Dual-inhibitory trypsin antibodies and their use

Abstract

Aspects of this application provide a dual inhibitory anti-trypsin 1 / trypsin 2 antibody and a method of using the same for treating pancreatitis.

Description

[Technical Field]

[0001] Related applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application USSN63 / 459,593, filed on 14 April 2023, and the entire contents thereof are incorporated herein by reference.

[0002] Reference to electronic sequence listings The contents of the electronic sequence listing (A140770002WO00-SEQ-LJG.xml; size: 152,469 bytes; and creation date: April 12, 2024) are incorporated herein by reference in their entirety. [Background technology]

[0003] Pancreatitis is an inflammatory disease of the pancreas and can be acute or chronic. In certain cases, pancreatitis may be associated with genetically or spontaneously occurring genetic abnormalities. However, there are other causes, including heavy alcohol consumption, gallstones, treatment with certain medications, and others. Effective treatment options remain limited, and as a result, pancreatitis can lead to significant morbidity and mortality. [Overview of the project] [Means for solving the problem]

[0004] Certain aspects of the present disclosure relate to the recognition that activation of trypsin (e.g., trypsin 1 and trypsin 2) in the pancreas is associated with the onset of pancreatitis. In some embodiments, methods and related compositions useful for inhibiting trypsin 1 and trypsin 2 for the purpose of treating pancreatitis are provided. Specifically, aspects of the present disclosure provide dual inhibitory antibodies (referred to as anti-trypsin 1 / trypsin 2 antibodies) that target both trypsin 1 and trypsin 2 and have high binding affinity and specificity for both through a common individual antigen-specific binding site. Thus, in some embodiments, the present disclosure provides methods and related antibody compositions for treating conditions associated with dysregulation of trypsin 1 and trypsin 2, such as hereditary pancreatitis, acute pancreatitis, recurrent acute pancreatitis, or chronic pancreatitis.

[0005] The accompanying drawings are incorporated herein and constitute a part hereof, illustrate certain embodiments, and together with the written description, serve to provide a non-limiting example of certain aspects of the compositions and methods disclosed herein.

Brief Description of the Drawings

[0006] [Figure 1] Graph showing that anti-trypsin 1 / trypsin 2 antibodies R1, R2, and R3 reduced acinar cell degeneration compared to the IgG control in rats with cerulein-induced pancreatitis.

[0007] [Figure 2] Graph showing that anti-trypsin 1 / trypsin 2 antibodies R1, R2, and R3 reduced edema compared to the IgG control in rats with cerulein-induced pancreatitis.

Modes for Carrying Out the Invention

[0008] As discussed herein, activation of trypsins (e.g., trypsin 1 and trypsin 2) in the pancreas is associated with the development of pancreatitis. In the pancreas, trypsin enzymes are synthesized in the rough endoplasmic reticulum as an inactive precursor, trypsinogen, and transported to the Golgi apparatus for sorting. Trypsinogen is synthesized and encapsulated with pancreatic secretory trypsin inhibitors (PSTIs) that inhibit its early activation. These zymogen granules are released into the lumen of the pancreatic duct, which transports digestive enzymes to the duodenum. Upon entering the duodenum, enteropeptidases activate trypsinogen to active trypsin. Trypsin 1 is the most abundant trypsin enzyme secreted by the pancreas, followed by trypsin 2. Therefore, this disclosure is based, at least in part, on the development of dual inhibitory antibodies and variants targeting trypsin 1 and trypsin 2. These dual inhibitory antibodies target trypsin 1 and trypsin 2 via a common, distinct antigen-specific binding site. Such dual inhibitory antibodies exhibit high binding affinity and specificity to trypsin 1 and trypsin 2 (anti-trypsin 1 / trypsin 2 antibodies). Also provided are methods for using anti-trypsin 1 / trypsin 2 antibodies and their variants in research, diagnostic / detection, and therapeutic applications.

[0009] I. Definition To administer: As used herein, the terms “to administer” or “to administer” mean to provide an antibody or a composition thereof to a subject in a physiologically and / or pharmacologically useful manner (for example, to treat a condition of the subject).

[0010] Affinity-matured antibodies: In this specification, the term “affinity-matured antibody” is used to refer to an antibody obtained by adding one or more modifications to one or more CDRs that result in improved antibody affinity (e.g., KD, kd, or ka) to a target antigen compared to an unmodified parent antibody. Exemplary affinity-matured antibodies may, in some embodiments, have nanomolar or even picomolar affinity to a target antigen. Various procedures are available for generating affinity-matured antibodies, including screening of combination antibody libraries prepared using biodisplay. For example, Marks et al., BioTechnology, 10:779-783 (1992) describes affinity maturation by shuffling of VH and VL domains. Random mutagenesis of CDRs and / or framework residues has been described by Barbas et al., Proc. Nat. Acad. Sci. USA, 91:3809-3813 (1994); Schier et al., Gene, 169:147-155 (1995); Yelton et al., J. Immunol., 155:1994-2004 (1995); Jackson et al., J. Immunol., 154(7):3310-3319 (1995); and Hawkins et al., J. Mol. Biol., 226:889-896 (1992). Selective mutagenesis sites and selective mutations at contact sites with activity-enhancing amino acid residues or at hypermutagenic sites have been described in U.S. Patent No. 6,914,128B1.

[0011] Antibody: As used herein, the term “antibody” refers to a polypeptide comprising at least one immunoglobulin variable domain containing at least one distinct antigen-specific binding site, or a portion (paratope or portion thereof) of an immunoglobulin variable domain containing at least one distinct antigen-specific binding site. In some embodiments, the antibody is a full-length antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. However, in some embodiments, the antibody is a Fab fragment, an F(ab')2 fragment, an Fv fragment, or an scFv fragment. In some embodiments, the antibody is a multispecific antibody (e.g., a bispecific antibody). In some embodiments, the antibody is a nanobody derived from a camelid antibody or a nanobody derived from a shark antibody. In some embodiments, the antibody is a diabody. In some embodiments, the antibody comprises a framework having a human germline sequence. In another embodiment, the antibody comprises a heavy chain constant domain selected from the group consisting of IgG, IgG1, IgG2, IgG2A, IgG2B, IgG2C, IgG3, IgG4, IgA1, IgA2, IgD, IgM, and IgE constant domains. In some embodiments, the antibody comprises a heavy (H) chain variable region (abbreviated herein as VH) and / or a light (L) chain variable region (abbreviated herein as VL). In some embodiments, the antibody comprises a constant domain, e.g., an Fc region. The immunoglobulin constant domain refers to either a heavy chain constant domain or a light chain constant domain. The amino acid sequences of the constant domains of human IgG heavy and light chains and their functional variations are known. With respect to the heavy chain, in some embodiments, the heavy chain of the antibody described herein may be an alpha (α), delta (Δ), epsilon (ε), gamma (γ), or mu (μ) heavy chain. In some embodiments, the heavy chains of the antibodies described herein may include human alpha (α), delta (Δ), epsilon (ε), gamma (γ), or mu (μ) heavy chains. In certain embodiments, the antibodies described herein include the CH1, CH2, and / or CH3 domains of human gamma 1. In some embodiments, the amino acid sequence of the VH domain includes the amino acid sequence of the constant region of the human gamma (γ) heavy chain, such as any known in the art.Non-limiting examples of human constant region sequences have been described in the Art; see, for example, U.S. Patent No. 5,693,780 and Kabat EA et al., (1991) cited above. In some embodiments, the VH domain comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or at least 99% identical to any of the variable chain constant regions provided herein. In some embodiments, the antibody is modified, for example, by glycosylation, phosphorylation, SUMOylation, and / or methylation. In some embodiments, the antibody is a glycosylated antibody conjugated to one or more sugar or carbohydrate molecules. In some embodiments, one or more sugar or carbohydrate molecules are conjugated to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glycieation (GPI anchor attachment), and / or phosphoglycosylation. In some embodiments, one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, one or more sugar or carbohydrate molecules are branched oligosaccharides or branched glycans. In some embodiments, one or more sugar or carbohydrate molecules include mannose units, glucose units, N-acetylglucosamine units, or phospholipid units. In some embodiments, the antibody is a construct comprising a polypeptide containing one or more antigen-binding fragments of the present disclosure linked to a linker polypeptide or an immunoglobulin constant domain. The linker polypeptide contains two or more amino acid residues joined by a peptide bond and is used to link one or more antigen-binding moieties. Examples of linker polypeptides have been reported (see, for example, Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, RJ, et al. (1994) Structure 2:1121-11233). Furthermore, antibodies may be part of larger immunoadhesion molecules formed by the covalent or noncovalent association of an antibody or antibody moiety with one or more other proteins or peptides.Examples of such immunoadhesion molecules include the use of streptavidin core regions to construct tetrameric scFv molecules (Kipriyanov, SM, et al. (1995) Human Antibodies and Hybridomas 6:93-101), and the use of cysteine ​​residues, marker peptides, and C-terminal polyhistidine tags to construct divalent biotinylated scFv molecules (Kipriyanov, SM, et al. (1994) Mol.Immunol.31:1047-1058).

[0012] Approximately: As used herein, the terms “approximately” or “about” refer to values ​​similar to the described reference values ​​when applied to the values ​​of one or more subjects. In certain embodiments, unless otherwise stated or evident from the content (except where such numbers may exceed 100% of the possible values), the terms “approximately” or “about” refer to a range of values ​​that fall within 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, and 1% or less in either direction (above or below) the described reference values.

[0013] Bispecific antibodies: As used herein, the term “bispecific antibodies” refers to an antibody containing two distinct antigen-specific binding sites, or, in combination, two antibodies (covalently or noncovalently) linked, each containing two distinct antigen-specific binding sites. Non-limiting examples of the format or structure of bispecific antibodies are provided in Labrijn, AF, et al., Bispecific antibodies: a mechanistic review of the pipeline, Nature Reviews Drug Discovery volume 18, pages 585-608 (2019) and Brinkmann U and Kontermann EE, The making of bispecific antibodies, MAbs. 2017 Feb / Mar;9(2):182-212, the full contents of each of these are incorporated herein by reference.

[0014] CDR: As used herein, the term “CDR” refers to the complementarity-determining region within the antibody variable sequence. A typical antibody molecule contains a heavy chain variable region (VH) and a light chain variable region (VL), which are usually involved in antigen binding. The VH and VL regions can be further subdivided into hypervariable regions also known as “complementarity-determining regions” (“CDR”) and more conserved regions known as “framework regions” (“FR”). Each VH and VL typically consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The scope of the framework regions and CDRs can be precisely identified using methodologies known in the art, for example, by definitions such as Kabat, IMGT, Chothia, AbM, and / or contact definitions, all of which are well known in the art.For example, Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDepartment of Health and Human Services, NIH Publication No. 91-3242; IMGT®, the international ImMunoGeneTics information system®, Lefranc, M.-P. et al., Nucleic Acids. Res.,27:209-212(1999);Ruiz,M.et al.,Nucleic Acids Res.,28:219-221(2000);Lefranc,M.-P.,Nucleic Acids Res.,29:207-209(2001);Lefranc,M.-P.,Nucleic Acids Res.,31:307-310(2003);Lefranc,M.-P.et al.,In Silico Biol.,5,0006(2004)Epub,5:45-60(2005);Lefranc,M.-P.et al.,Nucleic Acids Res.,33:D593-597(2005);Lefranc,M.-P.et al.,Nucleic Acids Res.,37:D1006-1012(2009);Lefranc,M.-P.et al.,Nucleic Acids Res.,43:D413-422(2015);Chothia et al.,(1989)Nature 342:877;Chothia,C.et al. (1987) J. Mol. Biol. 196:901-917, Al-lazikani et al. See al(1997)J.Molec.Biol.273:927-948; and Almagro,J.Mol.Recognit.17:132-143(2004). See also hgmp.mrc.ac.uk and bioinf.org.uk / abs. As used herein, CDR may mean CDR as defined by any method known in the art.Two antibodies having the same CDR means that the amino acid sequences of the CDRs of the two antibodies are the same, as determined by the same method, for example, the IMGT definition.

[0015] In certain embodiments, three CDRs are present in each of the variable regions of the heavy and light chains, and these are designated as CDR1, CDR2, and CDR3 with respect to each variable region. As used herein, the term “CDR set” refers to a group of three CDRs occurring in a single variable region capable of binding to an antigen. The exact boundaries of these CDRs are defined differently depending on the system. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides a clear residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries that define three CDRs. These CDRs are sometimes called Kabat CDRs. The sub-parts of the CDRs may be designated as L1, L2, and L3, or H1, H2, and H3, where "L" and "H" represent the light chain region and heavy chain region, respectively. These regions are sometimes called Chothia CDRs and have boundaries that overlap with Kabat CDRs. Other boundaries that define CDRs that overlap with Kabat CDRs are described by Padlan (FASEB J.9:133-139 (1995)) and MacCallum (J Mol Biol This is described in 262(5):732-45(1996). Furthermore, other CDR boundary definitions may not strictly adhere to one of the above systems and, although they overlap with Kabat CDRs, they may be shortened or extended in consideration of predictions or experimental results that certain residues or groups of residues, or even the entire CDR, do not significantly affect antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, but preferred embodiments use Kabat or Chothia-defined CDRs.

[0016] In certain embodiments, the CDR of an antibody may have different amino acid sequences depending on the definition system used (e.g., IMGT definition, Kabat definition, Chothia definition, or any other known definition). The definition system annotates each amino acid of a given antibody sequence (e.g., VH or VL sequence) with a number, and the numbers corresponding to the heavy chain CDR and light chain CDR are shown in Table 2. Those skilled in the art can derive the CDR sequences using the different numbering systems for anti-trypsin 1 / trypsin 2 antibodies provided in Tables 1a and 1b. [Table 2]

[0017] CDR-transplanted antibody: As used herein, the term "CDR-transplanted antibody" refers to an antibody that contains heavy chain variable region sequences and light chain variable region sequences derived from one species, but in which one or more sequences of the VH and / or VL CDR regions are replaced with CDR sequences from another species. For example, in an antibody having mouse heavy chain variable region and light chain variable region, one or more mouse CDRs (e.g., CDR3) are replaced with human CDR sequences.

[0018] Chimeric antibody: As used herein, the term "chimeric antibody" refers to an antibody that contains a heavy chain variable region sequence and a light chain variable region sequence derived from one species and a constant region sequence derived from another species, such as an antibody in which the mouse heavy chain variable region and light chain variable region are linked to the human constant region.

[0019] Complementary: As used herein, the term “complementary” refers to the ability of two nucleotides or two sets of nucleotides to form a precise pairing. Specifically, complementarity is a term that characterizes the degree of hydrogen bond pairing that results in a bond between two nucleotides or two sets of nucleotides. For example, if a base at one position of an oligonucleotide can form a hydrogen bond with a base at a corresponding position in a target nucleic acid (e.g., mRNA), then those bases are considered complementary to each other at that position. Base pairings can include both canonical Watson-Crick base pairings and non-Watson-Crick base pairings (e.g., Wobble base pairings and Hoogsteen base pairings). For example, in some embodiments, in the case of complementary base pairing, an adenosine-type base (A) is complementary to a thymidine-type base (T) or a uracil-type base (U), a cytosine-type base (C) is complementary to a guanosine-type base (G), and universal bases such as 3-nitropyrrole or 5-nitroindole can hybridize to any A, C, U, or T and are considered complementary to them. Inosine (I) is also considered a universal base in the art and is considered complementary to any of A, C, U, or T.

[0020] Conservative amino acid substitutions: As used herein, “conservative amino acid substitutions” refer to amino acid substitutions that do not alter the relative charge or size properties of the protein being substituted. Variants can be prepared according to methods of modifying polypeptide sequences known to those skilled in the art, for example, according to references that summarize such methods, e.g., Molecular Cloning: A Laboratory Manual, J. Sambrook, et al., eds., Fourth Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2012, or according to methods found in Current Protocols in Molecular Biology, FMAusubel, et al., eds., John Wiley & Sons, Inc., New York. Conservative amino acid substitutions include substitutions made between amino acids in the following groups: (a) M, I, L, V; (b) F, Y, W; (c) K, R, H; (d) A, G; (e) S, T; (f) Q, N; and (g) E, D.

