphorylcholine containing polymer, wherein the polymer is covalently bonded to the antibody at a non-native cysteine outside a variable region of the antibody.2. The antibody conjugate according to arrangement 1, wherein the anti-HTRAl antibody comprises a light chain and a heavy chain, said heavy chain comprising an Fc region.3. The antibody conjugate according to arrangement 1 or 2, wherein the cysteine is in the Fc region of the heavy chain.4. The antibody conjugate according to any one of the preceding arrangements, wherein the anti-HTRAl antibody is an immunoglobulin G (IgG).5. The antibody conjugate according to any one of the preceding arrangements, wherein the anti-HTRAl antibody heavy chain comprises a heavy chain variable region (VH) comprising: a heavy chain complementarity determining region 1 (CDRHI) having an amino acid sequence of a CDRHI in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, or with a variation at no more than 5 residues thereof; a CDRH2 having an amino acid sequence of a CDRH2 in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12,7.17, and 8.1, or with a variation at no more than 5 residues thereof; and a CDRH3 having an amino acid sequence of a CDRH3 in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12,7.17, and 8.1, or with a variation at no more than 5 residues thereof, and wherein the anti-HTRAl antibody light chain comprises a light chain variable region (VL) comprising: a light chain complementarity determining region 1 (CDRLI ) having an amino acid sequence of a CDRLI in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, or with a variation at no more than 5 residues thereof; a CDRL2 having an amino acid sequence of a CDRL2 in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13,7.18, and 8.2, or with a variation at no more than 5 residues thereof; anda CDRL3 having an amino acid sequence of a CDRL3 in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, or with a variation at no more than 5 residues thereof.6. The antibody conjugate according to arrangement 5, wherein the anti-HTRAl antibody VH comprises 3 CDRs each having an amino acid sequence of the corresponding CDRs in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, or with a variation at no more than 5 residues thereof, and the anti-HTRAl antibody VL comprises 3 CDRs each having an amino acid sequence of the corresponding CDRs in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, or with a variation at no more than 5 residues thereof .7. The antibody conjugate according to arrangement 6, wherein the 3 VH CDR sequences are paired with the 3 VL CDR sequences according to any one of the paired arrangements of VH and VL sequences provided in FIG. 21 and Tables 0.1, 0.4, 0.5, 0.7, 0.10, 0.11, 0.12, 1.2, 6.3, and 7.1.8. The antibody conjugate according to arrangement 6, wherein the anti-HTRAl antibody VH comprises 3 CDRs each having an amino acid sequence of the corresponding CDRs in any one of SEQ ID NOs:725, 742, 744, 745, 746, and the anti-HTRAl antibody VL comprises 3 CDRs each having an amino acid sequence of the corresponding 3 CDRs in SEQ ID NO:748.9. The antibody conjugate according to any one of the preceding arrangements, wherein the anti-HTRAl antibody heavy chain variable region comprises CDRHI : FYHVH (SEQ ID NO: SEQ ID NO:830), CDRH2: SIYTSGYTEYASALES (SEQ ID NO:831), and CDRH3 : EGLQRVGVLDA (SEQ ID NO:834) or EGLQRVGVFDA (SEQ ID NO:832) or EGLQRVGVMDA (SEQ ID NO:833), and the anti-HTRAl antibody light chain variable region comprises CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO:841), and CDRL3 : QQATYFPYT (SEQ ID NO:839).10. The antibody conjugate according to any one of arrangements 1-8, wherein the anti-HTRAl antibody heavy chain variable region comprises CDRHI : GFSLTFYH (SEQ ID NO: SEQ ID NO:825), CDRH2: IYTSGYT (SEQ ID NO:826), and CDRH3 : AREGLQRVGVFDA (SEQ ID NO 827) or AREGLQRVGVMDA (SEQ ID NO: 828) orAREGLQRVGVLDA (SEQ ID NO:829), and the anti-HTRAl antibody light chain variable region comprises CDRLI : QSLLDEAGETY (SEQ ID NO:837), CDRL2: EV (SEQ ID NO: 838), and CDRL3 : QQATYFPYT (SEQ ID NO: 839).11. The antibody conjugate according to any one of arrangements 1-8, wherein the anti-HTRAl antibody heavy chain variable region comprises CDRHI : GFSLTFY (SEQ ID NO: SEQ ID NO:835), CDRH2: YTSGY (SEQ ID NO:836), and CDRH3 : EGLQRVGVLDA (SEQ ID NO:834) or EGLQRVGVFDA (SEQ ID NO:832) or EGLQRVGVMDA (SEQ ID NO:833), and the anti-HTRAl antibody light chain variable region comprises CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRi.2: EVSLLES (SEQ ID NO:841), and CDRL3 : QQATYFPYT (SEQ ID NO:839).12. The antibody conjugate according to any one of the preceding arrangements, wherein the anti-HTRAl antibody heavy chain isotype is human IgGl.13. The antibody conjugate according to any one of the preceding arrangements, wherein the heavy chain constant region of the anti-HTRAl antibody has one or more mutations relative to the constant region of human IgGl to modulate effector function.14. The antibody conjugate according to arrangement 13, wherein the mutations are to one or more of the following amino acid positions (EU numbering): E233X, L234X, L235X, G236X, G237X, A327X, A330X, and P331X wherein X is any natural or unnatural amino acid.15. The antibody conjugate according to arrangement 14, wherein the mutations are selected from the group consisting of (EU numbering): E233P, L234V, L234A, L235A, G237A, A327G, A33 OS, and P33 IS.16. The antibody conjugate according to arrangement 15, comprising the following mutations: L234A, L235A, and G237A (EU numbering).17. The antibody conjugate according to any one of the preceding arrangements, wherein the cysteine is in the anti-HTRAl antibody heavy chain and is Q347C (EU numbering) or L443C (EU numbering).18. The antibody conjugate according to any one of the preceding arrangements, wherein the cysteine is L443C (EU numbering).19. The antibody conjugate according to any one of the preceding arrangements, wherein the anti-HTRAl antibody heavy chain comprises a heavy chain variable region (VH)comprising an amino acid sequence at least 80% identical to any one of SEQ ID NOs:725, 742, 744, 745, 746, and the anti-HTRAl antibody light chain comprises a light chain variable region (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO:748.20. The antibody conjugate according to any one of the preceding arrangements, wherein the phosphorylcholine containing polymer comprises 2-(methacryloyloxyethyl)-2'- (trimethylammonium)ethyl phosphate (MPC) monomers as set forth below:21. The antibody conjugate according to any one of the preceding arrangements, wherein the polymer has three or more arms or is synthesized with an initiator comprising 3 or more polymer initiation sites.22. The antibody conjugate according to any one of the preceding arrangements, wherein the polymer has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 arms or is synthesized with an initiator comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 polymer initiation sites.23. The antibody conjugate according to any one of the preceding arrangements, wherein the polymer has 2, 3, 6, or 9 arms or is synthesized with an initiator comprising 2, 3, 6, or 9 polymer initiation sites.24. The antibody conjugate according to any one of the preceding arrangements, wherein the polymer has 9 arms or is synthesized with an initiator comprising 9 polymer initiation sites.25. The antibody conjugate according to any one of the preceding arrangements, wherein the polymer has a molecular weight between about 300,000 and about 1,750,000 Daas measured by size exclusion chromatography - multi angle light scattering (hereinafter “SEC-MALS”).26. The antibody conjugate according to arrangement 25, wherein the polymer has a molecular weight between about 500,000 and about 1,000,000 Da.27. The antibody conjugate according to arrangement 26, wherein the polymer has a molecular weight between about 750,000 to about 850,000 Da.28. The antibody conjugate according to any one of the preceding arrangements, which is purified.29. The antibody conjugate according to any one of the preceding arrangements, which is polydisperse in the polymer.30. The antibody conjugate according to arrangement 29, wherein the polymer has a poly dispersity value (PDI) of less than about 1.2.31. An antibody conjugate comprising an anti-HTRAl immunoglobulin G (IgG) bonded to a polymer, which polymer comprises MPC monomers, wherein the anti-HTRAl antibody heavy chain comprises: a heavy chain variable region (VH) comprising an amino acid sequence at least 80% identical to any one of SEQ ID NOs:725, 742, 744, 745, 746, C-terminally fused to a heavy chain constant region (HC) comprising an amino acid sequence of SEQ ID NO:536, wherein the polymer is bonded to C326 of SEQ ID NO:536, and wherein the anti-HTRAl antibody light chain comprises: a light chain variable region (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 748, C-terminally fused to a light chain constant region (LC) comprising an amino acid sequence of SEQ ID NO:537.32. The antibody conjugate of any one of the preceding arrangements, wherein the polymer has 9 arms; and the polymer has a molecular weight of between about 600,000 to about 900,000 Da.33. The antibody conjugate of any one of the preceding arrangements, which has the structure of Formula (I):wherein: each heavy chain of the anti-HTRAl antibody is denoted by the letter H, and each light chain of the anti-HTRAl antibody is denoted by the letter L; the polymer is bonded to the anti-HTRAl antibody through the sulfhydryl of C443 (EU numbering), which bond is depicted on one of the heavy chains;PC is , where the curvy line indicates the point of attachment to the rest of the polymer, where X is a) -OR where R is -H, methyl, ethyl, propyl, isopropyl; b) -H; c) any halogen, including -Br, -Cl, or -I; d) -SCN; or e) - NCS; andwherein either i) nl, n2, n3, n4, n5, n6, n7, n8 and n9 are the same or different and are integers from 0 to 3000; or ii) nl, n2, n3, n4, n5, n6, n7, n8 and n9 are the same or different such that the sum of nl, n2, n3, n4, n5, n6, n7, n8 and n9 is 2500 plus or minus 15%.34. An antibody conjugate comprising an anti-HTRAl immunoglobulin G (IgG) covalently bonded to a polymer, which polymer comprises MPC monomers, wherein the anti- HTRAl antibody heavy chain comprises: a heavy chain variable region (VH) comprising an amino acid sequence comprising SEQ ID NOs:725, 742, 744, 745, 746, C-terminally fused to a heavy chain constant region (HC) comprising an amino acid sequence of SEQ ID NO:536, wherein the