Molecules that bind to a PLA2g7 polypeptide

Abstract

This document relates to methods and materials involved in binding a molecule (e.g., an antibody domain, an antigen binding fragment, or an antibody) to a PLA2G7 polypeptide. For example, this document provides binders (e.g.. antibody domains, antigen binding fragments, and antibodies) that bind to a PLA2G7 polypeptide. This document also provides methods and materials for using such binders to treat a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity).

Description

[0001] Atorney Docket No. 45049-0092W01 / 06870

[0002] MOLECULES THAT BIND TO A PLA2G7 POLYPEPTIDE

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 735.109, filed December 17, 2024. The disclosure of the prior application is considered part of (and is incorporated by reference in) the disclosure of this application.

[0005] TECHNICAL FIELD

[0006] This document relates to methods and materials involved in binding a molecule (e.g., an antibody domain, an antigen binding fragment, or an antibody) to a phospholipase A2 Group 7 (PLA2G7) polypeptide. For example, this document provides binders (e.g., ant body domains, antigen binding fragments, and antibodies) that bind to a PLA2G7 polypeptide. This document also provides methods and materials for using such binders to treat a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity).

[0007] BACKGROUND

[0008] Macrophages play an important role in eliminating diseased and damaged cells through their programmed cell death. PLA2G7, which is mainly secreted by macrophages, interacts with oxidized low-density lipoprotein (oxLDL) and associates with several vascular diseases and cancers. Recent studies have also demonstrated PLA2G7 as a pan-cancer diagnostic and prognostic marker (Xie et al., Heliyon, 10: e2790610 (2024)). PLA2G7 not only directly promotes tumor growth and migration (Low et al.. Oncotarget, 77:55473-90 (2016)). but also contributes to the immunosuppressive nature of the tumor microenvironment. Notably, immunosuppressive, high PLA2G7 expressing macrophages impede CD8 T-cell function, and inhibition of PLA2G7 by darapladib has been shown to enhance the efficacy of anti-PD-1 antibody immunotherapy in hepatocellular carcinoma (HCC) mouse models (Zhang et al., J. Immunother. Cancer, 12: e00809410 (2024)). Atorney Docket No. 45049-0092W01 / 06870

[0009] SUMMARY

[0010] This document provides methods and materials involved in binding a molecule (e.g., an antibody domain, an antigen binding fragment, or an antibody) to a PLA2G7 polypeptide. For example, this document provides binders (e.g.. antibody domains, antigen binding fragments, and antibodies) that bind to a PLA2G7 polypeptide and methods and materials for using one or more such binders to treat a mammal (e.g., a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity' (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity).

[0011] As described herein, binders (e.g., antibody domains, antigen binding fragments, and / or antibodies) can be designed to have the ability to bind to a PLA2G7 polypeptide. For example, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein can include an antigen binding domain having the ability' to bind to a polypeptide comprising, consisting essentially of, or consisting of the amino acid sequence of a human PLA2G7 polypeptide as set forth in SEQ ID NO 33 (see, e.g., Example 2).

[0012] This document also provides methods and materials for inhibiting PLA2G7 polypeptide activity. For example, this document provides binders (e.g., antibody domains, antigen binding fragments, and antibodies) that can target (e.g., target and bind) a PLA2G7 polypeptide and inhibit the activity7of the PLA2G7 polypeptide.

[0013] This document also provides methods for using binders (e.g., antibody domains, antigen binding fragments, and / or antibodies) having the ability to bind to a PLA2G7 polypeptide or cells expressing one or more binders (e.g., antibody domains, antigen binding fragments, and / or antibodies) having the ability to bind to a PLA2G7 polypeptide to treat a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity).

[0014] As described herein, binders provided herein can be used to treat a mammal (e.g., a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity7(e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity). For example, a mammal (e.g., a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide Atorney Docket No. 45049-0092W01 / 06870 activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) can be administered a composition comprising one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, a vector, or a host cell provided herein) to reduce the level of PLA2G7 polypeptide activity within the mammal and / or to increase the survival duration of the mammal from the condition or disease. Having the ability to reduce the level of PLA2G7 polypeptide activity in a mammal using one or more of the binders provided herein provides a unique and unrealized opportunity to treat conditions or diseases associated with an increased level of PLA2G7 polypeptide activity.