[0021] Cross-reactivity: As used herein, the term “cross-reactivity” refers to the property of a drug to specifically bind to multiple antigens of similar type or class (e.g., multiple homologous, paralogous, or orthologous antigens) with similar affinity or binding strength. For example, in some embodiments, an antibody that cross-reactive to human and non-human primate antigens of similar type or class (e.g., human trypsin 1 and non-human primate trypsin 1, human trypsin 2 and non-human primate trypsin 2) can bind to human and non-human primate antigens with similar affinity or binding strength. In some embodiments, the antibody cross-reactive to human and rodent antigens of similar type or class. In some embodiments, the antibody cross-reactive to rodent antigens and non-human primate antigens of similar type or class. In some embodiments, the antibody cross-reactive to human, non-human primate, and rodent antigens of similar type or class.

[0022] Dual-inhibitory antibody: As used herein, the term “dual-inhibitory antibody” refers to an antibody that targets at least two (e.g., 2, 3) different antigens via a common individual antigen-specific binding site and inhibits the activity of those antigens. In some embodiments, a dual-inhibitory antibody targets at least two different proteins (e.g., expressed from two different genes (e.g., endogenous genes, e.g., homologs, paralogs)) via a common individual antigen-specific binding site and inhibits the activity of at least two different proteins (e.g., enzymes such as proteases). In some embodiments, a dual-inhibitory antibody targets at least two different proteases (e.g., expressed from two different endogenous genes, e.g., trypsin 1 and trypsin 2) via a common individual antigen-specific binding site and inhibits the activity of at least two different proteases. In some embodiments, the common individual antigen-specific binding site binds to similar (e.g., homologous) domains shared between or among at least two different antigens. For example, in some embodiments, the common individual antigen-specific binding site binds to similar (e.g., homologous) catalytic domains or substrate-binding sites shared between or among at least two different enzymes, e.g., proteases. In some embodiments, the common individual antigen-specific binding site of a dual inhibitory antibody includes amino acids in one or more complementarity-determining regions of the antibody. In some embodiments, the common individual antigen-specific binding site of a dual inhibitory antibody is located within the heavy chain variable region and / or light chain variable region of the antibody. In some embodiments, the common individual antigen-specific binding site of a dual inhibitory antibody includes one or more complementarity-determining regions in the heavy chain variable region and / or light chain variable region of the antibody. In some embodiments, the common individual antigen-specific binding site of a dual inhibitory antibody includes HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 in the heavy chain variable region and light chain variable region of the antibody.

[0023] Effective dose: As used herein, “effective dose” refers to the amount of each activator (e.g., anti-trypsin 1 / trypsin 2 antibody) required to deliver the desired effect (e.g., therapeutic effect on a subject), either alone or in combination with one or more other activators. In some embodiments, the therapeutic effect is a reduction in trypsin 1 and / or trypsin 2 activity and / or relief of a disease (e.g., pancreatitis) or related symptoms, such as an improvement in barrier function.

[0024] Framework: As used herein, the terms “framework” or “framework sequence” refer to the sequence remaining after removing the CDRs from the variable region. Since the precise definition of a CDR sequence can be determined by various systems, the meaning of the framework sequence is also subject to different interpretations accordingly. The six CDRs (CDR-L1, CDR-L2, and CDR-L3 of the light chain, and CDR-H1, CDR-H2, and CDR-H3 of the heavy chain) divide the framework regions of the light and heavy chains into four sub-regions (FR1, FR2, FR3, and FR4) on each chain, with CDR1 located between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. When a framework region is referred to by others without specifying a particular sub-region as FR1, FR2, FR3, or FR4, it represents a combination of FRs within the variable region of a single naturally occurring immunoglobulin chain. As used herein, FR represents one of four subregions, and multiple FRs represent two or more of the four subregions that constitute a framework region. Human heavy and light chain acceptor sequences are known in the art. In one embodiment, acceptor sequences known in the art may be used in the antibodies disclosed herein.

[0025] Human Antibodies: As used herein, the term “human antibody” is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of this disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro, or by somatic mutation in vivo) in the CDR, specifically CDR3. However, as used herein, the term “human antibody” is not intended to include antibodies in which a CDR sequence derived from the germline of another mammalian species, such as mouse, has been transplanted into a human framework sequence.

[0026] Humanized Antibodies: As used herein, the term “humanized antibody” refers to an antibody that contains heavy chain variable region sequences and light chain variable region sequences derived from a non-human species (e.g., mouse), but in which at least a portion of the VH and / or VL sequences has been modified to be more “human-like,” i.e., more similar to human germline variable sequences. One type of humanized antibody is a CDR-transplant antibody in which a human CDR sequence is introduced into non-human VH and VL sequences to replace the corresponding non-human CDR sequence. In one embodiment, a humanized antibody is provided. Such an antibody may be produced by obtaining a mouse monoclonal antibody using conventional hybridoma technology and then humanizing it using in vitro genetic engineering, such as that disclosed in PCT publication number WO2005 / 123126 A2 by Kasaian et al.

[0027] A humanized antibody is a human immunoglobulin (recipient antibody) in which residues from the recipient's complementarity-determining region (CDR) are replaced with residues from the CDR of a non-human species (donor antibody), such as mouse, rat, or rabbit, having the desired specificity, affinity, and capabilities. In some embodiments, Fv framework region (FR) residues of the human immunoglobulin are replaced with corresponding non-human residues. Furthermore, the humanized antibody may include residues not found in the recipient antibody or the transferred CDR or framework sequence, but included to further improve and optimize the antibody's performance. Generally, a humanized antibody may include substantially all of at least one, typically two, variable domains, where all or substantially all of the CDR region corresponds to that of a non-human immunoglobulin, and all or substantially all of the FR region corresponds to that of the human immunoglobulin consensus sequence. The humanized antibody also includes, optimally, at least a portion of the immunoglobulin constant region or domain (Fc), typically at least a portion of the constant region or domain (Fc) of the human immunoglobulin. Antibodies may have modified Fc regions as described in WO99 / 58572. Other forms of humanized antibodies have one or more modified CDRs (1, 2, 3, 4, 5, 6) relative to the original antibody, also called one or more CDRs derived from one or more CDRs of the original antibody. Humanized antibodies may also undergo affinity maturation.

[0028] In some embodiments, humanization involves using a CDR (e.g., one shown in Table 1a or 1b) to create a human variable domain (e.g., IGKV1-NL1). * 01 and IGHV1-3 * This is achieved by transplanting (01 human variable domain). In some embodiments, the antibodies of this disclosure are humanized variants comprising one or more amino acid substitutions (e.g., in the VH framework region) compared to any one of the VHs listed in Table 1a or 1b, and / or comprising one or more amino acid substitutions (e.g., in the VL framework region) compared to any one of the VLs listed in Table 1a or 1b.

[0029] Isolated Antibodies: As used herein, “isolated antibodies” is intended to mean antibodies that substantially do not contain other antibodies with different antigen specificities (for example, isolated dual inhibitory antibodies that specifically bind to trypsin 1 and trypsin 2 substantially do not contain antibodies that specifically bind to antigens other than trypsin 1 and trypsin 2). However, isolated antibodies may, in some embodiments, exhibit cross-reactivity to other antigens. Furthermore, isolated antibodies may substantially do not contain other cellular material and / or chemical substances.

[0030] Kabat Numbering: As used herein, the terms “Kabat Numbering,” “Kabat Definition,” and “Kabat Labeling” are interchangeable. These terms, as recognized in the Art, refer to a system for numbering amino acid residues that are more variable than other amino acid residues (i.e., hypervariable) in the heavy chain variable region and light chain variable region of an antibody, or in their antigen-binding regions (Kabat et al. (1971) Ann. NY Acad, Sci. 190:382-391 and Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USD Department of Health and Human Services, NIH Publication No. 91-3242). In the heavy chain variable region, the hypervariable region ranges from amino acid positions 31-35 in CDR1, from amino acid positions 50-65 in CDR2, and from amino acid positions 95-102 in CDR3. In the case of the light chain variable region, the hypervariable region is located at amino acid positions 24-34 in CDR1, amino acid positions 50-56 in CDR2, and amino acid positions 89-97 in CDR3.

[0031] Multispecific antibody: As used herein, the term “multispecific antibody” refers to an antibody comprising at least two distinct antigen-specific binding sites, or, in combination, at least two (covalently or noncovalently) linked antibodies comprising at least two distinct antigen-specific binding sites. In some embodiments, a multispecific antibody is a bispecific antibody. Non-limiting examples of the format or structure of multispecific antibodies are provided in Sawant MS, et al., Toward Drug-Like Multispecific Antibodies by Design, Int J Mol Sci. 2020 Oct 12;21(20):7496; Klein C, et al., The use of CrossMAb technology for the generation of bi- and multispecific antibodies, MAbs 2016 Aug-Sep;8(6):1010-20; and Brinkmann U and Kontermann EE, The making of bispecific antibodies, MAbs. 2017 Feb / Mar;9(2):182-212, the full contents of each of these are incorporated herein by reference.

[0032] Recombinant Antibodies: As used herein, the term “recombinant antibodies” is intended to include all antibodies prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using recombinant expression vectors transfected into host cells (as described in more detail herein), including, for example, antibodies isolated from recombinant combinatorial human antibody libraries (Hoogenboom HR, (1997) TIB Tech. 15:62-70; Azzazy H., and Highsmith WE, (2002) Clin. Biochem. 35:425-445; Gavilondo JV, and Larrick JW (2002) BioTechniques 29:128-145; Hoogenboom H., and Chames P. (2000) Immunology Today 21:371-378), antibodies isolated from animals (e.g., mice) into which human immunoglobulin genes have been transfected (e.g., Taylor, LD, et al.) This includes antibodies prepared, expressed, created or isolated by any other method involving splicing a human immunoglobulin gene sequence with another DNA sequence (see al. (1992) Nucl. Acids Res. 20:6287-6295; Kellermann SA., and Green LL (2002) Current Opinion in Biotechnology 13:593-597; Little M. et al (2000) Immunology Today 21:364-370), or by any other method involving splicing a human immunoglobulin gene sequence with another DNA sequence. In some embodiments, recombinant human antibodies are provided herein. In certain embodiments, such recombinant human antibodies have a variable region and a constant region derived from a human germline immunoglobulin sequence. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, if an animal into which a human Ig sequence has been genetically modified is used, in vivo somatic mutagenesis), and therefore the amino acid sequences of the VH and VL regions of the recombinant antibody are derived from and related to human germline VH and VL sequences, but may not naturally exist within the in vivo human antibody germline repertoire.One embodiment of the present disclosure provides a fully human antibody, e.g., a human antibody VH domain and a human antibody VL domain, which can be generated using appropriate techniques, e.g., but not limited to, human Ig phage libraries such as those disclosed in PCT Publication No. WO2005 / 007699 A2 by Jermutus et al.

[0033] Selective: As used herein, the term "selective" or "selectively" refers to the ability of a molecule to produce an effect (e.g., inhibition, antagonism, agonize, etc.) with respect to its target molecule as compared to a reference molecule. For example, a molecule that selectively inhibits its target molecule means that this molecule can inhibit its target molecule to a distinguishable extent from the reference molecule in an inhibition assay or other inhibitory situation. For example, with respect to an inhibitor, the term "selectively inhibits" refers to the ability of the inhibitor to inhibit its target molecule to an extent that enables selective inhibition of the target molecule, e.g., as described herein, to a distinguishable extent from a reference molecule that does not substantially inhibit in an inhibition assay. When the reaction is complete, the signal generated by the inhibition of the target molecule can be measured. The maximum half-inhibitor concentration for the target molecule and the reference molecule can be calculated.

[0034] Specifically binds: As used herein, the term "specifically binds" refers to the ability of a molecule to bind to a binding partner with an affinity or binding strength that enables the use of the molecule to distinguish the binding partner from appropriate controls in a binding assay or other binding situation. With respect to an antibody, the term "specifically binds" refers to the ability of the antibody to bind to a specific antigen with an affinity or binding strength that enables the use of the antibody to distinguish the specific antigen from others, as described herein, as compared to an appropriate reference antigen(s). In some embodiments, the K for the antibody to bind to its target D is at least about 10 -4 M, 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10-10 M, 10 -11 M, 10 -12 M, 10 -13 If the M value is M or less, the antibody binds specifically to the target. In some embodiments, the antibody binds specifically to trypsin 1 or trypsin 2.

[0035] Subject: As used herein, the term "subject" refers to mammals. In some embodiments, the subject is a non-human primate or rodent. In some embodiments, the subject is a human. In some embodiments, the subject is a patient who has or is suspected of having a disease, e.g., a human patient.

[0036] Treatment: As used herein, “to treat” or “treatment” means the application or administration of a composition comprising one or more activators (e.g., anti-trypsin 1 / trypsin 2 antibodies) to a subject with a predisposition to a target disease or disorder, symptoms of a disease / disorder, or a disease / disorder, for the purpose of treating, curing, alleviating, reducing, modifying, remedying, improving, or influencing the disorder, symptoms of a disease, or predisposition to a disease or disorder. Alleviation of a target disease / disorder includes delaying or preventing the onset or progression of the disease, or reducing the severity of the disease.

[0037] II. Dual inhibitory antibodies targeting trypsin 1 and trypsin 2 In some embodiments, the anti-trypsin 1 / trypsin 2 antibody is an antibody specific to both trypsin 1 and trypsin 2 via a common specific antigen-binding site. In some embodiments, antibodies are provided herein that bind with high specificity and affinity to trypsin 1 (e.g., human trypsin 1, or non-human primate trypsin 1) and trypsin 2 (e.g., human trypsin 2, or non-human primate trypsin 2) via a common antigen-binding site. In some embodiments, the anti-trypsin 1 / trypsin 2 antibody described herein specifically binds to the epitope of trypsin 1 that is exposed to or will be exposed to the antibody, and to the epitope of trypsin 2 that is exposed to or will be exposed to the antibody. In some embodiments, the anti-trypsin 1 / trypsin 2 antibody provided herein specifically binds to trypsin 1 derived from humans, non-human primates, etc. In some embodiments, the anti-trypsin 1 antibody provided herein specifically binds to human trypsin 1. In some embodiments, the anti-trypsin 1 antibody provided herein specifically binds to mouse trypsin 1.

[0038] Trypsin-1, also known as cationic trypsinogen, is a protease encoded by the PRSS1 gene on chromosome 7. Trypsin-1 is the major isoform of trypsinogen secreted by the pancreas. The PRSS1 gene encodes trypsinogen, which belongs to the trypsin family of serine proteases. This enzyme is secreted by the pancreas and cleaved in the small intestine to become active. It is active against peptide bonds containing carboxyl groups of lysine or arginine. Certain mutations within the PRSS1 gene are autosomal dominant mutations that lead to hyperactivation of trypsin-1, and these are associated with hereditary pancreatitis. Furthermore, trypsin-1 activity (with or without PRSS1 mutations) is associated with the development of pancreatitis (e.g., Gui et al., Trypsin activity governs increased susceptibility to pancreatitis in mice expressing human PRSS1). R122H,J Clin Invest.2020;130(1):189-202;Sendler et al.,The Complex Role of Trypsin in Pancreatitis,Gastroenterology,EDITORIAL VOLUME 158,ISSUE 4,P822-826,MARCH 2020;Logsdon,Phosphatidylinositol 3-kinase and Trypsin activation in pancreatitis,J Clin Invest.2001 Nov 1;108(9):1267-1268.