polymer is bonded to C326 of SEQ ID NO:536, and wherein the anti-HTRAl antibody light chain comprises: a light chain variable region (VL) comprising an amino acid sequence comprising SEQ ID NO:748, C-terminally fused to a light chain constant region (LC) comprising an amino acid sequence of SEQ ID NO:537.35. An anti-HTRAl antibody which comprises a heavy chain and a light chain, wherein the heavy chain comprises: a CDRnl having an amino acid sequence of a CDRul in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12,7.17, and 8.1; a CDRH2 having an amino acid sequence of a CDRH2 in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12,7.17, and 8.1; and a CDRH3 having an amino acid sequence of a CDRH3 in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12,7.17, and 8.1, and wherein the anti-HTRAl antibody light chain comprises a light chain variable region (VL) comprising: a CDRLI having an amino acid sequence of a CDRLI in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13,7.18, and 8.2;a CDRL2 having an amino acid sequence of a CDRL2 in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2; a CDRL3 having an amino acid sequence of a CDRL3 in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2.36. The antibody according to arrangement 35, wherein the anti-HTRAl antibody VH comprises 3 CDRs each having an amino acid sequence of the corresponding CDRs in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, and the anti-HTRAl antibody VL comprises 3 CDRs each having an amino acid sequence of the corresponding CDRs in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2.37. The antibody according to arrangement 36, wherein the 3 VH CDR sequences are paired with the 3 VL CDR sequences according to any one of the paired arrangements of VH and VL sequences provided in FIG. 21 and Tables 0.4, 0.5, 0.7, 0.10, 0.11, 0.12, 1.2, 6.3, and 7.1.38. The antibody according to arrangement 36, wherein the anti-HTRAl antibody VH comprises 3 CDRs each having an amino acid sequence of the corresponding CDRs in SEQ ID NO:725, 742, 744, 745, or 746, and the anti-HTRAl antibody VL comprises 3 CDRs each having an amino acid sequence of the corresponding 3 CDRs in SEQ ID NO: 748.39. An anti-HTRAl antibody which comprises a heavy chain and a light chain, wherein the heavy chain comprises CDRHI : FYHVH (SEQ ID NO:830), CDRH2: SIYTSGYTEYASALES (SEQ ID NO:831), and CDRH3: EGLQRVGVLDA (SEQ ID NO 834) or EGLQRVGVFDA (SEQ ID NO:832) or EGLQRVGVMDA (SEQ ID NO:833), and the light chain comprises CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO: 841), and CDRL3 : QQATYFPYT (SEQ ID NO: 839), and the heavy chain isotype is IgGl, wherein the IgGl constant region comprises one or more of the following mutations to modulate effector function (EU numbering): L234A, L235A, and G237A.40. An anti-HTRAl antibody which comprises a heavy chain and a light chain, wherein the heavy chain comprises CDRHI : GFSLTFYH (SEQ ID NO: SEQ ID NO:825),CDRH2: IYTSGYT (SEQ ID NO:826), and CDRH3 : AREGLQRVGVFDA (SEQ ID NO:827) or AREGLQRVGVMDA (SEQ ID NO: 828) or AREGLQRVGVLDA (SEQ ID NO: 829), and the anti-HTRAl antibody light chain variable region comprises CDRLI : QSLLDEAGETY (SEQ ID NO:837), CDRL2: EV (SEQ ID NO:838), and CDRL3 : QQATYFPYT (SEQ ID NO:839), and the heavy chain isotype is IgGl, wherein the IgGl constant region comprises one or more of the following mutations to modulate effector function (EU numbering): L234A, L235A, and G237A.41. An anti-HTRAl antibody which comprises a heavy chain and a light chain, wherein the heavy chain comprises CDRul : GFSLTFY (SEQ ID NO: SEQ ID NO:835), CDRH2: YTSGY (SEQ ID NO:836), and CDRH3 : EGLQRVGVLDA (SEQ ID NO:834) or EGLQRVGVFDA (SEQ ID NO:832) or EGLQRVGVMDA (SEQ ID NO:833), and the anti- HTRAl antibody light chain variable region comprises CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO:841), and CDRL3 : QQATYFPYT (SEQ ID NO: 839), wherein the IgGl constant region comprises one or more of the following mutations to modulate effector function (EU numbering): L234A, L235A, and G237A.42. The antibody according to any one of arrangements 35-41, comprising the following mutations (EU numbering): L234A, L235A, and G237A.43. The antibody according to any one of arrangements 35-42, wherein the anti- HTRAl antibody heavy chain comprises a heavy chain variable region (VH) comprising an amino acid sequence at least 80% identical to at least one of SEQ ID NOs:725, 742, 744, 745, 746, and the anti-HTRAl antibody light chain comprises a light chain variable region (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO:748.44. An antibody comprising: a heavy chain amino acid variable region that comprises an amino acid sequence at least 80% identical to any one of SEQ ID NOs:725, 742, 744, 745, 746; and a light chain amino acid variable region that comprises an amino acid sequence at least 80% identical to SEQ ID NO: 748.45. The antibody of arrangement 44, wherein the antibody is a human IgGl, and wherein a heavy chain constant region comprises one or more mutations that reduce an immune-mediated effector function.46. The antibody of arrangement 44 or 45, wherein the antibody is further conjugated to a polymer to form a bioconjugate, and wherein the bioconjugate has a molecular weight between about 350,000 and 1,900,000 Daltons.47. The antibody of arrangement 46, wherein the Poly dispersity Index (PDI) is equal to or less than 1.5.48. An antibody that binds to HTRA1, the antibody comprising: a CDRHI that is the CDRHI in any one of SEQ ID NOs:725, 742, 744, 745, 746; a CDRH2 that is the CDRH2 in any one of SEQ ID NOs:725, 742, 744, 745, 746; a CDRH3 that is the CDRH3 in any one of SEQ ID NOs:725, 742, 744, 745, 746; a CDRLI that is the CDRLI in SEQ ID NO:748; a CDRL2 that is the CDRL2 in SEQ ID NO:748; a CDRL3 that is the CDRL3 in SEQ ID NO:748; at least one of the following mutations (EU numbering): L234A, L235A, and G237A; and at least one of the following mutations(EU numbering): Q347C or L443C.49. The antibody of arrangement 48, wherein the antibody comprises all three of the following mutations (EU numbering) L234A, L235A, and G237A, and wherein the antibody comprises L443C (EU numbering).50. The antibody or antibody conjugate of any one of the preceding arrangements, wherein the heavy chain comprises a heavy constant region having an amino acid sequence at least 80% identical to SEQ ID NO:536.51. The antibody or antibody conjugate of any one of the preceding arrangements, wherein the light chain comprises a light chain constant region having an amino acid sequence at least 80% identical to SEQ ID NO: 537.52. A pharmaceutical composition comprising the antibody conjugate and / or the antibody according to any one of the preceding arrangements, in a liquid solution.53. A pharmaceutical composition comprising the antibody conjugate and / or the antibody according to any one of the preceding arrangements, and a pharmaceutically acceptable carrier.54. A method for treatment or prophylaxis of an ocular disease comprising administering the antibody conjugate and / or the antibody according to any one of arrangements 1-51, or the pharmaceutical composition according to arrangement 52 or 53.55. The method for treatment or prophylaxis according to arrangement 54, wherein the ocular disease is selected from the group consisting of diabetic retinopathy, age-related macular degeneration (AMD) (e.g., early, intermediate, or advanced AMD), retinopathy of prematurity (ROP), dry AMD, geographic atrophy, wet AMD, polypoidal choroidal vasculopathy, and HTRA1 -associated disorders.56. The method for treatment or prophylaxis according to arrangement 55, wherein the disease is diabetic retinopathy.57. The method for treatment or prophylaxis according to arrangement 55, wherein the disease is early, intermediate or advanced AMD.58. The method for treatment or prophylaxis according to arrangement 54, wherein the ocular disease is an HTRA-1 -associated disorder.59. The method for treatment or prophylaxis according to arrangement 54 or 55, wherein the ocular disease is dry AMD or geographic atrophy.60. method for treatment or prophylaxis according to arrangement 59, wherein the dry AMD comprises early, intermediate or advanced dry AMD.61. A method of making an anti-HTRAl antibody conjugate, the method comprising conjugating the anti-HTRAl antibody of any one of arrangements 35-51 to a phosphorylcholine containing polymer, wherein the phosphorylcholine containing polymer comprises a sulfhydryl specific reacting group selected from the group consisting of a maleimide, a vinylsulfone, an orthopyridyl-disulfide, and an iodoacetamide, wherein the sulfhydryl specific reacting group on the phosphorylcholine containing polymer reacts with the cysteine residue on the anti-HTRAl antibody to make the antibody conjugate.62. A method of making an antibody conjugate comprising an anti-HTRAl antibody conjugated to a phosphorylcholine containing polymer, the method comprising the step of: conjugating an anti-HTRAl antibody to a phosphorylcholine containing polymer, wherein the anti-HTRAl antibody comprises a non-native cysteine residue outside a variable region of the antibody, wherein the phosphorylcholine containing polymer comprises a sulfhydryl specific reacting group selected from the group consisting of a maleimide, a vinylsulfone, an orthopyridyl-disulfide, and an iodoacetamide, and wherein the sulfhydryl specific reacting group on the phosphorylcholine containing polymer reacts with the cysteine residue on the anti-HTRAl antibody to make the antibody conjugate.63. The method according to arrangement 62, wherein the anti-HTRAl antibody is an immunoglobulin G (IgG) and the cysteine is in the Fc region of the antibody.64. The method according to arrangement 62 or 63 wherein the anti-HTRAl antibody comprises a light chain and a heavy chain, wherein the anti-HTRAl antibody heavy chain comprises CDRnl : FYHVH (SEQ ID NO:830), CDRn2: SIYTSGYTEYASALES (SEQ ID NO:831), and CDRH3 : EGLQRVGVLDA (SEQ ID NO:834) or EGLQRVGVFDA (SEQ ID NO:832) or EGLQRVGVMDA (SEQ ID NO:833), and the anti-HTRAl antibody light chain comprises CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO:841), and CDRL3 : QQATYFPYT (SEQ ID NO:839).65. The method according to any one of arrangements 62-64, wherein the anti- HTRAl antibody heavy chain isotype is IgGl.66. The method according to arrangement 65, wherein the anti-HTRAl antibody has one or more mutations relative to an IgGl constant region to modulate effector function.67. The method according to arrangement 66, wherein the mutations