[0015] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein can be used to detect the presence or absence of a PLA2G7 polypeptide. For example, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein can be used to determine whether or not a sample (e.g., a biological sample such as a tissue sample) obtained from a mammal (e g., a human) contains a PLA2G7 polypeptide. Having the ability7to detect the presence or absence of a PLA2G7 polypeptide using one or more of the binders provided herein can allow clinicians, health professionals, and patients to make better decisions about possible treatment options. For example, detection of a PLA2G7 polypeptide within a mammal can allow clinicians, health professionals, and patients to select an appropriate treatment that targets PLA2G7 polypeptide activity7. Such treatments that target PLA2G7 polypeptide activity can include a step of administering of an anti-PLA2G7 antibody such as one or more of the binders described herein having the ability to bind to a PLA2G7 polypeptide and / or a step of administering of one or more cells designed to express a binder described herein.

[0016] In general, one aspect of this document features single-domain antibodies each comprising: (i) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:3 (or SEQ ID NO:3 with one, two, or three amino acid additions, deletions, or substitutions); or (ii) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:9 (or Attorney Docket No. 45049-0092W01 / 06870

[0017] SEQ ID N0:9 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 10 (or SEQ ID NO: 10 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one, two, or three amino acid additions, deletions, or substitutions). The single-domain antibody can have the ability to bind to a polypeptide sequence set forth in SEQ ID NO:33. The singledomain antibody can include the heavy chain variable domain of (i). The heavy chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 8. The single-domain antibody can include the heavy chain variable domain of (ii). The heavy chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 16.

[0018] In another aspect, this document features nucleic acids including a nucleic acid sequence encoding a single-domain antibody including (i) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two. or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:3 (or SEQ ID NO:3 with one, two, or three amino acid additions, deletions, or substitutions); or (ii) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:9 (or SEQ ID NO:9 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NOTO (or SEQ ID NOTO with one, tw o, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one, two, or three amino acid additions, deletions, or substitutions). The single-domain antibody can have the ability to bind to a polypeptide sequence set forth in SEQ ID NO:33. The single-domain antibody can include the heavy chain variable domain of (i). The heavy' chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 8. The single-domain antibody can include the heavy chain variable domain of (ii). The heavy chain variable domain can include an amino acid sequence having at least 90 percent identity’ to the amino acid sequence set forth in SEQ ID NO: 16. The nucleic acid can encode the heavy chain variable domain of (i). The nucleic acid can encode the heavy chain variable domain of (ii). The nucleic acid can be a viral vector. Atorney Docket No. 45049-0092W01 / 06870

[0019] In another aspect, this document features host cells including a nucleic acid sequence encoding a single-domain antibody including (i) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO: 2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:3 (or SEQ ID NO:3 with one, two, or three amino acid additions, deletions, or substitutions); or (ii) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 9 (or SEQ ID NO: 9 with one, two, or three amino acid additions, deletions, or substitutions). SEQ ID NO: 10 (or SEQ ID NO: 10 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one, two, or three amino acid additions, deletions, or substitutions). The single-domain antibody can have the ability to bind to a polypeptide sequence set forth in SEQ ID NO:33. The single-domain antibody can include the heavy chain variable domain of (i). The heavy chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 8. The single-domain antibody can include the heavy chain variable domain of (ii). The heavy chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 16.

[0020] In another aspect, this document features antigen binding fragments each comprising: (i) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 w ith one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, two, or three amino acid additions, deletions, or substitutions); and (ii) a light chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:25 (or SEQ ID NO:25 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:26 (or SEQ ID NO:26 with one. two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:27 (or SEQ ID NO:27 with one, two, or three amino acid additions, deletions, or substitutions). The antigen binding fragment can have the ability to bind to a polypeptide sequence set forth in SEQ ID NO:33. The heavy chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:24. The light Atorney Docket No. 45049-0092W01 / 06870 chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:32.

[0021] In another aspect, this document features nucleic acids including a nucleic acid sequence encoding an antigen binding fragment including (i) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, two, or three amino acid additions, deletions, or substitutions); and (ii) a light chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:25 (or SEQ ID NO:25 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:26 (or SEQ ID NO:26 with one, tw o. or three amino acid additions, deletions, or substitutions), and SEQ ID NO:27 (or SEQ ID NO:27 with one, two, or three amino acid additions, deletions, or substitutions). The antigen binding fragment can have the ability to bind to a polypeptide sequence set forth in SEQ ID NO:33. The heavy chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:24. The light chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:32. The nucleic acid can be in the form of a viral vector.