[0039] Trypsin-2, also known as anionic trypsinogen, is a protease encoded by the PRSS2 gene on chromosome 7. Trypsin-2 is the second most abundant trypsin secreted by the pancreas. Trypsin-2 has also been shown to be associated with pancreatitis (e.g., Dixit, Role of trypsinogen activation in genesis of pancreatitis, Pancreapedia:Exocrine Pancreas Knowledge Base, DOI:10.3998 / panc.2016.25; Kemppainen et al., Increased serum trypsinogen 2 and trypsin 2-α1-antitrypsin complex values ​​identify endoscopic retrograde cholangiopancreatography induced pancreatitis with high accuracy, Gut 1997;41:690-695; Andersen et al., The ratio of trypsin-2-alpha(1)-antitrypsin to trypsinogen-1 discriminates biliary and alcohol-induced acute pancreatitis, Clinical Chemistry, 01 Feb 2001,47(2):231-236; Yu et al., Altered Gene Expression in See Caerulein-Stimulated Pancreatic Acinar Cells: Pathologic Mechanism of Acute Pancreatitis, Korean J Physiol Pharmacol 2009;13(6):409-416.

[0040] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein specifically bind to epitopes on human trypsin 1. Exemplary amino acid sequences of human trypsin 1 are described in NCBI accession number NP_002760.1 and UniProt accession number P07477 or P00760, and these entire sequences are incorporated herein by reference.

[0041] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein specifically bind to an epitope on human trypsin 1. In some embodiments, the antibodies described herein are produced by mutating serine to alanine in the catalytic domain of human trypsin 1. An exemplary amino acid sequence of human trypsin 1 with the serine-to-alanine mutation is given in SEQ ID NO: 103 (including a His tag at the C-terminus). [ka]

[0042] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein specifically bind to epitopes on human trypsin 2. Exemplary amino acid sequences of human trypsin 2 are described in NCBI accession number NP_001290343.1 or NP_002761.1 and UniProt accession number: P07478, and these entire sequences are incorporated herein by reference.

[0043] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein specifically bind to epitopes on human trypsin 2. In some embodiments, the antibodies described herein are produced by mutating serine to alanine in the catalytic domain of human trypsin 2. An exemplary amino acid sequence of human trypsin 2 with the serine-to-alanine mutation is described in SEQ ID NO: 104 (including a His tag at the C-terminus). [ka]

[0044] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein specifically bind to epitopes on trypsin 1 (e.g., catalytic domains / pockets of human trypsin 1 or non-human primate trypsin 1) and epitopes on trypsin 2 (e.g., catalytic domains / pockets of human trypsin 2 or non-human primate trypsin 2). In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein prevent trypsin 1 (e.g., catalytic domains / pockets of human trypsin 1 or non-human primate trypsin 1) and trypsin 2 (e.g., catalytic domains / pockets of human trypsin 2 or non-human primate trypsin 2) from cleaving their substrates. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein bind to fragments of trypsin 1 (e.g., the catalytic domain / pocket of human trypsin 1 or non-human primate trypsin 1) and fragments of trypsin 2 (e.g., the catalytic domain / pocket of human trypsin 2 or non-human primate trypsin 2). The fragments of trypsin 1 and / or trypsin 2 (e.g., human or non-human primate) may be about 5 to about 425 amino acids, about 10 to about 400 amino acids, about 50 to about 350 amino acids, about 100 to about 300 amino acids, about 150 to about 250 amino acids, about 200 to about 300 amino acids, about 75 to about 150 amino acids, about 25 to about 100 amino acids, and about 10 to about 30 amino acids in length. Without intending to be bound by any particular theory, in some embodiments, the heavy chain (HC) complementarity-determining region 3 (CDR3) of any one of the anti-trypsin 1 / trypsin 2 antibodies described herein inhibits trypsin 1 (e.g., human or non-human primate trypsin 1) and trypsin 2 (e.g., human or non-human primate trypsin 2) by binding to the catalytic domain / pocket of trypsin 1 and trypsin 2, respectively.

[0045] In some embodiments, the antibodies described herein are optimized versions (e.g., affinity-mature) of the parent antibody. In some embodiments, the antibodies described herein are trypsin 1 (e.g., human or non-human primate trypsin 1) and trypsin 2 (e.g., human or non-human primate trypsin 2) with at least about 10 -4 M, 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, 10 -13 M or lower binding affinity (e.g., K D It specifically binds to (as shown by). In some embodiments, the antibodies described herein bind to trypsin 1 (e.g., human or non-human primate trypsin 1) and trypsin 2 (e.g., human or non-human primate trypsin 2) at a rate of 1 × 10⁻¹⁶ -10 M~5×10 -9 M, 1×10 -10 M~1×10 -9 M, 5×10 -10 ~1 × 10 -9 M, 5×10 -11 ~1 × 10 -10 M, 1×10 -11 ~5×10 -10 M, or 5×10 -13 ~1 × 10 -12 Binding affinity of M (e.g., K DThe antibodies specifically bind to trypsin 1 protein (e.g., human or non-human primate trypsin 1) and trypsin 2 protein (e.g., human or non-human primate trypsin 2) with affinities of 1 pM to 500 nM, e.g., 50 pM to 100 nM, 500 pM to 50 nM, 1 pM to 100 pM, 10 pM to 100 pM, 50 pM to 100 pM, 100 pM to 500 pM, 500 pM to 1 nM, 1 nM to 5 nM, 1 nM to 10 nM, 5 nM to 25 nM, 10 nM to 50 nM, 50 nM to 100 nM, and 100 nM to 500 nM. This disclosure also includes antibodies that compete with any of the antibodies described herein for binding to trypsin 1 protein (e.g., human or non-human primate trypsin 1) and trypsin 2 protein (e.g., human or non-human primate trypsin 2) and have affinities of 100 nM or less (e.g., 80 nM or less, 50 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, 500 pM or less, 50 pM or less, 10 pM or less, or 5 pM or less). The affinity and binding reaction rate of the antibodies can be tested using any suitable method, including but not limited to biosensor technologies (e.g., OCTET or BIACORE). In some embodiments, the antibodies described herein have a sub-nanomolecular K D It then binds to trypsin-1 and trypsin-2.

[0046] Binding affinity (or binding specificity) can be determined by a variety of methods, including equilibrium dialysis, equilibrium binding, gel filtration, ELISA, surface plasmon resonance (SPR), fluorescence-activated cell sorting (FACS), or spectroscopy (e.g., using fluorescence assays). Exemplary conditions for evaluating binding affinity are HBS-P buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 0.005% (v / v) surfactant P2O) and PBS buffer (10 mM PO4-3, 137 mM NaCl, and 2.7 mM KCl). Using these techniques, the concentration of the binding protein can be measured as a function of the target protein concentration. Generally, the concentration of the binding protein ([[binding]]) is given by the following formula: [[Bound]]=[[Free]] / (Kd+[[Free]]) This is related to the concentration of free target protein (free).

[0047] K A While it is not always necessary to make an accurate determination, obtaining a quantitative measure of affinity determined using methods such as ELISA or FACS analysis is useful, as it indicates that K A Since it is proportional to the activity, it may be sufficient, and therefore can be used for comparisons to determine whether a higher affinity is, for example, twice as high, to obtain a qualitative measurement of affinity, or to infer affinity by activity in a functional assay (e.g., an in vitro or in vivo assay).

[0048] Exemplary anti-trypsin 1 / trypsin 2 antibody sequences (e.g., heavy chain variable domain (VH) and light chain variable domain (VL), CDR sequences) are provided in Tables 1a and 1b. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0049] In some embodiments, certain amino acid positions in the antibodies described herein (e.g., amino acids in the VH / VL region and / or CDR region) are substitutable, and this substitution results in an antibody having substantially similar binding and biological activity (e.g., substantially similar binding affinity, binding specificity, protease inhibitory activity, anti-inflammatory activity, or a combination thereof) to the reference antibody. To identify substitutable positions in an antibody, the amino acid sequence of that antibody is compared to the sequences of other antibodies belonging to the same group as that antibody. If the identity of that amino acid varies among related antibodies of different groups at any particular position, that position is a substitutable position in the antibody. In other words, a substitutable position is a position where the identity of the amino acid varies among related antibodies. Positions containing constant amino acids are not substitutable positions.

[0050] In some embodiments, the above method may be used to provide a consensus antibody sequence. In such a consensus sequence, non-substitutable positions are indicated by the amino acids present at those positions, and substitutable positions are indicated by "X".

[0051] Depending on how the antibody is adopted, X may be a) any amino acid, b) any amino acid present at that position in any of the related antibodies within that group, or a conservatively substituted variant thereof, or c) any amino acid present at that position in any of the related antibodies within that group. Any antibody having a sequence encompassed by consensus should bind to the same antigen as any of the related antibodies.

[0052] In some embodiments, the methods described above may be employed in a method for designing and producing variants of a parent antibody that at least maintain (e.g., maintain or increase) the antigen-binding activity of the parent antibody. Antibodies containing substitutions at substitutable positions can be produced and tested, and therefore substitutions at those positions should not significantly reduce the antibody's binding activity. Generally, antibody variants of a parent antibody have an antigen-binding affinity of 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%, or at least 100% (e.g., at least 150%, at least 200%, at least 500%, at least 1000%, and typically up to at least 10,000%) of the parent antibody's binding affinity to a particular antigen.

[0053] In some embodiments, the substitutable positions of the parent antibody may be substituted by: a) any of 20 naturally occurring amino acids to produce a random substitution; b) an amino acid with biochemical properties similar to an amino acid already present at the substitutable position to produce a conservative substitution; c) an amino acid present at the same position in the related antibody to produce a designated substitution; or d) an amino acid present at the same position in a similar human antibody to produce a humanization substitution. Substitutions may occur in any portion of the antibody variable region, including any framework region or CDR. In certain embodiments, a single substitutable amino acid may be substituted. However, in other embodiments, multiple substitutable amino acids (e.g., up to about 5 or 10 or more) may be substituted. In certain embodiments, the type of substitution that can be performed at each substitutable position may be indicated by the type of amino acid present at that position in the related antibody. For example, if an unrelated amino acid (e.g., Ala, Gly, Cys, Glu, and Thr) is present at a particular position in the group of related antibodies, any amino acid can be substituted at that position without significantly reducing the antibody's binding activity.

[0054] Exemplary amino acid substitutions of the anti-trypsin 1 / trypsin 2 antibodies described herein are shown in Table 1b: [Table 1-7] [Table 1-8] [Table 1-9]

[0055] In some embodiments, the antibodies of the present disclosure include: HC CDR1 containing the amino acid sequence FTFX1X2YAMX3 (SEQ ID NO: 85), where X1 is S or G, X2 is S or D, or X3 is S or W; HC CDR2 containing the amino acid sequence AISASGX4X5TYYADSVKG (SEQ ID NO: 86), where X4 is G or D, or X5 is S or V; HC CDR3 containing the amino acid sequence ARGSX6IGYSYARVSYYYYX7DV (SEQ ID NO: 87), where X6 is P or L, or X7 is M or S; LC CDR1 containing the amino acid sequence of SEQ ID NO: 4; LC CDR2 containing the amino acid sequence of SEQ ID NO: 5; and / or LC CDR3 containing the amino acid sequence QQGX8SFPLT (SEQ ID NO: 88), where X8 is N or W.

[0056] In some embodiments, the antibodies of this disclosure include: HC CDR1 containing the amino acid sequence GSISSX1YWX2 (SEQ ID NO: 89), where X1 is Y, N, or H, or X2 is S or H; HC CDR2 containing the amino acid sequence RIX3TSGSTX4YNPSLKS (SEQ ID NO: 90), where X3 is Y, H, or A, or X4 is N, F, or Y; HC CDR3 containing the amino acid sequence ARDX5TNYGX6X7KSIRFYX8MDV (SEQ ID NO: 91), where X5 is L or I, X6 is S, I, or W, X7 is G, T, or S, or X8 is G or P; LC CDR1 containing the amino acid sequence of SEQ ID NO: 14; LC CDR2 containing the amino acid sequence of SEQ ID NO: 15; and / or QQX9DX 10 LC CDR3 containing the amino acid sequence of FIT (SEQ ID NO: 92), where X9 is D, V, or T, or X 10 This includes the condition that it is N or T.

[0057] In some embodiments, the antibodies of the present disclosure include HC CDR1 containing the amino acid sequence YTFTX1X2YMH (SEQ ID NO: 93), where X1 is G or D, or X2 is Y or H; HC CDR2 containing the amino acid sequence X3INPSSGGTX4YAQKFQG (SEQ ID NO: 94), where X3 is S or A, or X4 is N or A; HC CDR3 containing the amino acid sequence ARVGGAAX5X6GKAYTASAFDI (SEQ ID NO: 95), where X5 is A or R, or X6 is A or V; LC CDR1 containing the amino acid sequence SEQ ID NO: 30; LC CDR2 containing the amino acid sequence SEQ ID NO: 31; and / or LC CDR3 containing the amino acid sequence SEQ ID NO: 32.

[0058] In some embodiments, the antibodies of this disclosure include HC CDR1 comprising the amino acid sequence YTFX1X2YX3IS (SEQ ID NO: 96), where X1 is T or D, X2 is S or D, or X2 is G or A; HC CDR2 comprising the amino acid sequence WISAX4X5X6DTNYAQKLQG (SEQ ID NO: 97), where X4 is Y, S, G, or T, X5 is S, T, or V, or X6 is G or A; ARX7X8EX9VGKX 10 TX 11 YX 12 X 13 X 14 HC CDR3 containing the amino acid sequence of DV (SEQ ID NO: 98), where X7 is G or Q, X8 is D or T, X9 is V or P, X 10 X is either M or R. 11 X is either Y or V. 12 X is Y, I, or L. 13 is G or D, or X 14 is M or T; LC CDR1 containing the amino acid sequence of SEQ ID NO: 4; LC CDR2 containing the amino acid sequence of SEQ ID NO: 5; and / or QQAX 15 SX 16 PX 17 LC CDR3 containing the amino acid sequence T (sequence number 99), where X 15 X is either N or S. 16 is F or L, or X 17 This includes being I or L.

[0059] In some embodiments, the antibodies of the present disclosure include HC CDR1 containing the amino acid sequence YTFX1GX2YMH (SEQ ID NO: 100), where X1 is T or E, or X2 is Y or H; HC CDR2 containing the amino acid sequence X3INPX4SGX5TNYAQKFQG (SEQ ID NO: 101), where X3 is S or A, X4 is S or Y, or X5 is G or Q; HC CDR3 containing the amino acid sequence ARDX6VLLLRQX7RILHESAFDI (SEQ ID NO: 102), where X6 is P or F, X7 is Q or S; LC CDR1 containing the amino acid sequence SEQ ID NO: 30; LC CDR2 containing the amino acid sequence SEQ ID NO: 31; and / or LC CDR3 containing the amino acid sequence SEQ ID NO: 32.

[0060] In some embodiments, the antibody of this disclosure comprises one or more HC CDR (e.g., HC CDR1, HC CDR2, or HC CDR3) amino acid sequences from any one of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b. In some embodiments, the antibody of this disclosure comprises an HC CDR3 amino acid sequence from any one of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b. In some embodiments, the antibody of this disclosure comprises HC CDR1, HC CDR2, and HC CDR3 provided for any one of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b. In some embodiments, the antibody of this disclosure comprises an LC CDR3 amino acid sequence from any one of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b. In some embodiments, the antibody of the Disclosure comprises one or more LC CDR (e.g., LC CDR1, LC CDR2, or LC CDR3) amino acid sequences from any one of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b. In some embodiments, the antibody of the Disclosure comprises LC CDR1, LC CDR2, and LC CDR3 provided for any one of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b.

[0061] In some embodiments, the antibodies of this disclosure include HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 provided for any one of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b. In some embodiments, the heavy chain CDR3 domain and / or light chain CDR3 domain of the antibody may play a particularly important role in the antibody's binding specificity / affinity to the antigen. Therefore, the antibodies of this disclosure may include at least the heavy chain CDR3 and / or light chain CDR3 of any one of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b.

[0062] Any variant of the exemplary anti-trypsin 1 / trypsin 2 antibody disclosed herein is also within the scope of this disclosure. The variant may contain one or more amino acid residue mutations in the VH and / or VL, or in one or more of the HC CDRs and / or one or more of the LC CDRs, compared to the reference antibody, but retain substantially similar binding activity and biological activity (e.g., substantially similar binding affinity, binding specificity, protease inhibitory activity, anti-inflammatory activity, or a combination thereof) to the reference antibody.