are to one or more of the following amino acid positions (EU numbering): E233X, L234X, L235X, G236X, G237X, G236X, D270X, K322X, A327X, P329X, A33 OX, A33 OX, P331X, and P331X, wherein X is any natural or non-natural amino acid.68. The method according to arrangement 67, wherein the mutations are selected from the group consisting of (EU numbering) E233P, L234V, L234A, L235A, G237A, A327G, A330S, and P331S.69. The method according to arrangement 68, wherein the mutations are (EU numbering) L234A, L235A, and G237A.70. The method according to any one of arrangements 62-69, wherein the nonnative cysteine residue is selected from the group consisting of Q347C (EU numbering) and L443C (EU numbering).71. The method according to arrangement 70 wherein the non-native cysteine residue is L443C (EU numbering).72. The method according to any one of arrangements 62-71, wherein the anti- HTRA1 antibody heavy chain comprises a heavy chain variable region (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 725, 742, 744, 745, 746 and the anti-HTRAl antibody light chain comprises a light chain variable region (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 748.73. The method according to any one of arrangements 61-72, wherein the sulfhydryl specific reacting group is maleimide.74. The method according to any one of arrangements 61-73, wherein the phosphorylcholine containing polymer comprises 2-(methacryloyloxyethyl)-2'- (trimethylammonium)ethyl phosphate (MPC) monomers as set forth below:75. The method according to any one of arrangements 61-74, wherein the polymer has three or more arms.76. The method according to any one of arrangements 61-75, wherein the polymer has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 arms.77. The method according to any one of arrangements 61-76, wherein the polymer has 2, 3, 6, or 9 arms.78. The method according to arrangement 77, wherein the polymer has 9 arms.79. The method according to any one of arrangements 61-78, wherein the polymer has a molecular weight between about 300,000 and 1,750,000 Da.80. The method according to arrangement 79, wherein the polymer has a molecular weight between about 600,000 and 1,000,000 Da.81. The method according to arrangement 80, wherein the polymer has a molecular weight of between about 600,000 to 850,000 Da.82. The method according to any one of arrangements 61-81, further comprising the step of contacting the anti-HTRAl antibody with a thiol reductant under conditions that produce a reduced cysteine sulfhydryl group to produce a reduced anti-HTRAl antibody in which all cysteine residues are reduced.83. The method according to arrangement 82, wherein the thiol reductant is selected from the group consisting of Tris[2-carboxyethyl]phosphine hydrochloride (TCEP), dithiothreitol (DTT), dithioerythritol (DTE), sodium borohydride (NaBH4), sodium cyanoborohydride (NaCNBHs), P-mcrcaptocthanol (BME), 3,3 ',3''- Phosphanetriyltris(benzenesulfonic acid) trisodium (TPPTS), cysteine hydrochloride, and cysteine.84. The method according to arrangement 83, wherein the thiol reductant is TCEP.85. The method according to any one of arrangements 82-84, wherein the concentration of the thiol reductant is between 1 and 100 fold molar excess relative to the concentration of the anti-HTRAl antibody.86. The method according to arrangement 85 wherein the concentration of the thiol reductant is between 20 to 50-fold molar excess relative to the concentration of the anti- HTRAl antibody.87. The method according to any one of arrangements 82-86, further comprising the steps of removing the thiol reductant from the reduced anti-HTRAl antibody, and treating the reduced anti-HTRAl antibody with an oxidizing agent.88. The method according to arrangement 87, wherein the oxidizing agent is air, aqueous CuSC , or dehydroascorbic acid (DHAA).89. The method according to any one of arrangements 82-88, further comprising the step of purifying the antibody conjugate.90. The method according to arrangement 89, wherein the antibody conjugate is purified using a technique selected from the group consisting of ion exchange chromatography, hydrophobic interaction chromatography, size exclusion chromatography, affinity chromatography, and combinations thereof.91. The method according to arrangement 89 or 90, wherein the purified antibody conjugate retains at least 20% biological activity relative to an unconjugated anti-HTRAl antibody.92. The method according to arrangement 91, wherein the purified antibody conjugate retains at least 50% biological activity relative to an unconjugated anti-HTRAl antibody.93. The method according to arrangement 92, wherein the purified antibody conjugate retains at least 90% biological activity relative to an unconjugated anti-HTRAl antibody.94. The method according to any one of arrangements 58-93, wherein the purified antibody conjugate has an increased half-life relative to an unconjugated anti-HTRAl antibody.95. The method according to arrangement 94, wherein the purified antibody conjugate has at least a 1.5-fold increase in half-life relative to an unconjugated anti-HTRAl antibody.96. An isolated cell line that produces an anti-HTRAl antibody of any one of arrangements 34-51.97. The isolated cell line of arrangement 96, wherein the cell line is selected from the group consisting of CHO, klSV, XCeed, CHOK1SV, and GS-KO.98. An isolated nucleic acid encoding an anti-HTRAl antibody of any one of arrangements 35-51.99. A recombinant expression vector comprising the nucleic acid of arrangement 98.100. A host cell comprising the expression vector of arrangement 99.101. A method of producing an anti-HTRAl antibody, comprising: culturing a cell line that recombinantly produces an anti-HTRAl antibody of any one of arrangements 35-51, under conditions wherein the antibody is produced; and recovering the antibody.102. A method of producing an anti-HTRAl antibody, comprising: culturing a cell line comprising: a nucleic acid encoding a heavy chain comprising any one of the heavy chain variable region (VH) amino acid sequences shown in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1; and a nucleic acid encoding a light chain comprising any one of the light chain variable region (VL) amino acid sequences shown in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, under conditions wherein an antibody comprising the heavy chain and the light chain is produced; and recovering the antibody.103. The method of arrangement 102, wherein the heavy and light chains of the antibody are encoded on separate vectors.104. The method of arrangement 102, wherein the heavy and light chains of the antibody are encoded on the same vector.105. An antibody that specifically binds to HTRA1, wherein the antibody inhibits a protease activity ofHTRAl.106. The antibody of arrangement 105, wherein the antibody inhibits the protease activity of HTRAl with an ICso of about 2.0 x 10'10M or less.107. An antibody that specifically binds to HTRA1, wherein the antibody binds to HTRA1 with a binding affinity (KD) of 1.0 X 10'10M or less.108. An antibody that specifically binds to HTRA1 , wherein the antibody does not bind a loop A peptide of HTRA1.109. An antibody that specifically binds to HTRA1, wherein the antibody does not bind a loop A peptide of HTRA1 and wherein the antibody inhibits a protease activity of HTRA1.110. The antibody of arrangement 108 or 109, wherein the loop A peptide of HTRA1 comprises or consists of FRKLPFSKREVPV (SEQ ID NO:851).111. The method, antibody, or antibody conjugate of any one of the preceding arrangements, wherein the antibody or conjugate thereof inhibits casein digestion.112. The method, antibody, or antibody conjugate of any one of the preceding arrangements, wherein the antibody or conjugate thereof selectively binds to a trimeric form of HTRA1 over a monomeric form of HTRA1.113. The method, antibody, or antibody conjugate of any one of the preceding arrangements, wherein the antibody or conjugate thereof does not bind to a loop A peptide of HTRA1.114. The method, antibody, or antibody conjugate of any one of the preceding arrangements, wherein the antibody or conjugate thereof includes at least one of the pairings of VH and VL as follows, or at least a VH / VL pairing where each VH and VL sequence is at least 80% identical to a corresponding VH and VL sequence of one of the following sequence pairs:115. The method, antibody, or antibody conjugate of any one of the preceding arrangements, wherein the antibody or conjugate thereof includes at least one of the pairings of VH and VL as follows, or at least a VH / VL pairing where each VH and VL sequence is at least 80% identical to a corresponding VH and VL sequence of the sequence pairs provided in FIG. 21 and Tables 0.1, 0.4, 0.5, 0.7, 0.10, 0.11, 0.12, 1.2, 6.3, and 7.1.116. The method, antibody, or antibody conjugate of any one of the preceding arrangements, wherein the antibody or conjugate thereof, wherein the antibody or conjugate thereof includes at least one VH point mutation, one VL point mutation, or both from the following:117. The method, antibody, or antibody conjugate of any one of the preceding arrangements, wherein the antibody or conjugate thereof neutralizes HTRA1 cleavage activity.118. The method, antibody, or antibody conjugate of any one of the preceding arrangements, wherein the antibody or conjugate thereof neutralizes HTRA1 serine protease activity.119. The method, antibody, or antibody conjugate of any one of the preceding arrangements, wherein the antibody or conjugate thereof comprises a humanized antibody.120. The method, antibody, or antibody conjugate of any one of the preceding arrangements, wherein the antibody or conjugate thereof comprises one or more of the following CDRs, or a variant thereof with no more than 3 point mutations per CDR:121. Use of an antibody conjugate or antibody of any one of arrangements 1-51, or the pharmaceutical composition of arrangement 52 or 53 for treatment or prophylaxis of an ocular disease in a subject in need thereof.122. Use of an antibody conjugate or antibody of any one of arrangements 1-51 for the preparation of a medicament for treatment or prophylaxis of an ocular disease in a subject in need thereof.123. The use of arrangement 121 or 122, wherein the ocular disease is selected from the group consisting of diabetic retinopathy, age-related macular degeneration (AMD) (e.g., early, intermediate, or advanced AMD), retinopathy of prematurity (ROP), dry AMD, geographic atrophy, wet AMD, polypoidal choroidal vasculopathy, and HTRA1 -associated disorders.