[0022] In another aspect, this document features host cells including a nucleic acid sequence encoding an antigen binding fragments including (i) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, two, or three amino acid additions, deletions, or substitutions); and (ii) a light chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:25 (or SEQ ID NO:25 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:26 (or SEQ ID NO:26 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:27 (or SEQ ID NO:27 with one, two, or three amino acid additions, deletions, or substitutions). The antigen binding fragment can have the ability to bind to a polypeptide sequence set forth in SEQ ID NO:33. The heavy chain variable domain can include an Atorney Docket No. 45049-0092W01 / 06870 amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:24. The light chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:32.

[0023] In another aspect, this document features bispecific antibodies each comprising: (i) an antigen binding fragment including a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, two, or three ammo acid additions, deletions, or substitutions) and a light chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:25 (or SEQ ID NO:25 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:26 (or SEQ ID NO:26 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:27 (or SEQ ID NO:27 wi th one, two, or three amino acid additions, deletions, or substitutions); and (ii) a heavy chain variable domain comprising: (a) the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:3 (or SEQ ID NO:3 with one, two, or three amino acid additions, deletions, or substitutions); or (b) the amino acid sequences set forth in SEQ ID NO: 9 (or SEQ ID NO: 9 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 10 (or SEQ ID NOTO with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NOT 1 (or SEQ ID NO: 11 with one, two, or three amino acid additions, deletions, or substitutions). The bispecific antibody can have the ability to bind to a polypeptide sequence set forth in SEQ ID NO:33. The heavy chain variable domain of (i) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:24. The light chain variable domain of (i) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:32. The heavy chain variable domain of (ii)(a) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 8. The heavy chain variable domain of (ii)(b) can include an amino acid sequence having at least 90 percent Atorney Docket No. 45049-0092W01 / 06870 identity to the amino acid sequence set forth in SEQ ID NO: 16. The heavy chain variable domains of (i) and (ii) can be attached by a polypeptide linker. The polypeptide linker can be a (648)2 polypeptide linker. The polypeptide linker can be a (648)3 polypeptide linker. The heavy chain variable domain of (i) can be attached to the C-terminus of the heavy chain variable domain of (ii).

[0024] In another aspect, this document features bispecific antibodies each comprising: (i) an antigen binding fragment comprising a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:19 (or SEQ ID NO: 19 with one, two, or three amino acid additions, deletions, or substitutions); and (ii) a heavy chain variable domain comprising: (a) the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two. or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:3 (or SEQ ID NO: 3 with one, two, or three amino acid additions, deletions, or substitutions); or (b) the amino acid sequences set forth in SEQ ID NO:9 (or SEQ ID NO:9 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 10 (or SEQ ID NO: 10 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one, two, or three amino acid additions, deletions, or substitutions). The bispecific antibody can have the ability to bind to a polypeptide sequence set forth in SEQ ID NO: 33. The heavy chain variable domain of (i) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:24. The heavy chain variable domain of said (ii)(a) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 8. The heavy chain variable domain of (ii)(b) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 16. (i) and (ii) can be attached by a polypeptide linker. The polypeptide linker can be a (648)2 polypeptide linker. The polypeptide linker can be a (648)3 polypeptide linker. Atorney Docket No. 45049-0092W01 / 06870