[0063] In some embodiments, the antibody of this disclosure has one or more CDR (e.g., HC CDR or LC CDR) sequences substantially similar to any of HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 from one of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b. In some embodiments, the positions of one or more CDRs along the VH (e.g., HC CDR1, HC CDR2, or HC CDR3) and / or VL (e.g., LC CDR1, LC CDR2, or LC CDR3) regions of the antibodies described herein can be mutated by only 1, 2, 3, 4, 5, or 6 amino acid positions, as long as specific binding to trypsin 1 (e.g., human or non-human primate trypsin 1) and trypsin 2 (e.g., human or non-human primate trypsin 2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the binding of the original antibody from which it is derived). For example, in some embodiments, the position defining the CDR of any antibody described herein can be mutated by shifting the N-terminal and / or C-terminal boundary of the CDR by 1, 2, 3, 4, 5, or 6 amino acids relative to any one CDR position of the antibody described herein, insofar as specific binding of trypsin 1 (e.g., human or non-human primate trypsin 1) and trypsin 2 (e.g., human or non-human primate trypsin 2) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the binding of the original antibody from which it originates).In another embodiment, the length of one or more CDRs along the VH (e.g., HC CDR1, HC CDR2, or HC CDR3) and / or VL (e.g., LC CDR1, LC CDR2, or LC CDR3) regions of the antibodies described herein may be mutated (e.g., shortened or lengthened) by only 1, 2, 3, 4, 5, or more amino acids, as long as immunospecific binding to trypsin 1 (e.g., human or non-human primate trypsin 1) and trypsin 2 (e.g., human or non-human primate trypsin 2) is maintained (e.g., substantially maintained at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the binding of the original antibody from which it originates).

[0064] Therefore, in some embodiments, the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein may be 1, 2, 3, 4, or 5 amino acids shorter than one or more of the CDRs described herein (e.g., CDRs from any of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b), as long as specific binding to trypsin 1 (e.g., human or non-human primate trypsin 1) and trypsin 2 (e.g., human or non-human primate trypsin 2) is maintained (e.g., substantially maintained by, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the binding of the original antibody from which it is derived). In some embodiments, the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein may be 1, 2, 3, 4, or 5 amino acids or longer than one or more of the CDRs described herein (e.g., CDRs from any of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b), provided that specific binding to trypsin 1 (e.g., human or non-human primate trypsin 1) and trypsin 2 (e.g., human or non-human primate trypsin 2) is maintained (e.g., substantially maintained by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the binding of the original antibody from which it is derived).In some embodiments, the amino portion of the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein can be extended by 1, 2, 3, 4, or 5 amino acids or more compared to one or more of the CDRs described herein (e.g., CDRs from any of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b), provided that specific binding to trypsin 1 (e.g., human or non-human primate trypsin 1) and trypsin 2 (e.g., human or non-human primate trypsin 2) is maintained (e.g., substantially maintained by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the binding of the original antibody from which it is derived). In some embodiments, the carboxyl portions of HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein can be extended by 1, 2, 3, 4, or 5 amino acids or more compared to one or more of the CDRs described herein (e.g., CDRs from any of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b), provided that specific binding to trypsin 1 (e.g., human or non-human primate trypsin 1) and trypsin 2 (e.g., human or non-human primate trypsin 2) is maintained (e.g., substantially maintained by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the binding of the original antibody from which it is derived).In some embodiments, the amino portion of the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein can be shortened by 1, 2, 3, 4, or 5 amino acids or more compared to one or more of the CDRs described herein (e.g., CDRs from any of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b), as long as specific binding to trypsin 1 (e.g., human or non-human primate trypsin 1) and trypsin 2 (e.g., human or non-human primate trypsin 2) is maintained (e.g., substantially maintained by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the binding of the original antibody from which it is derived). In some embodiments, the carboxyl portion of HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein can be shortened by 1, 2, 3, 4, or 5 amino acids or more compared to one or more of the CDRs described herein (e.g., CDRs from any of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b), as long as specific binding to trypsin 1 (e.g., human or non-human primate trypsin 1) and trypsin 2 (e.g., human or non-human primate trypsin 2) is maintained (e.g., substantially maintained by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the binding of the original antibody from which it is derived). To confirm whether specific binding to trypsin 1 (e.g., human or non-human primate trypsin 1) and trypsin 2 (e.g., human or non-human primate trypsin 2) is maintained, any method can be used, such as using the binding assays and conditions described in the Art.

[0065] In some cases, the antibodies of this disclosure have one or more CDR (e.g., HC CDR or LC CDR) sequences substantially similar to any one of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b. For example, the antibodies described herein may contain one or more CDR sequences from any of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b, containing up to 5, 4, 3, 2, or 1 amino acid residue mutations compared to the corresponding CDR region of any one of the CDRs provided herein (e.g., CDRs from any of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b), insofar as specific binding to trypsin 1 (e.g., human or non-human primate trypsin 1) and trypsin 2 (e.g., human or non-human primate trypsin 2) is maintained (e.g., substantially maintained by, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the binding of the original antibody from which it is derived). In some embodiments, any amino acid mutations in any of the CDRs provided herein may be conservative mutations. Conservative mutations can be introduced into a CDR at a position where the residue is unlikely to be involved in interaction with trypsin 1 (e.g., human or non-human primate trypsin 1) and / or trypsin 2 (e.g., human or non-human primate trypsin 2), for example, when determined based on the crystal structure. Some aspects of this disclosure provide antibodies comprising one or more heavy chain variable (VH) domains and / or light chain variable (VL) domains provided herein. In some embodiments, any VH domain provided herein comprises one or more of the HC CDR sequences provided herein (e.g., HC CDR1, HC CDR2, and HC CDR3), which are, for example, any of the HC CDR sequences provided for any one of the anti-trypsin 1 / trypsin 2 selected from Tables 1a and 1b.In some embodiments, each VL domain provided herein comprises one or more of the LC CDR sequences provided herein (e.g., LC CDR1, LC CDR2, and LC CDR3), which are, for example, any of the LC CDR sequences provided for any one of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b.

[0066] In some embodiments, the antibodies of the Disclosure include any antibody comprising a heavy chain variable domain and / or light chain variable domain of any one anti-trypsin 1 / trypsin 2 antibody selected from Tables 1a and 1b, as well as variants thereof. In some embodiments, the antibodies of the Disclosure include any antibody comprising a pair of heavy chain variable and light chain variable regions of any anti-trypsin 1 / trypsin 2 antibody selected from Tables 1a and 1b.

[0067] Aspects of this disclosure provide antibodies comprising heavy chain variable (VH) domain amino acid sequences and / or light chain variable (VL) domain amino acid sequences homologous to any of the amino acid sequences described herein. In some embodiments, the antibody comprises a heavy chain variable sequence or light chain variable sequence that is at least 75% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to any one of the heavy chain variable sequences and / or any light chain variable sequence of an anti-trypsin 1 / trypsin 2 antibody selected from Tables 1a and 1b. In some embodiments, the homologous heavy chain variable amino acid sequences and / or light chain variable amino acid sequences are not mutated in any of the CDR sequences provided herein. For example, in some embodiments, the degree of sequence variation (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the heavy chain variable sequence and / or light chain variable sequence, excluding any of the CDR sequences provided herein. In some embodiments, the antibodies provided herein include a heavy chain variable sequence and a light chain variable sequence that include a framework sequence which is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of any anti-trypsin 1 / trypsin 2 antibody selected from Tables 1a and 1b.

[0068] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure is an antibody comprising a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to any VH of any of the anti-trypsin 1 / trypsin 2 antibodies listed in Tables 1a and 1b. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure is an antibody comprising a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to any one VL of any of the anti-trypsin 1 / trypsin 2 antibodies listed in Tables 1a and 1b. In some embodiments, the heavy-chain variable amino acid sequence and / or light-chain variable amino acid sequence do not mutate within any of the CDR sequences provided herein. For example, in some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the heavy-chain variable sequence and / or light-chain variable sequence, excluding any of the CDR sequences provided herein. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or less amino acid mutations relative to the framework sequence of any one VH anti-trypsin 1 / trypsin 2 antibody selected from Tables 1a and 1b, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or less amino acid mutations relative to the framework sequence of any one VL anti-trypsin 1 / trypsin 2 antibody selected from Tables 1a and 1b.

[0069] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 57. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 58.

[0070] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, HC CDR3 having the amino acid sequence of SEQ ID NO: 3, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 6.

[0071] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3. As used anywhere in the Disclosure, “collectively” means that the total number of amino acid mutations in all three heavy chain CDRs is within a defined range. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 6.

[0072] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 6, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 6.

[0073] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 1; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 2; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO. 4; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO. 5; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO. 6.

[0074] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure is HC CDR1 having the amino acid sequence of SEQ ID NO: 1 and is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; HC CDR2 having the amino acid sequence of SEQ ID NO: 2 and is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR2 having the amino acid sequence of SEQ ID NO: 3 The CDR3 includes HC CDR3s that are at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 4; LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or LC CDR2 having the amino acid sequence of SEQ ID NO: 6 The CDR3 includes an LC CDR3 that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0075] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 57. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 58.

[0076] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO. 57. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO. 58. In some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the VH of SEQ ID NO: 57 and / or the VL of SEQ ID NO: 58, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VH framework sequence of SEQ ID NO: 57, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VL framework sequence of SEQ ID NO: 58.

[0077] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH described in SEQ ID NO: 57. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL described in SEQ ID NO: 58. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the VH of SEQ ID NO: 57 and / or within the VL of SEQ ID NO: 58, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the VH framework sequence of SEQ ID NO: 57, and / or a light chain variable sequence that includes a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the VL framework sequence of SEQ ID NO: 58.

[0078] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 59. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 60.

[0079] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 7, HC CDR2 having the amino acid sequence of SEQ ID NO: 8, HC CDR3 having the amino acid sequence of SEQ ID NO: 9, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 10.

[0080] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 7, HC CDR2 having the amino acid sequence of SEQ ID NO: 8, and HC CDR3 having the amino acid sequence of SEQ ID NO: 9. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 10.

[0081] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 7, HC CDR2 having the amino acid sequence of SEQ ID NO: 8, and HC CDR3 having the amino acid sequence of SEQ ID NO: 9, all of which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 10, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 10.

[0082] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 7; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 8; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 9. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO: 10.

[0083] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure is HC CDR1 having the amino acid sequence of SEQ ID NO: 7 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; HC CDR2 having the amino acid sequence of SEQ ID NO: 8 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; and / or HC CDR2 having the amino acid sequence of SEQ ID NO: 9 The CDR3 includes HC CDR3s that are at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 4; LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or LC CDR2 having the amino acid sequence of SEQ ID NO: 10 The CDR3 includes an LC CDR3 that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0084] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 59. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 60.

[0085] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO. 59. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO. 60. In some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the VH of SEQ ID NO: 59 and / or the VL of SEQ ID NO: 60, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VH framework sequence of SEQ ID NO: 59, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VL framework sequence of SEQ ID NO: 60.

[0086] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH described in SEQ ID NO: 59. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL described in SEQ ID NO: 60. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the VH of SEQ ID NO: 59 and / or the VL of SEQ ID NO: 60, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VH of SEQ ID NO: 59, and / or a light chain variable sequence that includes a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VL of SEQ ID NO: 60.

[0087] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 61. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 62.

[0088] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 11, HC CDR2 having the amino acid sequence of SEQ ID NO: 12, HC CDR3 having the amino acid sequence of SEQ ID NO: 13, LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 16.

[0089] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 11, HC CDR2 having the amino acid sequence of SEQ ID NO: 12, and HC CDR3 having the amino acid sequence of SEQ ID NO: 13. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 16.

[0090] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 11, HC CDR2 having the amino acid sequence of SEQ ID NO: 12, and HC CDR3 having the amino acid sequence of SEQ ID NO: 13, all of which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 16, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 16.

[0091] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 11; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 12; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 13. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO. 14; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO. 15; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO. 16.

[0092] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure is HC CDR1 having the amino acid sequence of SEQ ID NO: 11 and is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; HC CDR2 having the amino acid sequence of SEQ ID NO: 12 and is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR2 having the amino acid sequence of SEQ ID NO: 13 The CDR3 includes HC CDR3s that are at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure is LC CDR1 that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 14; LC CDR2 that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 15; and / or LC CDR2 having the amino acid sequence of SEQ ID NO: 16 The CDR3 includes an LC CDR3 that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0093] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 61. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 62.

[0094] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO. 61. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO. 62. In some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the VH of SEQ ID NO: 61 and / or the VL of SEQ ID NO: 62, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VH framework sequence of SEQ ID NO: 61, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VL framework sequence of SEQ ID NO: 62.

[0095] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH described in SEQ ID NO: 61. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL described in SEQ ID NO: 62. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the VH of SEQ ID NO: 61 and / or within the VL of SEQ ID NO: 62, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VH of SEQ ID NO: 61, and / or a light chain variable sequence that includes a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VL of SEQ ID NO: 62.

[0096] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 63. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 64.

[0097] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 17, HC CDR2 having the amino acid sequence of SEQ ID NO: 18, HC CDR3 having the amino acid sequence of SEQ ID NO: 19, LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 20.

[0098] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 17, HC CDR2 having the amino acid sequence of SEQ ID NO: 18, and HC CDR3 having the amino acid sequence of SEQ ID NO: 19. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 20.

[0099] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 17, HC CDR2 having the amino acid sequence of SEQ ID NO: 18, and HC CDR3 having the amino acid sequence of SEQ ID NO: 19, all of which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 20, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 20.

[0100] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO. 17; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO. 18; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO. 19. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO. 14; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO. 15; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO. 20.

[0101] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure is HC CDR1 having the amino acid sequence of SEQ ID NO: 17 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; HC CDR2 having the amino acid sequence of SEQ ID NO: 18 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 19 The CDR3 includes HC CDR3s that are at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 14; LC CDR2 having the amino acid sequence of SEQ ID NO: 15 is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 20 The CDR3 includes an LC CDR3 that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0102] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 63. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 64.

[0103] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO. 63. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO. 64. In some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the VH of SEQ ID NO: 63 and / or the VL of SEQ ID NO: 64, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VH framework sequence of SEQ ID NO: 63, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VL framework sequence of SEQ ID NO: 64.

[0104] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH described in SEQ ID NO: 63. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL described in SEQ ID NO: 64. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the VH of SEQ ID NO: 63 and / or within the VL of SEQ ID NO: 64, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VH of SEQ ID NO: 63, and / or a light chain variable sequence that includes a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VL of SEQ ID NO: 64.

[0105] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 65. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 66.

[0106] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 21, HC CDR2 having the amino acid sequence of SEQ ID NO: 22, HC CDR3 having the amino acid sequence of SEQ ID NO: 23, LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 24.

[0107] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 21, HC CDR2 having the amino acid sequence of SEQ ID NO: 22, and HC CDR3 having the amino acid sequence of SEQ ID NO: 23. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 24.

[0108] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 21, HC CDR2 having the amino acid sequence of SEQ ID NO: 22, and HC CDR3 having the amino acid sequence of SEQ ID NO: 23, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 21, HC CDR2 having the amino acid sequence of SEQ ID NO: 22, and HC CDR3 having the amino acid sequence of SEQ ID NO: 23. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 24, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1, LC CDR2 having the amino acid sequence of SEQ ID NO: 14, and LC CDR3 having the amino acid sequence of SEQ ID NO: 24.

[0109] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 21; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 22; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 23. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO. 14; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO. 15; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO. 24.

[0110] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure is HC CDR1 having the amino acid sequence of SEQ ID NO: 21 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; HC CDR2 having the amino acid sequence of SEQ ID NO: 22 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 23 The CDR3 includes HC CDR3s that are at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 14; LC CDR2 having the amino acid sequence of SEQ ID NO: 15 is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 24 The CDR3 includes an LC CDR3 that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0111] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 65. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 66.

[0112] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO. 65. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO. 66. In some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the VH of SEQ ID NO: 65 and / or the VL of SEQ ID NO: 66, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VH framework sequence of SEQ ID NO: 65, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VL framework sequence of SEQ ID NO: 66.