[0334] The following examples are offered for illustrative purposes only, and are not intended to limit the scope of the present disclosure in any way. Indeed, various modifications of the embodiments in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims.EXAMPLESExample 1 - Initial antibody generation and screening

[0335] This non-limiting example shows generation and screening of antibodies against HTRA1.

[0336] Antibodies against HTRA1 were generated and screened by AbCellera Biologies (Vancouver, Canada). 3 wild-type Sprague Dawley rats, 10 wild-type balb / c and 8 HTRA1 -knockout (Taconic Biosciences, Inc.) mice were immunized with recombinant his- tagged human HTRA1 protease domain (HTRA1 PD, OG2138, Table 1.1) in accordance with AbCellera’ s proprietary immunization strategy. Tissues from selected animals were harvestedand single antibody-secreting cells were isolated into nanoliter-volume chambers. This was followed by bead-based fluorescence assays to identify antibodies against HTRA1 with diverse epitope binding.Table 1.1 - HTRA1 and HTRA3 sequences

[0337] Secreted antibodies were captured on beads coated with anti-mouse IgG antibodies or the antigen (OG2161 or a specific HTRA1 epitope, OG2185, Table 1.1). Then secreted antibody binding was detected by the binding of a secondary fluorescent tagged protein based on assay format used. Binding to HTRA3 (OG2165; Table 1.1) was also evaluated. A total of 264 unique pairs of heavy and light chains were identified and sequenced (Table 1.2).Table 1.2 Unique mouse and rat antibody sequences recovered from single anti-HTRAl antibody producing cells.