[0025] In another aspect, this document features nucleic acids including a nucleic acid sequence encoding a bi specific antibody including (i) an antigen binding fragment including a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, two, or three amino acid additions, deletions, or substitutions) and a light chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 25 (or SEQ ID NO:25 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:26 (or SEQ ID NO:26 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:27 (or SEQ ID NO:27 with one, two, or three amino acid additions, deletions, or substitutions); and (ii) a heavy chain variable domain comprising: (a) the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one. two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, tw o. or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 3 (or SEQ ID NO:3 with one, two, or three amino acid additions, deletions, or substitutions); or (b) the amino acid sequences set forth in SEQ ID NO:9 (or SEQ ID NO:9 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 10 (or SEQ ID NO: 10 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one, tw o, or three amino acid additions, deletions, or substitutions) or a bispecific antibody including (i) an antigen binding fragment comprising a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, two, or three amino acid additions, deletions, or substitutions); and (ii) a heavy chain variable domain comprising: (a) the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:3 (or SEQ ID NO:3 with one, two, or three amino acid additions, deletions, or substitutions); or (b) the amino acid sequences set forth in SEQ ID NO:9 (or SEQ ID NON with one, two. Atorney Docket No. 45049-0092W01 / 06870 or three amino acid additions, deletions, or substitutions), SEQ ID NO: 10 (or SEQ ID NO: 10 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 wi th one, two, or three amino acid additions, deletions, or substitutions). The bispecific antibody can have the ability to bind to a polypeptide sequence set forth in SEQ ID NO: 33. The heavy chain variable domain of (i) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:24. The light chain variable domain of (i) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:32. The heavy chain variable domain of (ii)(a) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 8. The heavy chain variable domain of (ii)(b) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 16. The heavy chain variable domains of (i) and (ii) can be attached by a polypeptide linker. The polypeptide linker can be a (648)2 polypeptide linker. The polypeptide linker can be a (648)3 polypeptide linker. The heavy chain variable domain of (i) can be attached to the C-terminus of the heavy chain variable domain of (ii). The nucleic acid can be in the form of a viral vector.

[0026] In another aspect, this document features host cells including a nucleic acid encoding a bispecific antibody including (i) an antigen binding fragment including a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, two, or three amino acid additions, deletions, or substitutions) and a light chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:25 (or SEQ ID NO:25 with one, tw o, or three amino acid additions, deletions, or substitutions), SEQ ID NO:26 (or SEQ ID NO:26 with one. two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:27 (or SEQ ID NO:27 with one, two, or three amino acid additions, deletions, or substitutions); and (ii) a heavy chain variable domain comprising: (a) the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ Atorney Docket No. 45049-0092W01 / 06870

[0027] ID NO:3 (or SEQ ID NO:3 with one, two, or three amino acid additions, deletions, or substitutions); or (b) the amino acid sequences set forth in SEQ ID NO:9 (or SEQ ID NO: 9 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 10 (or SEQ ID NO: 10 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one. two, or three amino acid additions, deletions, or substitutions) or a bispecific antibody including (i) an antigen binding fragment comprising a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one, tw o, or three amino acid additions, deletions, or substitutions). SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, tw o. or three amino acid additions, deletions, or substitutions); and (ii) a heavy chain variable domain comprising: (a) the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, two. or three amino acid additions, deletions, or substitutions), and SEQ ID NO:3 (or SEQ ID NO:3 with one, tw o. or three amino acid additions, deletions, or substitutions); or (b) the amino acid sequences set forth in SEQ ID NO: 9 (or SEQ ID NO: 9 with one, two, or three amino acid additions, deletions, or substitutions). SEQ ID NO: 10 (or SEQ ID NO: 10 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one, tw o. or three amino acid additions, deletions, or substitutions). The bispecific antibody can have the ability7to bind to a polypeptide sequence set forth in SEQ ID NO: 33. The heavy chain variable domain of (i) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:24. The light chain variable domain of (i) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:32. The heavy chain variable domain of (ii)(a) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 8. The heavy chain variable domain of (ii)(b) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 16. The heavy chain variable domains of (i) and (ii) can be attached by a polypeptide linker. The polypeptide linker can be a (648)2 polypeptide linker. The polypeptide linker can be a (648)3 Atorney Docket No. 45049-0092W01 / 06870 polypeptide linker. The heavy chain variable domain of (i) can be atached to the C- terminus of the heavy chain variable domain of (ii).

[0028] In another aspect, this document features compositions including a single-domain antibody including (i) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two. or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:3 (or SEQ ID NO: 3 with one, two, or three amino acid additions, deletions, or substitutions); or (ii) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:9 (or SEQ ID NO:9 with one, two, or three ammo acid additions, deletions, or substitutions), SEQ ID NO: 10 (or SEQ ID NO: 10 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one, two, or three amino acid additions, deletions, or substitutions). The single-domain antibody can have the ability to bind to a polypeptide sequence set forth in SEQ ID NO:33. The single-domain antibody can include the heavy chain variable domain of (i). The heavy chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 8. The single-domain antibody can include the heavy chain variable domain of (ii). The heavy chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 16.