[0113] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH described in SEQ ID NO: 65. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL described in SEQ ID NO: 66. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the VH of SEQ ID NO: 65 and / or within the VL of SEQ ID NO: 66, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VH of SEQ ID NO: 65, and / or a light chain variable sequence that includes a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VL of SEQ ID NO: 66.

[0114] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 67. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 68.

[0115] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 21, HC CDR2 having the amino acid sequence of SEQ ID NO: 18, HC CDR3 having the amino acid sequence of SEQ ID NO: 25, LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 26.

[0116] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 21, HC CDR2 having the amino acid sequence of SEQ ID NO: 18, and HC CDR3 having the amino acid sequence of SEQ ID NO: 25. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 26.

[0117] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 21, HC CDR2 having the amino acid sequence of SEQ ID NO: 18, and HC CDR3 having the amino acid sequence of SEQ ID NO: 25, all of which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 26, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 26.

[0118] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO. 21; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO. 18; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO. 25. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO. 14; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO. 15; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO. 26.

[0119] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure is HC CDR1 having the amino acid sequence of SEQ ID NO: 21 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; HC CDR2 having the amino acid sequence of SEQ ID NO: 18 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 25 The CDR3 includes HC CDR3s that are at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure is LC CDR1 that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 14; LC CDR2 that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 15; and / or LC CDR2 having the amino acid sequence of SEQ ID NO: 26 The CDR3 includes an LC CDR3 that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0120] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 67. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 68.

[0121] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO. 67. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO. 68. In some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the VH of SEQ ID NO: 67 and / or the VL of SEQ ID NO: 68, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VH framework sequence of SEQ ID NO: 67, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VL framework sequence of SEQ ID NO: 68.

[0122] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH described in SEQ ID NO: 67. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL described in SEQ ID NO: 68. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the VH of SEQ ID NO: 67 and / or within the VL of SEQ ID NO: 68, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VH of SEQ ID NO: 67, and / or a light chain variable sequence that includes a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VL of SEQ ID NO: 68.

[0123] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 69. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 70.

[0124] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 27, HC CDR2 having the amino acid sequence of SEQ ID NO: 28, HC CDR3 having the amino acid sequence of SEQ ID NO: 29, LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32.

[0125] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 27, HC CDR2 having the amino acid sequence of SEQ ID NO: 28, and HC CDR3 having the amino acid sequence of SEQ ID NO: 29. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32.

[0126] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 27, HC CDR2 having the amino acid sequence of SEQ ID NO: 28, and HC CDR3 having the amino acid sequence of SEQ ID NO: 29, all of which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32.

[0127] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO. 27; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO. 28; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO. 29. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO. 30; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO. 31; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO. 32.

[0128] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure is HC CDR1 having the amino acid sequence of SEQ ID NO: 27 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; HC CDR2 having the amino acid sequence of SEQ ID NO: 28 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 29 The CDR3 includes HC CDR3s that are at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 30; LC CDR2 having the amino acid sequence of SEQ ID NO: 31 is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 32 The CDR3 includes an LC CDR3 that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0129] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 69. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 70.

[0130] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO. 69. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO. 70. In some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the VH of SEQ ID NO: 69 and / or the VL of SEQ ID NO: 70, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VH framework sequence of SEQ ID NO: 69, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VL framework sequence of SEQ ID NO: 70.

[0131] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH described in SEQ ID NO: 69. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL described in SEQ ID NO: 70. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the VH of SEQ ID NO: 69 and / or within the VL of SEQ ID NO: 70, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VH of SEQ ID NO: 69, and / or a light chain variable sequence that includes a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VL of SEQ ID NO: 70.

[0132] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 71. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 70.

[0133] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 33, HC CDR2 having the amino acid sequence of SEQ ID NO: 34, HC CDR3 having the amino acid sequence of SEQ ID NO: 35, LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32.

[0134] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 33, HC CDR2 having the amino acid sequence of SEQ ID NO: 34, and HC CDR3 having the amino acid sequence of SEQ ID NO: 35. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32.

[0135] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 33, HC CDR2 having the amino acid sequence of SEQ ID NO: 34, and HC CDR3 having the amino acid sequence of SEQ ID NO: 35, all of which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32.

[0136] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO. 33; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO. 34; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO. 35. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO. 30; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO. 31; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO. 32.

[0137] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure is HC CDR1 having the amino acid sequence of SEQ ID NO: 33 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; HC CDR2 having the amino acid sequence of SEQ ID NO: 34 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 35 The CDR3 includes HC CDR3s that are at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 30; LC CDR2 having the amino acid sequence of SEQ ID NO: 31 is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 32 The CDR3 includes an LC CDR3 that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0138] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 71. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 70.

[0139] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO: 71. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO: 70. In some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the VH of SEQ ID NO: 71 and / or the VL of SEQ ID NO: 70, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VH framework sequence of SEQ ID NO: 71, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VL framework sequence of SEQ ID NO: 70.

[0140] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH described in SEQ ID NO: 71. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL described in SEQ ID NO: 70. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the VH of SEQ ID NO: 71 and / or within the VL of SEQ ID NO: 70, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VH of SEQ ID NO: 71, and / or a light chain variable sequence that includes a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VL of SEQ ID NO: 70.

[0141] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 72. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 73.

[0142] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 36, HC CDR2 having the amino acid sequence of SEQ ID NO: 37, HC CDR3 having the amino acid sequence of SEQ ID NO: 38, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39.

[0143] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 36, HC CDR2 having the amino acid sequence of SEQ ID NO: 37, and HC CDR3 having the amino acid sequence of SEQ ID NO: 38. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39.

[0144] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 36, HC CDR2 having the amino acid sequence of SEQ ID NO: 37, and HC CDR3 having the amino acid sequence of SEQ ID NO: 38, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39.

[0145] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO. 36; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO. 37; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO. 38. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO. 4; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO. 5; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO. 39.

[0146] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure is HC CDR1 having the amino acid sequence of SEQ ID NO: 36 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; HC CDR2 having the amino acid sequence of SEQ ID NO: 37 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 38 The CDR3 includes HC CDR3s that are at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include: LC CDR1 having the amino acid sequence of SEQ ID NO: 4, which is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1; LC CDR2 having the amino acid sequence of SEQ ID NO: 5, which is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or LC CDR2 having the amino acid sequence of SEQ ID NO: 39 The CDR3 includes an LC CDR3 that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0147] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 72. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 73.

[0148] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO. 72. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO. 73. In some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the VH of SEQ ID NO: 72 and / or the VL of SEQ ID NO: 73, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VH framework sequence of SEQ ID NO: 72, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VL framework sequence of SEQ ID NO: 73.

[0149] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH described in SEQ ID NO: 72. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL described in SEQ ID NO: 73. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the VH of SEQ ID NO: 72 and / or within the VL of SEQ ID NO: 73, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the VH framework sequence of SEQ ID NO: 72, and / or a light chain variable sequence that includes a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the VL framework sequence of SEQ ID NO: 73.

[0150] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 74. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 73.

[0151] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, HC CDR3 having the amino acid sequence of SEQ ID NO: 38, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39.

[0152] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, and HC CDR3 having the amino acid sequence of SEQ ID NO: 38. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39.

[0153] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, and HC CDR3 having the amino acid sequence of SEQ ID NO: 38, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, and HC CDR3 having the amino acid sequence of SEQ ID NO: 38. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39.

[0154] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 40; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 41; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 38. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO. 4; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO. 5; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO. 39.

[0155] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure is HC CDR1 having the amino acid sequence of SEQ ID NO: 40, which is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; HC CDR2 having the amino acid sequence of SEQ ID NO: 41, which is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR2 having the amino acid sequence of SEQ ID NO: 38 The CDR3 includes HC CDR3s that are at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include: LC CDR1 having the amino acid sequence of SEQ ID NO: 4, which is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1; LC CDR2 having the amino acid sequence of SEQ ID NO: 5, which is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or LC CDR2 having the amino acid sequence of SEQ ID NO: 39 The CDR3 includes an LC CDR3 that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0156] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 74. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 73.

[0157] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO: 74. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO: 73. In some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the VH of SEQ ID NO: 74 and / or the VL of SEQ ID NO: 73, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VH framework sequence of SEQ ID NO: 74, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VL framework sequence of SEQ ID NO: 73.

[0158] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH described in SEQ ID NO: 74. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL described in SEQ ID NO: 73. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the VH of SEQ ID NO: 74 and / or within the VL of SEQ ID NO: 73, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VH of SEQ ID NO: 74, and / or a light chain variable sequence that includes a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VL of SEQ ID NO: 73.

[0159] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 75. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 73.

[0160] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, HC CDR3 having the amino acid sequence of SEQ ID NO: 42, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39.

[0161] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, and HC CDR3 having the amino acid sequence of SEQ ID NO: 42. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39.

[0162] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, and HC CDR3 having the amino acid sequence of SEQ ID NO: 42, all of which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39.

[0163] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 40; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 41; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 42. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO. 4; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO. 5; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO. 39.

[0164] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure is HC CDR1 having the amino acid sequence of SEQ ID NO: 40 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; HC CDR2 having the amino acid sequence of SEQ ID NO: 41 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 42 The CDR3 includes HC CDR3s that are at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include: LC CDR1 having the amino acid sequence of SEQ ID NO: 4, which is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1; LC CDR2 having the amino acid sequence of SEQ ID NO: 5, which is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or LC CDR2 having the amino acid sequence of SEQ ID NO: 39 The CDR3 includes an LC CDR3 that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0165] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 75. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 73.

[0166] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO: 75. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO: 73. In some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the VH of SEQ ID NO: 75 and / or the VL of SEQ ID NO: 73, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VH framework sequence of SEQ ID NO: 75, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VL framework sequence of SEQ ID NO: 73.

[0167] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH described in SEQ ID NO: 75. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL described in SEQ ID NO: 73. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the VH of SEQ ID NO: 75 and / or within the VL of SEQ ID NO: 73, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VH of SEQ ID NO: 75, and / or a light chain variable sequence that includes a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VL of SEQ ID NO: 73.

[0168] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 76. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 73.

[0169] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, HC CDR3 having the amino acid sequence of SEQ ID NO: 43, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39.

[0170] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, and HC CDR3 having the amino acid sequence of SEQ ID NO: 43. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39.

[0171] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, and HC CDR3 having the amino acid sequence of SEQ ID NO: 43, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, and HC CDR3 having the amino acid sequence of SEQ ID NO: 43. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39.

[0172] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 40; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 41; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 43. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO. 4; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO. 5; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO. 39.

[0173] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure is HC CDR1 having the amino acid sequence of SEQ ID NO: 40 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; HC CDR2 having the amino acid sequence of SEQ ID NO: 41 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 43 The CDR3 includes HC CDR3s that are at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include: LC CDR1 having the amino acid sequence of SEQ ID NO: 4, which is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1; LC CDR2 having the amino acid sequence of SEQ ID NO: 5, which is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or LC CDR2 having the amino acid sequence of SEQ ID NO: 39 The CDR3 includes an LC CDR3 that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0174] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 76. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 73.

[0175] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO: 76. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO: 73. In some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the VH of SEQ ID NO: 76 and / or the VL of SEQ ID NO: 73, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VH framework sequence of SEQ ID NO: 76, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VL framework sequence of SEQ ID NO: 73.

[0176] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH described in SEQ ID NO: 76. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL described in SEQ ID NO: 73. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the VH of SEQ ID NO: 76 and / or within the VL of SEQ ID NO: 73, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VH of SEQ ID NO: 76, and / or a light chain variable sequence that includes a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VL of SEQ ID NO: 73.

[0177] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 77. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 78.

[0178] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, HC CDR3 having the amino acid sequence of SEQ ID NO: 44, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 45.

[0179] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, and HC CDR3 having the amino acid sequence of SEQ ID NO: 44. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 45.

[0180] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, and HC CDR3 having the amino acid sequence of SEQ ID NO: 44, all of which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 45, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 45.

[0181] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 40; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 41; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 44. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO: 45.

[0182] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure is HC CDR1 having the amino acid sequence of SEQ ID NO: 40, which is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; HC CDR2 having the amino acid sequence of SEQ ID NO: 41, which is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 44; and / or HC CDR2 having the amino acid sequence of SEQ ID NO: 44 The CDR3 includes HC CDR3s that are at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 4; LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or LC CDR2 having the amino acid sequence of SEQ ID NO: 45 The CDR3 includes an LC CDR3 that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0183] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 77. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 78.

[0184] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO. 77. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO. 78. In some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the VH of SEQ ID NO: 77 and / or the VL of SEQ ID NO: 78, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VH framework sequence of SEQ ID NO: 77, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VL framework sequence of SEQ ID NO: 78.

[0185] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH described in SEQ ID NO: 77. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL described in SEQ ID NO: 78. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the VH of SEQ ID NO: 77 and / or within the VL of SEQ ID NO: 78, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the VH framework sequence of SEQ ID NO: 77, and / or a light chain variable sequence that includes a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the VL framework sequence of SEQ ID NO: 78.

[0186] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 79. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 80.

[0187] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 46, HC CDR3 having the amino acid sequence of SEQ ID NO: 47, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 48.

[0188] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 46, and HC CDR3 having the amino acid sequence of SEQ ID NO: 47. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 48.

[0189] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 46, and HC CDR3 having the amino acid sequence of SEQ ID NO: 47, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 48, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 48.

[0190] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 40; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 46; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 47. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO: 48.

[0191] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure is HC CDR1 having the amino acid sequence of SEQ ID NO: 40 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; HC CDR2 having the amino acid sequence of SEQ ID NO: 46 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 47 The CDR3 includes HC CDR3s that are at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 4; LC CDR2 having the amino acid sequence of SEQ ID NO: 5; and / or LC CDR2 having the amino acid sequence of SEQ ID NO: 48 The CDR3 includes an LC CDR3 that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0192] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 79. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 80.

[0193] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO. 79. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO. 80. In some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the VH of SEQ ID NO: 79 and / or the VL of SEQ ID NO: 80, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VH framework sequence of SEQ ID NO: 79, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VL framework sequence of SEQ ID NO: 80.

[0194] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH described in SEQ ID NO: 79. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL described in SEQ ID NO: 80. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the VH of SEQ ID NO: 79 and / or within the VL of SEQ ID NO: 80, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VH of SEQ ID NO: 79, and / or a light chain variable sequence that includes a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VL of SEQ ID NO: 80.

[0195] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 81. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 82.

[0196] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 49, HC CDR2 having the amino acid sequence of SEQ ID NO: 50, HC CDR3 having the amino acid sequence of SEQ ID NO: 51, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 52.

[0197] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 49, HC CDR2 having the amino acid sequence of SEQ ID NO: 50, and HC CDR3 having the amino acid sequence of SEQ ID NO: 51. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 52.

[0198] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 49, HC CDR2 having the amino acid sequence of SEQ ID NO: 50, and HC CDR3 having the amino acid sequence of SEQ ID NO: 51, all of which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 52, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 52.

[0199] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 49; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO: 50; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO: 51. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO. 4; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO. 5; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO. 52.

[0200] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure is HC CDR1 having the amino acid sequence of SEQ ID NO: 49 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; HC CDR2 having the amino acid sequence of SEQ ID NO: 50 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 51 The CDR3 includes HC CDR3s that are at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 4; LC CDR2 having the amino acid sequence of SEQ ID NO: 5 having the amino acid sequence of LC CDR2 having the amino acid sequence of LC CDR2 having the amino acid sequence of LC CDR2 having the amino acid sequence of LC CDR2 having the amino acid sequence of SEQ ID NO: 5 having the amino acid sequence of LC CDR1 The CDR3 includes an LC CDR3 that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0201] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 81. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 82.

[0202] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO. 81. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO. 82. In some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the VH of SEQ ID NO: 81 and / or the VL of SEQ ID NO: 82, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VH framework sequence of SEQ ID NO: 81, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VL framework sequence of SEQ ID NO: 82.