[0338] In some embodiments, an antibody that binds to HTRA1, e.g., human HTRA1, is obtained by immunizing a host animal, e.g., a mouse or rat, with human HTRA1 protease domain. In some embodiments, an antibody that binds to HTRA1, e.g., human HTRA1, is obtained by selecting for a clone that binds to a human HTRA1 protease domain and / or binds or does not bind a HTRA1 loop A and / or does not bind HTRA3. In some embodiments, an antibody that binds to HTRA1, e.g., human HTRA1, is obtained by selectingfor a clone that binds to a human HTRA1 protease domain and / or a HTRA1 loop A and / or does not bind HTRA3. In some embodiments, an antibody that binds to HTRA1, e.g., human HTRA1, is obtained by selecting for a clone that binds to a human HTRA1 protease domain and / or does not bind to a HTRA1 loop A and / or does not bind HTRA3. In some embodiments, an anti-HTRAl antibody of the present disclosure has 3 heavy chain CDR (CDRH) of the 3 CDRH of at least one of the antibody clones set forth in Table 1.2, and has 3 light chain CDR (CDRL) of the 3 CDRL of the corresponding antibody clone. In some embodiments, an anti- HTRAl antibody of the present disclosure has a VH having the amino acid sequence of the VH domain of at least one of the antibody clones set forth in Table 1.2, and has a VL having the amino acid sequence of the VL of the corresponding antibody clone.Example 2 - Binding characterization of chimeric anti-HTRAl antibodies

[0339] One hundred (out of 264) representative sequences for each clonal family (aHTRAl l - aHTRAl lOO, Table 1.2) were chosen to be recombinantly expressed in Expi293 cells and purified using MabSelect™. These selected pairs of variable regions were expressed in fusion with constant regions of a...

Claims

WHAT IS CLAIMED IS:

1. An antibody conjugate comprising (1) an anti-HTRAl antibody and (2) a phosphorylcholine containing polymer, wherein the polymer is covalently bonded to the antibody at a non-native cysteine outside a variable region of the antibody.

2. The antibody conjugate according to claim 1, wherein the anti-HTRAl antibody comprises a light chain and a heavy chain, said heavy chain comprising an Fc region.

3. The antibody conjugate according to claim 1 or 2, wherein the cysteine is in the Fc region of the heavy chain.

4. The antibody conjugate according to any one of the preceding claims, wherein the anti-HTRAl antibody is an immunoglobulin G (IgG).

5. The antibody conjugate according to any one of the preceding claims, wherein the anti-HTRAl antibody heavy chain comprises a heavy chain variable region (VH) comprising: a heavy chain complementarity determining region 1 (CDRHI) having an amino acid sequence of a CDRHI in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, or with a variation at no more than 5 residues thereof; a CDRn2 having an amino acid sequence of a CDRn2 in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, or with a variation at no more than 5 residues thereof; and a CDRH3 having an amino acid sequence of a CDRH3 in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, or with a variation at no more than 5 residues thereof, and wherein the anti-HTRAl antibody light chain comprises a light chain variable region (VL) comprising: a light chain complementarity determining region 1 (CDRLI) having an amino acid sequence of a CDRLI in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, or with a variation at no more than 5 residues thereof;a CDRL2 having an amino acid sequence of a CDRL2 in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, or with a variation at no more than 5 residues thereof; and a CDRL3 having an amino acid sequence of a CDRL3 in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, or with a variation at no more than 5 residues thereof.

6. The antibody conjugate according to claim 5, wherein the anti-HTRAl antibody VH comprises 3 CDRs each having an amino acid sequence of the corresponding CDRs in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, or with a variation at no more than 5 residues thereof, and the anti-HTRAl antibody VL comprises 3 CDRs each having an amino acid sequence of the corresponding CDRs in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, or with a variation at no more than 5 residues thereof .

7. The antibody conjugate according to claim 6, wherein the 3 VH CDR sequences are paired with the 3 VL CDR sequences according to any one of the paired arrangements of VH and VL sequences provided in FIG. 21 and Tables 0.1, 0.4, 0.5, 0.7, 0.10, 0.11, 0.12, 1.2, 6.3, and 7.1.

8. The antibody conjugate according to claim 6, wherein the anti-HTRAl antibody VH comprises 3 CDRs each having an amino acid sequence of the corresponding CDRs in any one of SEQ ID NOs:725, 742, 744, 745, 746, and the anti-HTRAl antibody VL comprises 3 CDRs each having an amino acid sequence of the corresponding 3 CDRs in SEQ ID NO:748.

9. The antibody conjugate according to any one of the preceding claims, wherein the anti-HTRAl antibody heavy chain variable region comprises CDRHI : FYHVH (SEQ ID NO: SEQ ID NO:830), CDRH2: SIYTSGYTE YAS ALES (SEQ ID NO:831), and CDRH3 : EGLQRVGVLDA (SEQ ID NO:834) or EGLQRVGVFDA (SEQ ID NO:832) or EGLQRVGVMDA (SEQ ID NO:833), and the anti-HTRAl antibody light chain variable region comprises CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO:841), and CDRL3 : QQATYFPYT (SEQ ID NO:839).

10. The antibody conjugate according to any one of claims 1-8, wherein the anti- HTRA1 antibody heavy chain variable region comprises CDRHI : GFSLTFYH (SEQ ID NO: SEQ ID NO:825), CDRH2: IYTSGYT (SEQ ID NO:826), and CDRH3 : AREGLQRVGVFDA (SEQ ID NO: 827) or AREGLQRVGVMDA (SEQ ID NO: 828) or AREGLQRVGVLDA (SEQ ID NO:829), and the anti-HTRAl antibody light chain variable region comprises CDRLI : QSLLDEAGETY (SEQ ID NO:837), CDRL2: EV (SEQ ID NO:838), and CDRL3 : QQATYFPYT (SEQ ID NO:839).

11. The antibody conjugate according to any one of claims 1-8, wherein the anti- HTRAl antibody heavy chain variable region comprises CDRHI : GFSLTFY (SEQ ID NO: SEQ ID NO: 835), CDRH2: YTSGY (SEQ ID NO: 836), and CDRH3 : EGLQRVGVLDA (SEQ ID NO:834) or EGLQRVGVFDA (SEQ ID NO:832) or EGLQRVGVMDA (SEQ ID NO:833), and the anti-HTRAl antibody light chain variable region comprises CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO:841), and CDRL3 : QQATYFPYT (SEQ ID NO:839).

12. The antibody conjugate according to any one of the preceding claims, wherein the anti-HTRAl antibody heavy chain isotype is human IgGl.

13. The antibody conjugate according to any one of the preceding claims, wherein the heavy chain constant region of the anti-HTRAl antibody has one or more mutations relative to the constant region of human IgGl to modulate effector function.

14. The antibody conjugate according to claim 13, wherein the mutations are to one or more of the following amino acid positions (EU numbering): E233X, L234X, L235X, G236X, G237X, A327X, A330X, and P331X wherein X is any natural or unnatural amino acid.

15. The antibody conjugate according to claim 14, wherein the mutations are selected from the group consisting of (EU numbering): E233P, L234V, L234A, L235A, G237A, A327G, A33 OS, and P33 IS.

16. The antibody conjugate according to claim 15, comprising the following mutations: L234A, L235A, and G237A (EU numbering).

17. The antibody conjugate according to any one of the preceding claims, wherein the cysteine is in the anti-HTRAl antibody heavy chain and is Q347C (EU numbering) or L443C (EU numbering).

18. The antibody conjugate according to any one of the preceding claims, wherein the cysteine is L443C (EU numbering).

19. The antibody conjugate according to any one of the preceding claims, wherein the anti-HTRAl antibody heavy chain comprises a heavy chain variable region (VH) comprising an amino acid sequence at least 80% identical to any one of SEQ ID NOs:725, 742, 744, 745, 746, and the anti-HTRAl antibody light chain comprises a light chain variable region (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO:748.

20. The antibody conjugate according to any one of the preceding claims, wherein the phosphorylcholine containing polymer comprises 2-(methacryloyloxyethyl)-2'- (trimethylammonium)ethyl phosphate (MPC) monomers as set forth below:

21. The antibody conjugate according to any one of the preceding claims, wherein the polymer has three or more arms or is synthesized with an initiator comprising 3 or more polymer initiation sites.