[0029] In another aspect, this document features compositions including an antigen binding fragment including (i) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one. two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, two, or three amino acid additions, deletions, or substitutions); and (ii) a light chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:25 (or SEQ ID NO:25 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:26 (or SEQ ID NO:26 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:27 (or SEQ ID NO:27 with one, two, or three amino acid additions, deletions, or substitutions). The antigen binding fragment can have the ability to bind to a polypeptide sequence set forth in SEQ Atorney Docket No. 45049-0092W01 / 06870

[0030] ID NO:33. The heavy chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 24. The light chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:32.

[0031] In another aspect, this document includes a composition including a bispecific antibody including (i) an antigen binding fragment including a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one, tw o, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, two, or three amino acid additions, deletions, or substitutions) and a light chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:25 (or SEQ ID NO:25 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:26 (or SEQ ID NO:26 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:27 (or SEQ ID NO:27 with one, two, or three amino acid additions, deletions, or substitutions); and (ii) a heavy chain variable domain comprising: (a) the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:3 (or SEQ ID NO: 3 with one, two, or three amino acid additions, deletions, or substitutions); or (b) the amino acid sequences set forth in SEQ ID NO:9 (or SEQ ID NO:9 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NOTO (or SEQ ID NO: 10 with one, two. or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one, two, or three amino acid additions, deletions, or substitutions) or a bispecific antibody including (i) an antigen binding fragment comprising a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, two, or three amino acid additions, deletions, or substitutions); and (ii) a heavy chain variable domain comprising: (a) the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two, or three ammo acid additions, deletions, or Atorney Docket No. 45049-0092W01 / 06870 substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:3 (or SEQ ID NO:3 with one, two, or three amino acid additions, deletions, or substitutions); or (b) the amino acid sequences set forth in SEQ ID NO: 9 (or SEQ ID NO: 9 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 10 (or SEQ ID NO: 10 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one, two, or three amino acid additions, deletions, or substitutions). The bispecific antibody can have the ability to bind to a poly peptide sequence set forth in SEQ ID NO:33. The heavy chain variable domain of (i) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:24. The light chain variable domain of (i) can include an amino acid sequence having at least 90 percent identity7to the amino acid sequence set forth in SEQ ID NO:32. The heavy7chain variable domain of (ii)(a) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 8. The heavy chain variable domain of (ii)(b) can include an amino acid sequence having at least 90 percent identity7to the amino acid sequence set forth in SEQ ID NO: 16. The heavy chain variable domains of (i) and (ii) can be attached by a polypeptide linker. The polypeptide linker can be a (648)2 polypeptide linker. The polypeptide linker can be a (648)3 polypeptide linker. The heavy chain variable domain of (i) can be attached to the C-terminus of the heavy chain variable domain of (ii).

[0032] In another aspect, this document features methods for treating a mammal having a condition or disease associated with an increased level of PLA267 polypeptide activity7. The methods can include, or consist essentially administering, to the mammal, a composition including a single-domain antibody, and antigen binding fragment, or a bispecific antibody. The single-domain antibody can include (i) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one. two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 3 (or SEQ ID NO:3 w ith one, two, or three amino acid additions, deletions, or substitutions); or (ii) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:9 (or SEQ ID NON with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 10 (or SEQ ID Atorney Docket No. 45049-0092W01 / 06870

[0033] NO: 10 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one, two, or three amino acid additions, deletions, or substitutions). The single-domain antibody can have the ability to bind to a polypeptide sequence set forth in SEQ ID NO:33. The single-domain antibody can include the heavy chain variable domain of (i). The heavy chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 8. The single-domain antibody can include the heavy chain variable domain of (ii). The heavy chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 16. The antigen binding fragment antigen binding fragments can include (i) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one, tw o, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one. two, or three amino acid additions, deletions, or substitutions); and (ii) a light chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:25 (or SEQ ID NO:25 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:26 (or SEQ ID NO:26 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:27 (or SEQ ID NO:27 with one, two, or three amino acid additions, deletions, or substitutions). The antigen binding fragment can have the ability to bind to a polypeptide sequence set forth in SEQ ID NO:33. The heavy chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:24. The light chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:32. The bispecific antibody can include (i) an antigen binding fragment including a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one. two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, two, or three amino acid additions, deletions, or substitutions) and a light chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:25 (or SEQ ID NO:25 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID Atorney Docket No. 45049-0092W01 / 06870