[0203] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH described in SEQ ID NO: 81. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL described in SEQ ID NO: 82. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the VH of SEQ ID NO: 81 and / or within the VL of SEQ ID NO: 82, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VH of SEQ ID NO: 81, and / or a light chain variable sequence that includes a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VL of SEQ ID NO: 82.

[0204] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 83. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 70.

[0205] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 27, HC CDR2 having the amino acid sequence of SEQ ID NO: 28, HC CDR3 having the amino acid sequence of SEQ ID NO: 53, LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32.

[0206] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 27, HC CDR2 having the amino acid sequence of SEQ ID NO: 28, and HC CDR3 having the amino acid sequence of SEQ ID NO: 53. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the present disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32.

[0207] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 27, HC CDR2 having the amino acid sequence of SEQ ID NO: 28, and HC CDR3 having the amino acid sequence of SEQ ID NO: 53, all of which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32.

[0208] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO. 27; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO. 28; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO. 53. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO. 30; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO. 31; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO. 32.

[0209] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure is HC CDR1 having the amino acid sequence of SEQ ID NO: 27 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; HC CDR2 having the amino acid sequence of SEQ ID NO: 28 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 53 The CDR3 includes HC CDR3s that are at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 30; LC CDR2 having the amino acid sequence of SEQ ID NO: 31 is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 32 The CDR3 includes an LC CDR3 that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0210] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 83. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 70.

[0211] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO: 83. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO: 70. In some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the VH of SEQ ID NO: 83 and / or the VL of SEQ ID NO: 70, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VH framework sequence of SEQ ID NO: 83, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VL framework sequence of SEQ ID NO: 70.

[0212] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH described in SEQ ID NO: 83. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL described in SEQ ID NO: 70. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the VH of SEQ ID NO: 83 and / or within the VL of SEQ ID NO: 70, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VH of SEQ ID NO: 83, and / or a light chain variable sequence that includes a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VL of SEQ ID NO: 70.

[0213] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises heavy chain variable domains HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 84. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises light chain variable domains LC CDR1, LC CDR2, and LC CDR3 having the amino acid sequence of SEQ ID NO: 70.

[0214] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having the amino acid sequence of SEQ ID NO: 54, HC CDR2 having the amino acid sequence of SEQ ID NO: 55, HC CDR3 having the amino acid sequence of SEQ ID NO: 56, LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32.

[0215] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise HC CDR1, HC CDR2, and HC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO: 54, HC CDR2 having the amino acid sequence of SEQ ID NO: 55, and HC CDR3 having the amino acid sequence of SEQ ID NO: 56. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of the Disclosure comprise LC CDR1, LC CDR2, and LC CDR3, which collectively contain 5 or fewer amino acid mutations (e.g., 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32.

[0216] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises HC CDR1, HC CDR2, and HC CDR3 having the amino acid sequence of SEQ ID NO: 54, HC CDR2 having the amino acid sequence of SEQ ID NO: 55, and HC CDR3 having the amino acid sequence of SEQ ID NO: 56, all of which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32, which are collectively at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32.

[0217] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure includes HC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR1 having the amino acid sequence of SEQ ID NO. 54; HC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR2 having the amino acid sequence of SEQ ID NO. 55; and / or HC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to HC CDR3 having the amino acid sequence of SEQ ID NO. 56. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibodies of this disclosure include LC CDR1 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR1 having the amino acid sequence of SEQ ID NO. 30; LC CDR2 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR2 having the amino acid sequence of SEQ ID NO. 31; and / or LC CDR3 having 3 or fewer amino acid mutations (e.g., 3, 2, or 1 or fewer amino acid mutations) compared to LC CDR3 having the amino acid sequence of SEQ ID NO. 32.

[0218] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the Disclosure is HC CDR1 having the amino acid sequence of SEQ ID NO: 54 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1; HC CDR2 having the amino acid sequence of SEQ ID NO: 55 and being at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to HC CDR1 having the amino acid sequence of SEQ ID NO: 56 The CDR3 includes HC CDR3s that are at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 30; LC CDR2 having the amino acid sequence of SEQ ID NO: 31 is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to LC CDR1 having the amino acid sequence of SEQ ID NO: 32 The CDR3 includes an LC CDR3 that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0219] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 84. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 70.

[0220] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VH containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH described in SEQ ID NO: 84. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of this disclosure comprises a VL containing 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VL described in SEQ ID NO: 70. In some embodiments, the number of amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) may occur within the VH of SEQ ID NO: 84 and / or the VL of SEQ ID NO: 70, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VH framework sequence of SEQ ID NO: 84, and / or a light chain variable sequence comprising a framework sequence containing 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations relative to the VL framework sequence of SEQ ID NO: 70.

[0221] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VH described in SEQ ID NO: 84. Alternatively or additionally, the anti-trypsin 1 / trypsin 2 antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the VL described in SEQ ID NO: 70. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within the VH of SEQ ID NO: 84 and / or within the VL of SEQ ID NO: 70, excluding any CDR sequences within them. In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies provided herein include a heavy chain variable sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VH of SEQ ID NO: 84, and / or a light chain variable sequence that includes a framework sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the framework sequence of VL of SEQ ID NO: 70.

[0222] The antibodies described herein may be in any antibody form, including but not limited to intact (i.e., full-length) antibodies, their antigen-binding fragments (Fab, F(ab'), F(ab')2, Fv, etc.), single-chain antibodies, bispecific antibodies, or nanobodies. In some embodiments, the anti-trypsin 1 / trypsin 2 antibody described herein is scFv. In some embodiments, the anti-trypsin 1 / trypsin 2 antibody described herein is scFv-Fab (e.g., scFv fused to a portion of the constant region).

[0223] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody of this disclosure is a chimeric antibody, which may include a heavy chain constant region and a light chain constant region derived from a human antibody. A chimeric antibody refers to an antibody having a variable region or a portion of a variable region derived from a first species and a constant region derived from a second species. Typically, in these chimeric antibodies, both the light chain and heavy chain variable regions mimic the variable regions of an antibody derived from one species of mammal (e.g., a non-human mammal such as a mouse, rabbit, and rat), while the constant region is homologous to the sequence in an antibody derived from another mammal, such as a human. In some embodiments, amino acid modifications may occur in the variable region and / or the constant region.

[0224] In some embodiments, the antibodies of this disclosure comprise a VL domain and / or VH domain of any one of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b, and include a constant region comprising the amino acid sequence of the constant region of an IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule, any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or any subclass (e.g., IgG2a and IgG2b) immunoglobulin molecule. Non-limiting examples of human constant regions have been described in the Art; see, for example, Kabat EA et al., (1991), cited above.

[0225] In some embodiments, the light chain of any of the anti-trypsin 1 / trypsin 2 antibodies described herein may further comprise a light chain constant region (CL), which may be any CL known in the art. In some examples, the CL is a kappa light chain. In other examples, the CL is a lambda light chain. In some embodiments, the CL is a kappa light chain. In some embodiments, the antibody of the Disclosure comprises the VL domain and / or VH domain of any one of the anti-trypsin 1 / trypsin 2 antibodies selected from Tables 1a and 1b, and further comprises a kappa light chain constant domain.

[0226] Other antibody heavy chain constant regions and light chain constant regions are well known in the art, for example, those provided in the IMGT database or VBASE2, both of which are incorporated herein by reference.

[0227] In some embodiments, conservative mutations may be introduced into the antibody sequence (e.g., CDR or framework sequence) at a position where the residue is unlikely to be involved in interaction with the target antigen (e.g., human or non-human primate trypsin 1 and / or human or non-human primate trypsin 2), for example, if determined based on the crystal structure. In some embodiments, one, two or more mutations (e.g., amino acid substitutions) may be introduced into the Fc region (numbered according to the Kabat numbering system (e.g., the EU index in Kabat), for example, the CH2 domain (residues 231-340 of human IgG1) and / or the CH3 domain (residues 341-447 of human IgG1) and / or the hinge region) of the anti-trypsin 1 / trypsin 2 antibody described herein to modify one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding and / or antigen-dependent cytotoxicity.

[0228] In some embodiments, one, two, or more mutations (e.g., amino acid substitutions) are introduced into the hinge region of the Fc domain (CH1 domain) to modify (e.g., increase or decrease) the number of cysteine ​​residues in the hinge region, as described, for example, in U.S. Patent No. 5,677,425. Modifying the number of cysteine ​​residues in the hinge region of the CH1 domain can, for example, facilitate the assembly of light and heavy chains, or modify (e.g., increase or decrease) the stability of the antibody, or facilitate linker conjugation.

[0229] In some embodiments, one, two, or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of the antibodies described herein (numbered according to the Kabat numbering system (e.g., the EU index in Kabat), for example, the CH2 domain (residues 231-340 of human IgG1) and / or the CH3 domain (residues 341-447 of human IgG1) and / or the hinge region) to increase or decrease the affinity of the antibody to Fc receptors (e.g., activated Fc receptors) on the surface of effector cells. Mutations in the Fc region of antibodies that decrease or increase the affinity of an antibody to Fc receptors, and techniques for introducing such mutations into Fc receptors or fragments thereof, are known to those skilled in the art. Examples of antibody mutations at the Fc receptor that can be used to alter the affinity of an antibody to the Fc receptor are described, for example, in Smith P et al., (2012) PNAS 109:6181-6186, U.S. Patent No. 6,737,056, and International Publication Nos. WO02 / 060919; WO98 / 23289; and WO97 / 34631, which are incorporated herein by reference.

[0230] In some embodiments, one, two, or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into the IgG constant domain or its FcRn binding fragment (preferably an Fc or hinge-Fc domain fragment) to modify (e.g., decrease or increase) the in vivo half-life of the antibody. See, for example, International Publication Nos. WO02 / 060919; WO98 / 23289; and WO97 / 34631; and U.S. Patents 5,869,046, 6,121,022, 6,277,375, and 6,165,745 for examples of mutations that modify (e.g., decrease or increase) the in vivo half-life of the antibody.

[0231] In some embodiments, one, two, or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into the IgG constant domain or its FcRn binding fragment (preferably an Fc or hinge-Fc domain fragment) to reduce the half-life of an anti-trypsin 1 / trypsin 2 antibody in vivo. In some embodiments, one, two, or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into the IgG constant domain or its FcRn binding fragment (preferably an Fc or hinge-Fc domain fragment) to increase the half-life of the antibody in vivo. In some embodiments, the antibody may have one or more amino acid mutations (e.g., substitutions) in a second constant (CH2) domain (residues 231-340 of human IgG1) and / or a third constant (CH3) domain (residues 341-447 of human IgG1), numbered according to the EU index in Kabat (Kabat EA et al., (1991), cited above). In some embodiments, the constant region of IgG1 of the antibodies described herein, numbered according to the EU index as set forth in Kabat, includes a methionine (M) to tyrosine (Y) substitution at position 252, a serine (S) to threonine (T) substitution at position 254, and a threonine (T) to glutamic acid (E) substitution at position 256. See U.S. Patent No. 7,658,921, which is incorporated herein by reference. This type of mutant IgG is called a “YTE mutant” and has been shown to exhibit a four-fold increased half-life compared to the wild-type version of the same antibody (see Dall'Acqua WF et al., (2006) J Biol Chem 281:23514-24). In some embodiments, the antibody includes an IgG constant domain that contains one, two, three or more amino acid substitutions of amino acid residues at positions 251–257, 285–290, 308–314, 385–389, and 428–436, numbered according to the EU index as found in Kabat.

[0232] In some embodiments, the antibody includes an Fc region that has been modified, for example, by introducing substitutions of M428L and / or N434A, for the purpose of extending the half-life. Non-limiting examples of such Fc variants that affect the circulating half-life are provided in Saunders KO, Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life, Front Immunol. 2019;10:1296, which is incorporated herein by reference.

[0233] In some embodiments, the effector function(s) of an anti-trypsin 1 / trypsin 2 antibody is modified by introducing one, two, or more amino acid substitutions into the IgG constant domain Fc region, for example, by introducing Leu234Ala and Leu235Ala mutations (commonly referred to as LALA mutations). The effector ligand whose affinity is modified may be, for example, the Fc receptor or the C1 component of complement. This technique is described in U.S. Patents 5,624,821 and 5,648,260. In some embodiments, deletion or inactivation of the constant domain (via point mutation or other means) can reduce the binding of the circulating antibody to the Fc receptor, thereby increasing tumor localization. For a description of mutations that delete or inactivate the constant domain and thereby increase tumor localization, see, for example, U.S. Patents 5,585,097 and 8,591,886. In some embodiments, one or more amino acid substitutions may be introduced into the Fc region of the antibodies described herein to remove potential glycosylation sites on the Fc region, thereby reducing Fc receptor binding (see, for example, Shields RL et al., (2001) J Biol Chem 276:6591-604).

[0234] In some embodiments, one or more amino acids in the constant region of the anti-trypsin 1 / trypsin 2 antibody described herein can be replaced with different amino acid residues, thereby giving the antibody modified C1q binding and / or reduced or ineffective complement-dependent cell-mediated cytotoxicity (CDC). This technique is described in detail in U.S. Patent No. 6,194,551 (Idusogie et al). In some embodiments, one or more amino acid residues in the N-terminal region of the CH2 domain of the antibody described herein are modified, thereby altering the antibody's ability to immobilize complement. This technique is further described in International Publication No. WO94 / 29351. In some embodiments, the Fc region of the antibody described herein is modified to increase the antibody's ability to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) and / or increase the antibody's affinity for the Fcγ receptor. This technique is further described in International Publication No. WO00 / 42072.

[0235] In some embodiments, the antibody comprises an Fc variant containing amino acid substitutions L234A, L235E, and P329G, in which case the numbering follows the EU index. In some embodiments, the antibody comprising the Fc variant exhibits reduced affinity for one or more or each of FcyRJ, FcyRIIA, FcyRIIIA, and Clq compared to the antibody comprising the wild-type human Fc region. Examples of such Fc variants are provided in International Patent Application Publication No. WO2021 / 055669, title, FC VARIANTS WITH REDUCED EFFECTOR FUNCTION, published March 25, 2021; and U.S. Patent Application Publication No. US2021-0087271, title, FC VARIANTS WITH REDUCED EFFECTOR FUNCTION, published March 25, 2021, the contents of which are incorporated herein by reference.

[0236] In some embodiments, as described elsewhere herein, variable domain(s) sequences(options) of the heavy and / or light chains of the antibodies provided herein can be used to generate, for example, CDR-implanted, chimeric, humanized, or compound human antibodies or antigen-binding fragments. As will be understood by those skilled in the art, any variant, CDR-implanted, chimeric, humanized, or compound antibody derived from any of the antibodies provided herein may be useful in the compositions and methods described herein, and the variant, CDR-implanted, chimeric, humanized, or compound antibody will maintain the ability to specifically bind to trypsin 1 and trypsin 2 such that it has at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or more binding to trypsin 1 and trypsin 2 compared to the original antibody from which it is derived.

[0237] In some embodiments, the antibodies provided herein include mutations that confer desirable properties to the antibody. For example, to avoid potential complications from Fab-arm exchange, which are known to occur with natural IgG4 mAbs, the antibodies provided herein may include a stabilizing "Adair" mutation (Angal S., et al., “A single amino acid substitution abolishes the heterogeneity of chimeric mouse / human (IgG4) antibody,” Mol Immunol 30, 105-108; 1993), in which serine 228 (EU numbering; residue 241 Kabat numbering) is converted to proline, resulting in an IgG1-like hinge sequence. Thus, any of the antibodies may include a stabilizing "Adair" mutation.