22. The antibody conjugate according to any one of the preceding claims, wherein the polymer has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 arms or is synthesized with an initiator comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 polymer initiation sites.

23. The antibody conjugate according to any one of the preceding claims, wherein the polymer has 2, 3, 6, or 9 arms or is synthesized with an initiator comprising 2, 3, 6, or 9 polymer initiation sites.

24. The antibody conjugate according to any one of the preceding claims, wherein the polymer has 9 arms or is synthesized with an initiator comprising 9 polymer initiation sites.

25. The antibody conjugate according to any one of the preceding claims, wherein the polymer has a molecular weight between about 300,000 and about 1,750,000 Da as measured by size exclusion chromatography - multi angle light scattering (hereinafter “SEC- MALS”).

26. The antibody conjugate according to claim 25, wherein the polymer has a molecular weight between about 500,000 and about 1,000,000 Da.

27. The antibody conjugate according to claim 26, wherein the polymer has a molecular weight between about 750,000 to about 850,000 Da.

28. The antibody conjugate according to any one of the preceding claims, which is purified.

29. The antibody conjugate according to any one of the preceding claims, which is polydisperse in the polymer.

30. The antibody conjugate according to claim 29, wherein the polymer has a poly dispersity value (PDI) of less than about 1.2.

31. An antibody conjugate comprising an anti-HTRAl immunoglobulin G (IgG) bonded to a polymer, which polymer comprises MPC monomers, wherein the anti-HTRAl antibody heavy chain comprises: a heavy chain variable region (VH) comprising an amino acid sequence at least 80% identical to any one of SEQ ID NOs:725, 742, 744, 745, 746, C-terminally fused to a heavy chain constant region (HC) comprising an amino acid sequence of SEQ ID NO:536, wherein the polymer is bonded to C326 of SEQ ID NO:536, and wherein the anti-HTRAl antibody light chain comprises: a light chain variable region (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO:748, C-terminally fused to a light chain constant region (LC) comprising an amino acid sequence of SEQ ID NO:537.

32. The antibody conjugate of any one of the preceding claims, wherein the polymer has 9 arms; and the polymer has a molecular weight of between about 600,000 to about900,000 Da.

33. The antibody conjugate of any one of the preceding claims, which has the structure of Formula (I):wherein: each heavy chain of the anti-HTRAl antibody is denoted by the letter H, and each light chain of the anti-HTRAl antibody is denoted by the letter L; the polymer is bonded to the anti-HTRAl antibody through the sulfhydryl of C443 (EU numbering), which bond is depicted on one of the heavy chains;PC is , where the curvy line indicates the point of attachment to the rest of the polymer, where X is a) -OR where R is -H, methyl, ethyl,propyl, isopropyl; b) -H; c) any halogen, including -Br, -Cl, or -I; d) -SCN; or e) - NCS; and wherein either i) nl, n2, n3, n4, n5, n6, n7, n8 and n9 are the same or different and are integers from 0 to 3000; or ii) nl, n2, n3, n4, n5, n6, n7, n8 and n9 are the same or different such that the sum of nl, n2, n3, n4, n5, n6, n7, n8 and n9 is 2500 plus or minus 15%.

34. An antibody conjugate comprising an anti-HTRAl immunoglobulin G (IgG) covalently bonded to a polymer, which polymer comprises MPC monomers, wherein the anti- HTRAl antibody heavy chain comprises: a heavy chain variable region (VH) comprising an amino acid sequence comprising SEQ ID NOs:725, 742, 744, 745, 746, C-terminally fused to a heavy chain constant region (HC) comprising an amino acid sequence of SEQ ID NO:536, wherein the polymer is bonded to C326 of SEQ ID NO:536, and wherein the anti-HTRAl antibody light chain comprises: a light chain variable region (VL) comprising an amino acid sequence comprising SEQ ID NO: 748, C-terminally fused to a light chain constant region (LC) comprising an amino acid sequence of SEQ ID NO:537.

35. An anti-HTRAl antibody which comprises a heavy chain and a light chain, wherein the heavy chain comprises: a CDRnl having an amino acid sequence of a CDRul in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12,7.17, and 8.1; a CDRH2 having an amino acid sequence of a CDRH2 in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12,7.17, and 8.1; and a CDRH3 having an amino acid sequence of a CDRH3 in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12,7.17, and 8.1, and wherein the anti-HTRAl antibody light chain comprises a light chain variable region (VL) comprising:a CDRLI having an amino acid sequence of a CDRLI in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2; a CDRL2 having an amino acid sequence of a CDRL2 in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2; a CDRL3 having an amino acid sequence of a CDRL3 in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2.

36. The antibody according to claim 35, wherein the anti-HTRAl antibody VH comprises 3 CDRs each having an amino acid sequence of the corresponding CDRs in any one of the VH sequences in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1, and the anti-HTRAl antibody VL comprises 3 CDRs each having an amino acid sequence of the corresponding CDRs in any one of the VL sequences in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2.

37. The antibody according to claim 36, wherein the 3 VH CDR sequences are paired with the 3 VL CDR sequences according to any one of the paired arrangements of VH and VL sequences provided in FIG. 21 and Tables 0.4, 0.5, 0.7, 0.10, 0.11, 0.12, 1.2, 6.3, and 7.1.

38. The antibody according to claim 36, wherein the anti-HTRAl antibody VH comprises 3 CDRs each having an amino acid sequence of the corresponding CDRs in SEQ ID NO:725, 742, 744, 745, or 746, and the anti-HTRAl antibody VL comprises 3 CDRs each having an amino acid sequence of the corresponding 3 CDRs in SEQ ID NO:748.

39. An anti-HTRAl antibody which comprises a heavy chain and a light chain, wherein the heavy chain comprises CDRHI : FYHVH (SEQ ID NO:830), CDRH2: SIYTSGYTEYASALES (SEQ ID NO:831), and CDRH3 : EGLQRVGVLDA (SEQ ID NO 834) or EGLQRVGVFDA (SEQ ID NO:832) or EGLQRVGVMDA (SEQ ID NO:833), and the light chain comprises CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO:841), and CDRL3 : QQATYFPYT (SEQ ID NO:839), and the heavy chain isotype is IgGl,wh erein the IgGl constant region comprises one or more of the following mutations to modulate effector function (EU numbering): L234A, L235A, and G237A.

40. An anti-HTRAl antibody which comprises a heavy chain and a light chain, wherein the heavy chain comprises CDRul: GFSLTFYH (SEQ ID NO: SEQ ID NO:825), CDRH2: IYTSGYT (SEQ ID NO:826), and CDRH3 : AREGLQRVGVFDA (SEQ ID NO:827) or AREGLQRVGVMDA (SEQ ID NO: 828) or AREGLQRVGVLDA (SEQ ID NO: 829), and the anti-HTRAl antibody light chain variable region comprises CDRLI : QSLLDEAGETY (SEQ ID NO:837), CDRL2: EV (SEQ ID NO:838), and CDRL3 : QQATYFPYT (SEQ ID NO:839), and the heavy chain isotype is IgGl, wherein the IgGl constant region comprises one or more of the following mutations to modulate effector function (EU numbering): L234A, L235A, and G237A.

41. An anti-HTRAl antibody which comprises a heavy chain and a light chain, wherein the heavy chain comprises CDRHI : GFSLTFY (SEQ ID NO: SEQ ID NO:835), CDRH2: YTSGY (SEQ ID NO:836), and CDRH3 : EGLQRVGVLDA (SEQ ID NO:834) or EGLQRVGVFDA (SEQ ID NO:832) or EGLQRVGVMDA (SEQ ID NO:833), and the anti- HTRAl antibody light chain variable region comprises CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO:841), and CDRL3 : QQATYFPYT (SEQ ID NO: 839), wherein the IgGl constant region comprises one or more of the following mutations to modulate effector function (EU numbering): L234A, L235A, and G237A.