[0034] NO:26 (or SEQ ID NO:26 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:27 (or SEQ ID NO:27 with one, two, or three amino acid additions, deletions, or substitutions); and (ii) a heavy chain variable domain comprising: (a) the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO: 2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:3 (or SEQ ID NO:3 with one, two, or three amino acid additions, deletions, or substitutions); or (b) the amino acid sequences set forth in SEQ ID NO:9 (or SEQ ID NO: 9 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 10 (or SEQ ID NO: 10 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one, two, or three amino acid additions, deletions, or substitutions) or (i) an antigen binding fragment comprising a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one. two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, two, or three amino acid additions, deletions, or substitutions); and (ii) a heavy chain variable domain comprising: (a) the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:3 (or SEQ ID NO:3 with one, two, or three amino acid additions, deletions, or substitutions); or (b) the amino acid sequences set forth in SEQ ID NO:9 (or SEQ ID NO:9 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 10 (or SEQ ID NO: 10 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one, two, or three amino acid additions, deletions, or substitutions). The bispecific antibody can have the ability to bind to a polypeptide sequence set forth in SEQ ID NO: 33. The heavy chain variable domain of (i) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:24. The light chain variable domain of (i) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 32. The heavy chain variable domain of (ii)(a) can include an amino acid sequence having at least 90 percent identity to Atorney Docket No. 45049-0092W01 / 06870 the amino acid sequence set forth in SEQ ID NO:8. The heavy chain variable domain of (ii)(b) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 16. The heavy chain variable domains of (i) and (ii) can be attached by a polypeptide linker. The polypeptide linker can be a (648)2 polypeptide linker. The polypeptide linker can be a (648)3 polypeptide linker. The heavy chain variable domain of (i) can be attached to the C-terminus of the heavy chain variable domain of (ii). The mammal can be a human. The condition or disease associated with an increased level of PLA267 polypeptide activity can be a cancer. The cancer can be colorectal cancer, colon cancer, gastric cancer, gastrointestinal cancer, or pancreatic cancer. The condition or disease associated with an increased level of PLA267 polypeptide activity can be a cardiovascular disease. The cardiovascular disease can be atherosclerosis, coronary' artery' disease, or ischemic stroke. The increased level of PLA267 polypeptide activity' can reduced following the administration.

[0035] In another aspect, this document features methods for binding a binding molecule to a PLA267 polypeptide. The methods can include, or consist essential of, contacting the PLA267 polypeptide with a single-domain antibody, an antigen binding fragment, or a bispecific antibody. The single-domain antibody can include (i) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, tw o, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 3 (or SEQ ID NO:3 with one, tw o, or three amino acid additions, deletions, or substitutions); or (ii) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:9 (or SEQ ID NO: 9 with one, two. or three amino acid additions, deletions, or substitutions), SEQ ID NOTO (or SEQ ID NOTO with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NOT 1 (or SEQ ID NO: 11 with one, two, or three amino acid additions, deletions, or substitutions). The single-domain antibody can have the ability to bind to a polypeptide sequence set forth in SEQ ID NO:33. The single-domain antibody can include the heavy chain variable domain of (i). The heavy chain variable domain can include an amino acid sequence having at least 90 percent identity' to the amino acid sequence set forth in SEQ ID NO: 8. The single-domain antibody can include the heavy’ chain variable domain of (ii). The heavy chain variable domain can include an amino acid sequence having at least Atorney Docket No. 45049-0092W01 / 06870

[0036] 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 16. The antigen binding fragment antigen binding fragments can include (i) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one, tw o, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one. two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, two, or three amino acid additions, deletions, or substitutions); and (ii) a light chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:25 (or SEQ ID NO:25 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:26 (or SEQ ID NO:26 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:27 (or SEQ ID NO:27 with one, two, or three amino acid additions, deletions, or substitutions). The antigen binding fragment can have the ability7to bind to a polypeptide sequence set forth in SEQ ID NO:33. The heavy chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:24. The light chain variable domain can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:32. The bispecific antibody can include (i) an antigen binding fragment including a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, two, or three amino acid additions, deletions, or substitutions) and a light chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:25 (or SEQ ID NO:25 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:26 (or SEQ ID NO:26 with one, tw o. or three amino acid additions, deletions, or substitutions), and SEQ ID NO:27 (or SEQ ID NO:27 with one, two, or three amino acid additions, deletions, or substitutions); and (ii) a heavy chain variable domain comprising: (a) the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:3 (or SEQ ID NO:3 with one, two, or three amino acid additions, deletions, or substitutions); or (b) the amino acid sequences set forth in SEQ ID NO:9 (or SEQ ID Atorney Docket No. 45049-0092W01 / 06870