[0238] In some embodiments, the antibody is modified, for example, by glycosylation, phosphorylation, SUMOylation, and / or methylation. In some embodiments, the antibody is a glycosylated antibody conjugated to one or more sugar or carbohydrate molecules. In some embodiments, one or more sugar or carbohydrate molecules are conjugated to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glyciation (GPI anchor attachment), and / or phosphoglycosylation. In some embodiments, one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, one or more sugar or carbohydrate molecules are branched oligosaccharides or branched glycans. In some embodiments, one or more sugar or carbohydrate molecules include mannose units, glucose units, N-acetylglucosamine units, N-acetylgalactosamine units, galactose units, fucose units, or phospholipid units. In some embodiments, there are about 1–10, about 1–5, about 5–10, about 1–4, about 1–3, or about 2 sugar molecules. In some embodiments, the glycosylated antibody is completely or partially glycosylated. In some embodiments, the antibody is glycosylated by chemical reaction or enzymatic means. In some embodiments, the antibody is glycosylated in vitro or intracellularly, which may optionally be deficient in enzymes of the N- or O-glycosylation pathway, such as glycosyltransferase. In some embodiments, the antibody is functionalized with sugar molecules or carbohydrate molecules, as described in International Patent Application Publication No. WO2014065661, published May 1, 2014, titled "Modified antibody, antibody-conjugate and process for the preparation thereof".

[0239] In some embodiments, any one of the anti-trypsin 1 / trypsin 2 antibodies described herein may include a signal peptide (e.g., an N-terminal signal peptide) in the heavy chain sequence and / or light chain sequence. In some embodiments, the anti-trypsin 1 / trypsin 2 antibody described herein includes either a VH sequence or a VL sequence, either an IgG heavy chain sequence or a light chain sequence, or either an F(ab') heavy chain sequence or a light chain sequence described herein, and further includes a signal peptide (e.g., an N-terminal signal peptide).

[0240] In some embodiments, the antibodies provided herein are multispecific antibodies (e.g., bispecific antibodies). For example, in some embodiments, one or more anti-trypsin 1 / trypsin 2 antibodies may be combined with one or more different anti-trypsin 1 / trypsin 2 antibodies to produce multispecific or bispecific anti-trypsin 1 / trypsin 2 antibodies. For example, one or more anti-trypsin 1 / trypsin 2 antibodies described herein (Tables 1a and 1b) can be combined with one or more different anti-trypsin 1 / trypsin 2 antibodies described herein (Tables 1a and 1b) to produce multispecific antibodies.

[0241] In some embodiments, one or more anti-trypsin 1 / trypsin 2 antibodies may be combined with any other suitable therapeutic antibody to generate multispecific or bispecific anti-trypsin 1 / trypsin 2 / additional target antibodies. For example, the anti-trypsin 1 / trypsin 2 antibodies described herein (Tables 1a and 1b) can be combined with any suitable antibody to generate a bispecific antibody. Such additional therapeutic antibody may be, for example, an anti-intercellular adhesion molecule-1 (ICAM-1) antibody (see, e.g., Werner et al., Specific Therapy for Local and Systemic Complications of Acute Pancreatitis With Monoclonal Antibodies Against ICAM-1, Ann Surg. 1999 Jun;229(6):834).

[0242] III. Preparation of anti-trypsin 1 / trypsin 2 antibodies The antibodies described herein can be prepared by any method known in the art. For example, see Harlow and Lane, (1998) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York.

[0243] In some embodiments, antibodies specific to a target antigen (e.g., trypsin 1 and / or trypsin 2) can be produced by conventional hybridoma techniques. A host animal can be immunized to produce antibodies that bind to a full-length target antigen or a fragment thereof, optionally coupled to a carrier protein such as KLH. The routes and schedules of immunization of the host animal are generally consistent with established conventional techniques for antibody stimulation and production, as further described herein. Common techniques for mouse, humanization, and human antibody production are known in the art and described herein. Any mammalian subject, including human or human-derived antibody-producing cells, is intended to be manipulated to serve as a basis for the production of mammalian, e.g., human hybridoma cell lines. Typically, the host animal is inoculated intraperitoneally, intramuscularly, orally, subcutaneously, plantarly, and / or intradermally with a certain amount of immunogen, including those described herein.

[0244] If desired, the antibody of interest (monoclonal or polyclonal) (e.g., produced by a hybridoma) may be sequenced, and the polynucleotide sequence may then be cloned into a vector for expression or proliferation. The sequence encoding the antibody of interest may be maintained in a vector within host cells, and the host cells may then be grown and frozen for future use. Alternatively, the polynucleotide sequence may be used for genetic engineering to "humanize" the antibody, or to improve the antibody's affinity (affinity maturation) or other properties. For example, when the antibody is to be used in clinical trials and human treatments, the constant region may be manipulated to more closely resemble the human constant region in order to avoid an immune response. Genetic engineering of the antibody sequence may be desirable to obtain higher affinity and higher efficacy against the target antigen. It will be apparent to those skilled in the art that one or more polynucleotide changes can be made to an antibody while still maintaining its binding specificity to the target antigen.

[0245] In other embodiments, fully human antibodies can be obtained by using commercially available mice engineered to express specific human immunoglobulin proteins. Transgenic animals designed to produce a more desirable (e.g., fully human antibodies) or more robust immune response can also be used to produce humanized antibodies or human antibodies. Examples of such techniques include Xenomouse® from Amgen, Inc. (Fremont, CA), HuMAb-Mouse® and TC mice® from Medarex, Inc. (Princeton, NJ), or H2L2 mice from Harbor Antibodies BV (Holland). Alternatively, antibodies can be recombinantly produced by phage display or yeast technology. See, for example, U.S. Patent Nos. 5,565,332; 5,580,717; 5,733,743; and 6,265,150; and Winter et al., (1994) Annu. Rev. Immunol. 12:433-455. Alternatively, phage display technology (McCafferty et al., (1990) Nature 348:552-553) can be used to generate human antibodies and antibody fragments in vitro from a gene repertoire of immunoglobulin variable (V) domains derived from non-immunized donors.

[0246] Antigen-binding fragments of intact antibodies (full-length antibodies) can be prepared by conventional methods. For example, the F(ab')2 fragment can be produced by pepsin digestion of the antibody molecule, and the Fab fragment can be produced by reducing the disulfide crosslinks of the F(ab')2 fragment. Genetically modified antibodies, such as humanized antibodies, chimeric antibodies, single-chain antibodies, and bispecific antibodies, can be produced, for example, by conventional recombination techniques. In one example, DNA encoding a monoclonal antibody specific to a target antigen can be readily isolated and sequenced using conventional procedures (for example, by using oligonucleotide probes capable of specifically binding to the genes encoding the heavy and light chains of the monoclonal antibody). Hybridoma cells serve as a preferred source of such DNA. After isolation, the DNA may be placed in one or more expression vectors, which are then transfected into host cells that do not otherwise produce immunoglobulin proteins, such as E. coli cells, Simian COS cells, Chinese hamster ovary (CHO) cells, human HEK293 cells, or myeloma cells, to synthesize monoclonal antibodies in the recombinant host cells. See, for example, PCT publication number WO87 / 04462. The DNA can then be modified, for example, by substituting the coding sequences of the constant domains of human heavy and light chains for homologous mouse sequences (Morrison et al., (1984) Proc. Nat. Acad. Sci. 81:6851), or by covalently binding all or part of the coding sequence of a non-immunoglobulin polypeptide to the immunoglobulin coding sequence. In this way, genetically modified antibodies, such as “chimeric” or “hybrid” antibodies, which have binding specificity to target antigens, can be prepared.

[0247] Single-chain antibodies can be prepared via recombinant techniques by linking nucleotide sequences encoding a heavy chain variable region and a light chain variable region. Preferably, a movable linker is incorporated between the two variable regions.

[0248] Antibodies obtained according to methods known in the art and described herein can be characterized using methods well known in the art. For example, one method is to identify the epitopes to which the antigen binds, or "epitope mapping." There are many methods known in the art for mapping and characterizing the location of epitopes on proteins, including analysis of the crystalline structure of antibody-antigen complexes, competitive assays, gene fragment expression assays, and synthetic peptide-based assays, for example, Chapter 11 of Harlow and Lane, Using Antibodies, a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1999. In one example, epitope mapping can be achieved using H / D-Ex (hydrogen-deuterium exchange) combined with proteolysis and mass spectrometry. In an additional example, epitope mapping can be used to determine the sequences to which the antibody binds. Epitopes can be linear epitopes, i.e., epitopes contained within a sequence of amino acids, or they can be structural epitopes formed by three-dimensional interactions of amino acids that are not necessarily contained within a sequence (a linear sequence of primary structure). Peptides of various lengths (e.g., at least 4-6 amino acid lengths) can be isolated or synthesized (e.g., by recombination) and used in antibody binding assays. In another example, the epitope to which the antibody binds can be determined in systematic screening by using duplicate peptides derived from the target antigen sequence and determining antibody binding. In gene fragment expression assays, an open reading frame encoding the target antigen is fragmented either randomly or by a specific gene construct, and the reactivity of the expressed antigen fragments with the antibody being tested is determined. The gene fragments can be generated, for example, by PCR, and then transcribed in vitro in the presence of radioactive amino acids and translated into proteins. The binding of antibodies to the radioactively labeled antigen fragments is then determined by immunoprecipitation and gel electrophoresis.A particular epitope can also be identified by using a large library of random peptide sequences presented on the surface of phage particles (a phage library). Alternatively, a defined library of overlapping peptide fragments can be tested for binding to a test antibody in a simple binding assay. In further examples, antigen-binding domain mutagenesis, domain swapping experiments, and alanine scanning mutagenesis can be performed to identify the sufficient and / or required residues for epitope binding. Alternatively, a competitive assay can be performed using other antibodies known to bind to the same antigen to determine whether an antibody binds to the same epitope as other antibodies. Competitive assays are well known to those skilled in the art.

[0249] In some cases, the antibodies described herein are prepared by recombinant techniques as illustrated below. The nucleic acids encoding the heavy and light chains of the antibodies described herein can be cloned into a single expression vector, with each nucleotide sequence operably ligated to a suitable promoter. In one example, each of the nucleotide sequences encoding the heavy and light chains is operably ligated to a separate promoter. Alternatively, the nucleotide sequences encoding the heavy and light chains can be operably ligated to a single promoter so that both the heavy and light chains are expressed from the same promoter. If necessary, an intra-sequence ribosome entry site (IRES) can be inserted between the heavy chain coding sequence and the light chain coding sequence.

[0250] In some cases, the nucleotide sequences encoding the two chains of an antibody can be cloned into two vectors, and these can be introduced into the same or different cells. If these two chains are expressed in different cells, each of them can be isolated from the host cell expressing such a chain, and the isolated heavy and light chains can be mixed and incubated under suitable conditions to enable antibody formation.

[0251] Generally, nucleic acid sequences encoding one or all of an antibody chain can be cloned into a suitable expression vector in an operable linked state with a suitable promoter using methods known in the art. For example, the nucleotide sequence and vector can be contacted with restriction enzymes under suitable conditions to create complementary ends on each molecule that can pair with each other and be ligated together. Alternatively, synthetic nucleic acid linkers can be ligated to the ends of the gene. These synthetic linkers contain nucleic acid sequences corresponding to specific restriction sites in the vector. The choice of expression vector / promoter will depend on the type of host cell to be used for antibody production.

[0252] Various promoters can be used for the expression of the antibodies described herein, but are not limited to, the initial promoter of cytomegalovirus (CMV), viral LTRs such as Rous sarcoma virus LTR, HIV-LTR, HTLV-1 LTR, Simian virus 40 (SV40) initial promoter, E. coli lac UV promoter, and herpes simplex virus tk promoter.

[0253] Controllable promoters can also be used. Such controllable promoters include those that use an E. coli-derived lac repressor as a transcription modulator to control transcription from lac operator-containing mammalian cell promoters (Brown, M. et al., Cell, 49:603-612 (1987)), and those that use a tetracycline repressor (tetR) (Gossen, M., and Bujard, H., Proc. Natl. Acad. Sci. USA 89:5547-555115 (1992); Yao, F. et al., Human Gene Therapy, 9:1939-1950 (1998); Shockelt, P., et al., Proc. Natl. Acad. Sci. USA, 92:6522-6526 (1995)). Other systems include FK506 dimers, VP16 or p65 using estradiol, RU486, diphenol murislerone, or rapamycin. Among these, derivable systems are available from Invitrogen, Clontech, and Ariad.

[0254] A controllable promoter containing a repressor together with an operon can be used. In one embodiment, the lac repressor derived from E. coli can function as a transcription regulator that controls transcription from a mammalian cell promoter carrying the lac operator [[M.Brown et al.,Cell,49:603-612(1987)]]; Gossen and Bujard (1992); [[M.Gossen et al.,Natl.Acad.Sci.USA,89:5547-5551(1992)]] combined the tetracycline repressor (tetR) with a transcriptional activator (VP16) to create a tetR-mammalian cell transcriptional activator fusion protein, tTa (tetR-VP16), and together with a minimal promoter carrying tetO derived from the human cytomegalovirus (hCMV) promoter, created a tetR-tet operator system for controlling gene expression in mammalian cells. In one embodiment, a tetracycline-inducible switch is used. The tetracycline repressor (tetR) alone can function as a potent trans-regulatory factor for controlling gene expression in mammalian cells when the tetracycline operator is appropriately placed downstream of the TATA element of the CMVIE promoter (Yao et al., Human Gene Therapy). One particular advantage of this tetracycline-inducible switch is that it does not require the use of a tetracycline repressor-mammalian cell transcriptional activator or repressor fusion protein, which may in some cases be toxic to the cells, to achieve its controllable effect (Gossen 5 et al., Natl.Acad.Sci.USA,89:5547-5551(1992); Shockett et al., Proc.Natl.Acad.Sci.USA,92:6522-6526(1995)).

[0255] Furthermore, the vector may contain, for example, some or all of the following: selection marker genes, e.g., neomycin genes for selection of stable or transient transtransferants in mammalian cells; enhancer / promoter sequences from the pre-early genes of human CMV for high levels of transcription; transcription termination and RNA processing signals from SV40 for mRNA stability; SV40 polyomatous replication origin and ColE1 for proper episomal replication; intrasequence ribosome binding sites (IRESs), versatile multiplexing sites; and T7 and SP6 RNA promoters for in vitro transcription of sense and antisense RNAs. Appropriate vectors and methods for generating vectors containing transgenes are well known and available in the art. Examples of polyadenylation signals useful for carrying out the methods described herein include, but are not limited to, human collagen I polyadenylation signals, human collagen II polyadenylation signals, and SV40 polyadenylation signals.

[0256] One or more vectors (e.g., expression vectors) containing nucleic acids encoding any of the antibodies (e.g., nucleic acid coding sequences listed in Table 3) can be introduced into suitable host cells for antibody production. Non-limiting examples of host cells include Chinese hamster ovary (CHO) cells, dhfr-CHO cells, human embryonic kidney (HEK)-293 cells, verda reno (VERO) cells, non-secretory null (NS0) cells, human embryonic retina (PER.C6) cells, Sp2 / 0 cells, baby hamster kidney (BHK) cells, Madin-Darby canine kidney (MDCK) cells, Madin-Darby bovine kidney (MDBK) cells, and SV40-transformed monkey kidney CV1 (COS) cells. In some embodiments, the host cells expressing the antibodies described herein are CHO cells. The host cells can be cultured under conditions suitable for the expression of the antibody or any polypeptide chain thereof. Such antibodies or their polypeptide chains can be recovered by cultured cells (e.g., from cells or culture supernatant) via conventional methods, such as affinity purification. If necessary, the polypeptide chains of the antibodies can be incubated under suitable conditions for a suitable period of time that allows for antibody production. In some embodiments, the host cells contain nucleic acids encoding the heavy chain of the antibodies described herein. In some embodiments, the host cells contain nucleic acids encoding the light chain of the antibodies described herein. In some embodiments, the host cells contain nucleic acids encoding both the heavy chain and the light chain.

[0257] In some embodiments, the method for preparing the antibodies described herein involves a recombinant expression vector encoding both the heavy and light chains of the antibodies described herein, as also described herein. The recombinant expression vector can be introduced into suitable host cells (e.g., dhfr-CHO cells) by conventional methods, such as calcium phosphate-mediated transfection. Selected positive transformant host cells can be cultured under suitable conditions that allow expression of the two polypeptide chains that form the antibody, and these can be recovered from the cells or culture medium. If necessary, the two chains recovered from the host cells can be incubated under suitable conditions that allow antibody formation.