42. The antibody according to any one of claims 35-41, comprising the following mutations (EU numbering): L234A, L235A, and G237A.

43. The antibody according to any one of claims 35-42, wherein the anti-HTRAl antibody heavy chain comprises a heavy chain variable region (VH) comprising an amino acid sequence at least 80% identical to at least one of SEQ ID NOs:725, 742, 744, 745, 746, and the anti-HTRAl antibody light chain comprises a light chain variable region (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 748.

44. An antibody comprising: a heavy chain amino acid variable region that comprises an amino acid sequence at least 80% identical to any one of SEQ ID NOs:725, 742, 744, 745, 746; anda light chain amino acid variable region that comprises an amino acid sequence at least 80% identical to SEQ ID NO: 748.

45. The antibody of claim 44, wherein the antibody is a human IgGl, and wherein a heavy chain constant region comprises one or more mutations that reduce an immune- mediated effector function.

46. The antibody of claim 44 or 45, wherein the antibody is further conjugated to a polymer to form a bioconjugate, and wherein the bioconjugate has a molecular weight between about 350,000 and 1,900,000 Daltons.

47. The antibody of claim 46, wherein the Poly dispersity Index (PDI) is equal to or less than 1.5.

48. An antibody that binds to HTRA1, the antibody comprising: a CDRnl that is the CDRnl in any one of SEQ ID NOs:725, 742, 744, 745, 746; a CDRH2 that is the CDRH2 in any one of SEQ ID NOs:725, 742, 744, 745, 746; a CDRH3 that is the CDRH3 in any one of SEQ ID NOs:725, 742, 744, 745, 746; a CDRLI that is the CDRLI in SEQ ID NO:748; a CDRL2 that is the CDRL2 in SEQ ID NO:748; a CDRL3 that is the CDRL3 in SEQ ID NO:748; at least one of the following mutations (EU numbering): L234A, L235A, and G237A; and at least one of the following mutations(EU numbering): Q347C or L443C.

49. The antibody of claim 48, wherein the antibody comprises all three of the following mutations (EU numbering) L234A, L235A, and G237A, and wherein the antibody comprises L443C (EU numbering).

50. The antibody or antibody conjugate of any one of the preceding claims, wherein the heavy chain comprises a heavy constant region having an amino acid sequence at least 80% identical to SEQ ID NO:536.51 . The antibody or antibody conjugate of any one of the preceding claims, wherein the light chain comprises a light chain constant region having an amino acid sequence at least 80% identical to SEQ ID NO:537.

52. A pharmaceutical composition comprising the antibody conjugate and / or the antibody according to any one of the preceding claims, in a liquid solution.

53. A pharmaceutical composition comprising the antibody conjugate and / or the antibody according to any one of the preceding claims, and a pharmaceutically acceptable carrier.

54. A method for treatment or prophylaxis of an ocular disease comprising administering the antibody conjugate and / or the antibody according to any one of claims 1-51, or the pharmaceutical composition according to claim 52 or 53.

55. The method for treatment or prophylaxis according to claim 54, wherein the ocular disease is selected from the group consisting of diabetic retinopathy, age-related macular degeneration (AMD) (e.g., early, intermediate, or advanced AMD), retinopathy of prematurity (ROP), dry AMD, geographic atrophy, wet AMD, polypoidal choroidal vasculopathy, and HTRA1 -associated disorders.

56. The method for treatment or prophylaxis according to claim 55, wherein the disease is diabetic retinopathy.

57. The method for treatment or prophylaxis according to claim 55, wherein the disease is early, intermediate or advanced AMD.

58. The method for treatment or prophylaxis according to claim 54, wherein the ocular disease is an HTRA-1 -associated disorder.

59. The method for treatment or prophylaxis according to claim 54 or 55, wherein the ocular disease is dry AMD or geographic atrophy.

60. method for treatment or prophylaxis according to claim 59, wherein the dry AMD comprises early, intermediate or advanced dry AMD.

61. A method of making an anti-HTRAl antibody conjugate, the method comprising conjugating the anti-HTRAl antibody of any one of claims 35-51 to a phosphorylcholine containing polymer, wherein the phosphorylcholine containing polymer comprises a sulfhydryl specific reacting group selected from the group consisting of a maleimide, a vinylsulfone, an orthopyridyl-disulfide, and an iodoacetamide, wherein thesulfhydryl specific reacting group on the phosphorylcholine containing polymer reacts with the cysteine residue on the anti-HTRAl antibody to make the antibody conjugate.

62. A method of making an antibody conjugate comprising an anti-HTRAl antibody conjugated to a phosphorylcholine containing polymer, the method comprising the step of: conjugating an anti-HTRAl antibody to a phosphorylcholine containing polymer, wherein the anti-HTRAl antibody comprises a non-native cysteine residue outside a variable region of the antibody, wherein the phosphorylcholine containing polymer comprises a sulfhydryl specific reacting group selected from the group consisting of a maleimide, a vinylsulfone, an orthopyridyl-disulfide, and an iodoacetamide, and wherein the sulfhydryl specific reacting group on the phosphorylcholine containing polymer reacts with the cysteine residue on the anti-HTRAl antibody to make the antibody conjugate.

63. The method according to claim 62, wherein the anti-HTRAl antibody is an immunoglobulin G (IgG) and the cysteine is in the Fc region of the antibody.

64. The method according to claim 62 or 63 wherein the anti-HTRAl antibody comprises a light chain and a heavy chain, wherein the anti-HTRAl antibody heavy chain comprises CDRnl: FYHVH (SEQ ID NO:830), CDRu2: SIYTSGYTEYASALES (SEQ ID NO 831), and CDRH3: EGLQRVGVLDA (SEQ ID NO:834) or EGLQRVGVFDA (SEQ ID NO:832) or EGLQRVGVMDA (SEQ ID NO:833), and the anti-HTRAl antibody light chain comprises CDRLI : RSSQSLLDEAGETYLA (SEQ ID NO:840), CDRL2: EVSLLES (SEQ ID NO: 841), and CDRL3 : QQATYFPYT (SEQ ID NO: 839).

65. The method according to any one of claims 62-64, wherein the anti-HTRAl antibody heavy chain isotype is IgGl.

66. The method according to claim 65, wherein the anti-HTRAl antibody has one or more mutations relative to an IgGl constant region to modulate effector function.

67. The method according to claim 66, wherein the mutations are to one or more of the following amino acid positions (EU numbering): E233X, L234X, L235X, G236X, G237X,G236X, D270X, K322X, A327X, P329X, A330X, A330X, P331X, and P331X, wherein X is any natural or non-natural amino acid.

68. The method according to claim 67, wherein the mutations are selected from the group consisting of (EU numbering) E233P, L234V, L234A, L235A, G237A, A327G, A330S, and P331S.

69. The method according to claim 68, wherein the mutations are (EU numbering) L234A, L235A, and G237A.

70. The method according to any one of claims 62-69, wherein the non-native cysteine residue is selected from the group consisting of Q347C (EU numbering) and L443C (EU numbering).

71. The method according to claim 70 wherein the non-native cysteine residue is L443C (EU numbering).

72. The method according to any one of claims 62-71, wherein the anti-HTRAl antibody heavy chain comprises a heavy chain variable region (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 725, 742, 744, 745, 746, and the anti-HTRAl antibody light chain comprises a light chain variable region (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO:748.

73. The method according to any one of claims 61-72, wherein the sulfhydryl specific reacting group is maleimide.

74. The method according to any one of claims 61-73, wherein the phosphorylcholine containing polymer comprises 2-(methacryloyloxyethyl)-2'- (trimethylammonium)ethyl phosphate (MPC) monomers as set forth below:

75. The method according to any one of claims 61-74, wherein the polymer has three or more arms.

76. The method according to any one of claims 61-75, wherein the polymer has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 arms.

77. The method according to any one of claims 61-76, wherein the polymer has 2, 3, 6, or 9 arms.

78. The method according to claim 77, wherein the polymer has 9 arms.

79. The method according to any one of claims 61-78, wherein the polymer has a molecular weight between about 300,000 and 1,750,000 Da.

80. The method according to claim 79, wherein the polymer has a molecular weight between about 600,000 and 1,000,000 Da.

81. The method according to claim 80, wherein the polymer has a molecular weight of between about 600,000 to 850,000 Da.

82. The method according to any one of claims 61-81, further comprising the step of contacting the anti-HTRAl antibody with a thiol reductant under conditions that produce a reduced cysteine sulfhydryl group to produce a reduced anti-HTRAl antibody in which all cysteine residues are reduced.

83. The method according to claim 82, wherein the thiol reductant is selected from the group consisting of Tris[2-carboxyethyl]phosphine hydrochloride (TCEP), dithiothreitol (DTT), dithioerythritol (DTE), sodium borohydride (NaBH4), sodium cyanoborohydride(NaCNBH ), P-mercaptoethanol (BME), 3,3',3''-Phosphanetriyltris(benzenesulfonic acid) trisodium (TPPTS), cysteine hydrochloride, and cysteine.

84. The method according to claim 83, wherein the thiol reductant is TCEP.

85. The method according to any one of claims 82-84, wherein the concentration of the thiol reductant is between 1 and 100 fold molar excess relative to the concentration of the anti-HTRAl antibody.

86. The method according to claim 85 wherein the concentration of the thiol reductant is between 20 to 50-fold molar excess relative to the concentration of the anti- HTRAl antibody.

87. The method according to any one of claims 82-86, further comprising the steps of removing the thiol reductant from the reduced anti-HTRAl antibody, and treating the reduced anti-HTRAl antibody with an oxidizing agent.

88. The method according to claim 87, wherein the oxidizing agent is air, aqueous CuSCh, or dehydroascorbic acid (DHAA).

89. The method according to any one of claims 82-88, further comprising the step of purifying the antibody conjugate.

90. The method according to claim 89, wherein the antibody conjugate is purified using a technique selected from the group consisting of ion exchange chromatography, hydrophobic interaction chromatography, size exclusion chromatography, affinity chromatography, and combinations thereof.

91. The method according to claim 89 or 90, wherein the purified antibody conjugate retains at least 20% biological activity relative to an unconjugated anti-HTRAl antibody.

92. The method according to claim 91, wherein the purified antibody conjugate retains at least 50% biological activity relative to an unconjugated anti-HTRAl antibody.

93. The method according to claim 92, wherein the purified antibody conjugate retains at least 90% biological activity relative to an unconjugated anti-HTRAl antibody.

94. The method according to any one of claims 58-93, wherein the purified antibody conjugate has an increased half-life relative to an unconjugated anti-HTRAl antibody.

95. The method according to claim 94, wherein the purified antibody conjugate has at least a 1.5-fold increase in half-life relative to an unconjugated anti-HTRAl antibody.

96. An isolated cell line that produces an anti-HTRAl antibody of any one of claims34-51.

97. The isolated cell line of claim 96, wherein the cell line is selected from the group consisting of CHO, klSV, XCeed, CH0K1SV, and GS-KO.

98. An isolated nucleic acid encoding an anti-HTRAl antibody of any one of claims35-51.

99. A recombinant expression vector comprising the nucleic acid of claim 98.

100. A host cell comprising the expression vector of claim 99.

101. A method of producing an anti-HTRAl antibody, comprising: culturing a cell line that recombinantly produces an anti-HTRAl antibody of any one of claims 35-51, under conditions wherein the antibody is produced; and recovering the antibody.

102. A method of producing an anti-HTRAl antibody, comprising: culturing a cell line comprising: a nucleic acid encoding a heavy chain comprising any one of the heavy chain variable region (VH) amino acid sequences shown in Figs. 21, 22A, 23 A, and 24A, and Tables 1.2, 6.3, 6.5, 7.1, 7.4, 7.7, 7.12, 7.17, and 8.1; and a nucleic acid encoding a light chain comprising any one of the light chain variable region (VL) amino acid sequences shown in Figs. 21, 22B, 23B, and 24B, and Tables 1.2, 6.3, 6.6, 7.1, 7.5, 7.8, 7.13, 7.18, and 8.2, under conditions wherein an antibody comprising the heavy chain and the light chain is produced; and recovering the antibody.

103. The method of claim 102, wherein the heavy and light chains of the antibody are encoded on separate vectors.

104. The method of claim 102, wherein the heavy and light chains of the antibody are encoded on the same vector.

105. An antibody that specifically binds to HTRA1, wherein the antibody inhibits a protease activity ofHTRAl.

106. The antibody of claim 105, wherein the antibody inhibits the protease activity of HTRA1 with an IC50 of about 2.0 x IO'10M or less.

107. An antibody that specifically binds to HTRA1, wherein the antibody binds to HTRA1 with a binding affinity (KD) of 1.0 X 10'10M or less.

108. An antibody that specifically binds to HTRA1, wherein the antibody does not bind a loop A peptide of HTRA1.

109. An antibody that specifically binds to HTRA1, wherein the antibody does not bind a loop A peptide of HTRA1 and wherein the antibody inhibits a protease activity of HTRA1.

110. The antibody of claim 108 or 109, wherein the loop A peptide of HTRA1 comprises or consists of FRKLPFSKREVPV (SEQ ID NO:851).

111. The method, antibody, or antibody conjugate of any one of the preceding claims, wherein the antibody or conjugate thereof inhibits casein digestion.

112. The method, antibody, or antibody conjugate of any one of the preceding claims, wherein the antibody or conjugate thereof selectively binds to a trimeric form of HTRA1 over a monomeric form of HTRA1.

113. The method, antibody, or antibody conjugate of any one of the preceding claims, wherein the antibody or conjugate thereof does not bind to a loop A peptide of HTRA1.

114. The method, antibody, or antibody conjugate of any one of the preceding claims, wherein the antibody or conjugate thereof includes at least one of the pairings of VH and VL as follows, or at least a VH / VL pairing where each VH and VL sequence is at least 80% identical to a corresponding VH and VL sequence of one of the following sequence pairs:

115. The method, antibody, or antibody conjugate of any one of the preceding claims, wherein the antibody or conjugate thereof includes at least one of the pairings of VH and VL as follows, or at least a VH / VL pairing where each VH and VL sequence is at least 80% identical to a corresponding VH and VL sequence of the sequence pairs provided in FIG. 21 and Tables 0.1, 0.4, 0.5, 0.7, 0.10, 0.11, 0.12, 1.2, 6.3, and 7.1.

116. The method, antibody, or antibody conjugate of any one of the preceding claims, wherein the antibody or conjugate thereof, wherein the antibody or conjugate thereof includes at least one VH point mutation, one VL point mutation, or both from the following:

117. The method, antibody, or antibody conjugate of any one of the preceding claims, wherein the antibody or conjugate thereof neutralizes HTRA1 cleavage activity.

118. The method, antibody, or antibody conjugate of any one of the preceding claims, wherein the antibody or conjugate thereof neutralizes HTRA1 serine protease activity.

119. The method, antibody, or antibody conjugate of any one of the preceding claims, wherein the antibody or conjugate thereof comprises a humanized antibody.

120. The method, antibody, or antibody conjugate of any one of the preceding claims, wherein the antibody or conjugate thereof comprises one or more of the following CDRs, or a variant thereof with no more than 3 point mutations per CDR:

121. Use of an antibody conjugate or antibody of any one of claims 1-51, or the pharmaceutical composition of claim 52 or 53 for treatment or prophylaxis of an ocular disease in a subject in need thereof.

122. Use of an antibody conjugate or antibody of any one of claims 1-51 for the preparation of a medicament for treatment or prophylaxis of an ocular disease in a subject in need thereof.

123. The use of claim 121 or 122, wherein the ocular disease is selected from the group consisting of diabetic retinopathy, age-related macular degeneration (AMD) (e.g., early, intermediate, or advanced AMD), retinopathy of prematurity (ROP), dry AMD, geographic atrophy, wet AMD, polypoidal choroidal vasculopathy, and HTRA1 -associated disorders.

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