[0258] In one example, two recombinant expression vectors are provided, one encoding the heavy chain of an antibody and the other encoding the light chain of the antibody. Both of the two recombinant expression vectors can be introduced into a suitable host cell (e.g., dhfr-CHO cells) by a conventional method, such as calcium phosphate-mediated transfection.

[0259] Alternatively, each of the expression vectors can be introduced into a suitable host cell. Positive transformants can be selected and cultured under suitable conditions that allow expression of the polypeptide chains of the antibody. When the two expression vectors are introduced into the same host cell, the antibody produced in the cell can be recovered from the host cell or the culture medium. If necessary, the polypeptide chains can be recovered from the host cell or the culture medium and then incubated under suitable conditions that allow formation of the antibody. When the two expression vectors are introduced into different host cells, each of them can be recovered from the corresponding host cell or the corresponding culture medium. Then, the two polypeptide chains can be incubated under suitable conditions for antibody formation.

[0260] Standard molecular biology techniques are used to prepare the recombinant expression vectors, transfect the host cells, select the transformants, culture the host cells, and recover the antibody from the culture medium. For example, some antibodies can be isolated by affinity chromatography using a protein A or protein G binding matrix.

[0261] Nucleic acids encoding the heavy chain, light chain, or both of the antibodies described herein (e.g., those provided in Table 3), vectors containing the same (e.g., expression vectors); and host cells containing the vectors are all within the scope of the present disclosure.

Table 3-1

Table 3-2

[0262] In some embodiments, the Disclosure provides isolated nucleic acids comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 105 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 105. In some embodiments, the Disclosure provides an expression vector comprising an isolated nucleic acid comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 105 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 105.

[0263] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein are produced by expressing (i) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 105, and / or (ii) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 106.

[0264] In some embodiments, the Disclosure provides isolated nucleic acids comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 107 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 108. In some embodiments, the Disclosure provides an expression vector comprising an isolated nucleic acid comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 107 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 108.

[0265] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein are generated by expressing (i) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 107, and / or (ii) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 108.

[0266] In some embodiments, the Disclosure provides isolated nucleic acids comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to sequence SEQ ID NO: 109 and / or sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to sequence SEQ ID NO: 110. In some embodiments, the Disclosure provides an expression vector comprising an isolated nucleic acid comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 109 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 110.

[0267] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein are produced by expressing (i) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 110 (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 110.

[0268] In some embodiments, the Disclosure provides isolated nucleic acids comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 111 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 112. In some embodiments, the Disclosure provides an expression vector comprising an isolated nucleic acid comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 111 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 112.

[0269] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein are produced by expressing (i) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 112 (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 112.

[0270] In some embodiments, the Disclosure provides isolated nucleic acids comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 113 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 114. In some embodiments, the Disclosure provides an expression vector comprising an isolated nucleic acid comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 113 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 114.

[0271] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein are produced by expressing (i) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 113, and / or (ii) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 114.

[0272] In some embodiments, the Disclosure provides isolated nucleic acids comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 115 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 116. In some embodiments, the Disclosure provides an expression vector comprising an isolated nucleic acid comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 115 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 116.

[0273] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein are produced by expressing (i) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 115, and / or (ii) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 116.

[0274] In some embodiments, the Disclosure provides isolated nucleic acids comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 117 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 118. In some embodiments, the Disclosure provides an expression vector comprising an isolated nucleic acid comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 117 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 118.

[0275] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein are produced by expressing (i) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 118 (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 118.

[0276] In some embodiments, the Disclosure provides isolated nucleic acids comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 119 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 120. In some embodiments, the Disclosure provides an expression vector comprising an isolated nucleic acid comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 119 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 120.

[0277] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein are produced by expressing (i) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 120 (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 120.

[0278] In some embodiments, the Disclosure provides isolated nucleic acids comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 121 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 122. In some embodiments, the Disclosure provides an expression vector comprising an isolated nucleic acid comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 121 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 122.

[0279] In some embodiments, the anti-trypsin 1 / trypsin 2 antibody described herein is produced by expressing (i) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 122 (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 122.

[0280] In some embodiments, the Disclosure provides isolated nucleic acids comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 123 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 124. In some embodiments, the Disclosure provides an expression vector comprising an isolated nucleic acid comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 123 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 124.

[0281] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein are produced by expressing (i) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 123, and / or (ii) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 124.

[0282] In some embodiments, the Disclosure provides isolated nucleic acids comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 125 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 126. In some embodiments, the Disclosure provides an expression vector comprising an isolated nucleic acid comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 125 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 126.

[0283] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein are produced by expressing (i) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 125, and / or (ii) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 126.

[0284] In some embodiments, the Disclosure provides isolated nucleic acids comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 127 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 128. In some embodiments, the Disclosure provides an expression vector comprising an isolated nucleic acid comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 127 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 128.

[0285] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein are produced by expressing (i) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 128 (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 128.

[0286] In some embodiments, the Disclosure provides isolated nucleic acids comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 129 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 130. In some embodiments, the Disclosure provides an expression vector comprising an isolated nucleic acid comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 129 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 130.

[0287] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein are produced by expressing (i) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 130 (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 130.

[0288] In some embodiments, the Disclosure provides isolated nucleic acids comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 131 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 132. In some embodiments, the Disclosure provides an expression vector comprising an isolated nucleic acid comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 131 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 132.

[0289] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein are produced by expressing (i) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 132 (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 132.

[0290] In some embodiments, the Disclosure provides isolated nucleic acids comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 133 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 134. In some embodiments, the Disclosure provides an expression vector comprising an isolated nucleic acid comprising a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 133 and / or a sequence that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 134.

[0291] In some embodiments, the anti-trypsin 1 / trypsin 2 antibodies described herein are produced by expressing (i) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 133, and / or (ii) a nucleic acid that is at least 60% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to (i) SEQ ID NO: 134.

[0292] In some embodiments, the Disclosure provides isolat...

Claims

1. A dual inhibitory antibody that specifically binds to trypsin 1 and trypsin 2, (a) HC CDR1, HC CDR2, and HC CDR3 of the heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 57, and LC CDR1, LC CDR2, and LC CDR3 of the light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 58; (b) HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 59, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 60; (c) HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 61, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 62; (d) HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 63, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 64; (e) HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 65, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 66; (f) HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 67, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 68; (g) HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 69, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 70; (h) HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 71, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 70; (i) HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 72, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 73; (j) HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 74, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 73; (k) HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 75, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 73; (l) HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 76, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 73; (m) HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 77, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 78; (n) HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 79, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 80; (o) HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 81, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 82; (p) HC CDR1, HC CDR2 and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 83, and LC CDR1, LC CDR2 and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO: 70; or (q) The dual inhibitory antibody comprising HC CDR1, HC CDR2, and HC CDR3 heavy chain variable domains having the amino acid sequence of SEQ ID NO: 84, and LC CDR1, LC CDR2, and LC CDR3 light chain variable domains having the amino acid sequence of SEQ ID NO:

70.

2. The aforementioned dual inhibitory antibody (a) HC CDR1 having the amino acid sequence of SEQ ID NO: 1, HC CDR2 having the amino acid sequence of SEQ ID NO: 2, HC CDR3 having the amino acid sequence of SEQ ID NO: 3, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 6; (b) HC CDR1 having the amino acid sequence of SEQ ID NO: 7, HC CDR2 having the amino acid sequence of SEQ ID NO: 8, HC CDR3 having the amino acid sequence of SEQ ID NO: 9, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 10; (c) HC CDR1 having the amino acid sequence of SEQ ID NO: 11, HC CDR2 having the amino acid sequence of SEQ ID NO: 12, HC CDR3 having the amino acid sequence of SEQ ID NO: 13, LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 16; (d) HC CDR1 having the amino acid sequence of SEQ ID NO: 17, HC CDR2 having the amino acid sequence of SEQ ID NO: 18, HC CDR3 having the amino acid sequence of SEQ ID NO: 19, LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 20; (e) HC CDR1 having the amino acid sequence of SEQ ID NO: 21, HC CDR2 having the amino acid sequence of SEQ ID NO: 22, HC CDR3 having the amino acid sequence of SEQ ID NO: 23, LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 24; (f) HC CDR1 having the amino acid sequence of SEQ ID NO: 21, HC CDR2 having the amino acid sequence of SEQ ID NO: 18, HC CDR3 having the amino acid sequence of SEQ ID NO: 25, LC CDR1 having the amino acid sequence of SEQ ID NO: 14, LC CDR2 having the amino acid sequence of SEQ ID NO: 15, and LC CDR3 having the amino acid sequence of SEQ ID NO: 26; (g) HC CDR1 having the amino acid sequence of SEQ ID NO: 27, HC CDR2 having the amino acid sequence of SEQ ID NO: 28, HC CDR3 having the amino acid sequence of SEQ ID NO: 29, LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32; (h) HC CDR1 having the amino acid sequence of SEQ ID NO: 33, HC CDR2 having the amino acid sequence of SEQ ID NO: 34, HC CDR3 having the amino acid sequence of SEQ ID NO: 35, LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32; (i) HC CDR1 having the amino acid sequence of SEQ ID NO: 36, HC CDR2 having the amino acid sequence of SEQ ID NO: 37, HC CDR3 having the amino acid sequence of SEQ ID NO: 38, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39; (j) HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, HC CDR3 having the amino acid sequence of SEQ ID NO: 38, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39; (k) HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, HC CDR3 having the amino acid sequence of SEQ ID NO: 42, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39; (l) HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, HC CDR3 having the amino acid sequence of SEQ ID NO: 43, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 39; (m) HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 41, HC CDR3 having the amino acid sequence of SEQ ID NO: 44, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 45; (n) HC CDR1 having the amino acid sequence of SEQ ID NO: 40, HC CDR2 having the amino acid sequence of SEQ ID NO: 46, HC CDR3 having the amino acid sequence of SEQ ID NO: 47, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 48; (o) HC CDR1 having the amino acid sequence of SEQ ID NO: 49, HC CDR2 having the amino acid sequence of SEQ ID NO: 50, HC CDR3 having the amino acid sequence of SEQ ID NO: 51, LC CDR1 having the amino acid sequence of SEQ ID NO: 4, LC CDR2 having the amino acid sequence of SEQ ID NO: 5, and LC CDR3 having the amino acid sequence of SEQ ID NO: 52; (p) HC CDR1 having the amino acid sequence of SEQ ID NO: 27, HC CDR2 having the amino acid sequence of SEQ ID NO: 28, HC CDR3 having the amino acid sequence of SEQ ID NO: 53, LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO: 32; or (q) A dual inhibitory antibody according to claim 1, comprising HC CDR1 having the amino acid sequence of SEQ ID NO: 54, HC CDR2 having the amino acid sequence of SEQ ID NO: 55, HC CDR3 having the amino acid sequence of SEQ ID NO: 56, LC CDR1 having the amino acid sequence of SEQ ID NO: 30, LC CDR2 having the amino acid sequence of SEQ ID NO: 31, and LC CDR3 having the amino acid sequence of SEQ ID NO:

32.

3. The aforementioned dual inhibitory antibody (a) VH containing the amino acid sequence of SEQ ID NO: 57, and VL containing the amino acid sequence of SEQ ID NO: 58; (b) VH containing the amino acid sequence of SEQ ID NO: 59, and VL containing the amino acid sequence of SEQ ID NO: 60; (c) VH containing the amino acid sequence of SEQ ID NO: 61, and VL containing the amino acid sequence of SEQ ID NO: 62; (d) VH containing the amino acid sequence of SEQ ID NO: 63, and VL containing the amino acid sequence of SEQ ID NO: 64; (e) VH containing the amino acid sequence of SEQ ID NO: 65, and VL containing the amino acid sequence of SEQ ID NO: 66; (f) VH containing the amino acid sequence of SEQ ID NO: 67, and VL containing the amino acid sequence of SEQ ID NO: 68; (g) VH containing the amino acid sequence of SEQ ID NO: 69, and VL containing the amino acid sequence of SEQ ID NO: 70; (h) VH containing the amino acid sequence of SEQ ID NO: 71, and VL containing the amino acid sequence of SEQ ID NO: 70; (i) VH containing the amino acid sequence of SEQ ID NO: 72, and VL containing the amino acid sequence of SEQ ID NO: 73; (j) VH containing the amino acid sequence of SEQ ID NO: 74, and VL containing the amino acid sequence of SEQ ID NO: 73; (k) VH containing the amino acid sequence of SEQ ID NO: 75, and VL containing the amino acid sequence of SEQ ID NO: 73; (l) VH containing the amino acid sequence of SEQ ID NO: 76, and VL containing the amino acid sequence of SEQ ID NO: 73; (m) VH containing the amino acid sequence of SEQ ID NO: 77, and VL containing the amino acid sequence of SEQ ID NO: 78; (n) VH containing the amino acid sequence of SEQ ID NO: 79, and VL containing the amino acid sequence of SEQ ID NO: 80; (o) VH containing the amino acid sequence of SEQ ID NO: 81, and VL containing the amino acid sequence of SEQ ID NO: 82; (p) VH containing the amino acid sequence of SEQ ID NO: 83, and VL containing the amino acid sequence of SEQ ID NO: 70; or (q) A dual inhibitory antibody according to claim 1 or 2, comprising VH containing the amino acid sequence of SEQ ID NO: 84 and VL containing the amino acid sequence of SEQ ID NO:

70.

4. It is a dual inhibitory antibody, (i) any one of the antibodies listed in Tables 1a and 1b: HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3; or (ii) The dual inhibitory antibody comprising one of the VH and / or VL of any of the antibodies listed in Table 1a.

5. A composition comprising a dual inhibitory antibody according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

6. A nucleic acid encoding a dual inhibitory antibody according to any one of claims 1 to 4.

7. A method for treating pancreatitis, comprising administering an effective amount of a dual inhibitory antibody according to any one of claims 1 to 4 to a subject requiring treatment for pancreatitis.

8. The method according to claim 7, wherein the subject has hereditary pancreatitis, acute pancreatitis, recurrent acute pancreatitis, or chronic pancreatitis.

9. A method for treating pancreatitis, comprising administering an effective amount of at least one antibody that specifically binds to trypsin 1 and / or trypsin 2 to a subject in need of treatment for pancreatitis.

10. The method according to claim 9, wherein the at least one antibody specifically binds to trypsin 1.

11. The method according to claim 9 or 10, wherein the at least one antibody specifically binds to the active site of trypsin 1.

12. The method according to any one of claims 9 to 11, wherein the at least one antibody inhibits the protease activity of trypsin 1.

13. The method according to claim 9, wherein the at least one antibody specifically binds to trypsin 2.

14. The method according to claim 9 or 13, wherein the at least one antibody specifically binds to the active site of trypsin 2.

15. The method according to any one of claims 9 or 13 to 14, wherein the at least one antibody inhibits the protease activity of trypsin-2.

16. The method according to claim 9, further comprising administering to the subject at least one antibody that specifically binds to trypsin 1 and trypsin 2 and inhibits the respective protease activity thereof.

17. The method according to claim 16, wherein the at least one antibody is a dual inhibitory antibody that specifically binds to trypsin 1 and trypsin 2.

18. The method according to any one of claims 9 to 17, wherein the subject has hereditary pancreatitis, acute pancreatitis, recurrent acute pancreatitis, or chronic pancreatitis.

19. A polypeptide comprising the sequence or fragment thereof described in SEQ ID NO: 103, which is suitable for generating an antibody that specifically binds to trypsin 1 and inhibits its protease activity, wherein the polypeptide optionally comprises a detectable tag such as a His tag.

20. A polypeptide comprising the sequence or fragment thereof described in SEQ ID NO: 104, which is suitable for generating an antibody that specifically binds to trypsin-2 and inhibits its protease activity, wherein the polypeptide optionally comprises a detectable tag such as a His tag.

21. A method for producing a dual inhibitory anti-trypsin 1 / trypsin 2 antibody, comprising: i) producing an antibody that specifically binds to the polypeptide described in claim 19 and inhibits the protease activity of trypsin 1; and ii) producing an antibody that specifically binds to the polypeptide described in claim 20 and inhibits the protease activity of trypsin 2.

Images