[0037] NO: 9 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 10 (or SEQ ID NO: 10 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one, two, or three amino acid additions, deletions, or substitutions) or (i) an antigen binding fragment comprising a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, two, or three amino acid additions, deletions, or substitutions); and (ii) a heavy chain variable domain comprising: (a) the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:3 (or SEQ ID NO:3 with one, two, or three amino acid additions, deletions, or substitutions); or (b) the amino acid sequences set forth in SEQ ID NO:9 (or SEQ ID NO:9 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 10 (or SEQ ID NO: 10 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one, two, or three amino acid additions, deletions, or substitutions). The bispecific antibody can have the ability to bind to a polypeptide sequence set forth in SEQ ID NO: 33. The heavy chain variable domain of (i) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:24. The light chain variable domain of (i) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 32. The heavy chain variable domain of (ii)(a) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 8. The heavy chain variable domain of (ii)(b) can include an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 16. The heavy chain variable domains of (i) and (ii) can be attached by a polypeptide linker. The polypeptide linker can be a (G S polypeptide linker. The polypeptide linker can be a (648)3 polypeptide linker. The heavy chain variable domain of (i) can be attached to the C-terminus of the heavy chain variable domain of (ii). The contacting can be performed in vitro. The contacting can be performed in vivo. The contacting can be performed within a mammal by administering Atorney Docket No. 45049-0092W01 / 06870 the single-domain antibody, the antigen binding fragment, or the bispecific antibody to said mammal. The mammal can be a human.

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0039] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0040] BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figures 1A-1E. Generation and specificity of anti-PLA2G7 monoclonal antibodies (mAbs). Figure 1A) Binding of mouse anti-PLA2G7 mAb against recombinant human PLA2G7. Figure IB) Binding of anti-PLA2G7 mAbs (1H8 Fab, 1A9 VH, 1H8 IgG, and 1H8 IgG-lA9) to a human PLA2G7 polypeptide. Figure 1C) Competitive binding of 1H8 IgG with 1A9 VH (0, 1, 10, or 100 nM) to a human PLA2G7 polypeptide. Figure ID) Competitive binding of 1H8 IgG (lOOnM) or 1A9 VH (lOOnM) with a PLA2G7 small molecule inhibitor, darapladib, against a human PLA2G7 polypeptide. The binding of 1H8 IgG or 1A9 VH antibodies was detected. Figure IE) Kinetics of anti-PLA2G7 mAbs (1H8 Fab, 1A9 VH, 1H8 IgG, and 1H8 IgG-1 A9) binding to human PLA2G7-Fc, as measured by Bio-Layer Interferometry (BLItz).

[0042] Figures 2A-2D. Anti-PLA2G7 mAbs blocked PLA2G7 enz matic activity and cancer cell migration. Figure 2A) Blocking of PLA2G7 enzymatic activity by anti- PLA2G7 mAbs. Figures 2B-2D) Blocking of cell migration by anti-PLA2G7 mAbs on colorectal cancer cell lines. The relative cell migration (%) was normalized based on the baseline (0%, blank plate control) and PLA2G7 activation with PBS control (100%) Atorney Docket No. 45049-0092W01 / 06870

[0043] (Figures 2C-2D). Significance was determined by unpaired two-tailed student's t-test. *p < 0.05, **p < 0.01, ***p < 0.001, ns means not significant.

[0044] DETAILED DESCRIPTION

[0045] This document provides binders (e g., antibody domains, antigen binding fragments, and antibodies) that bind (e.g., specifically bind) to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide). A binder provided herein can be any appropriate binder including an antigen binding domain having the abi 1 i ty to bind to a PLA2G7 polypeptide. For example, this document provides antibody domains, antigen binding fragments, and antibodies that bind (e.g., specifically bind) to a polypeptide comprising, consisting essentially of. or consisting of the amino acid set forth in SEQ ID NO: 33 (see, e.g.. Example 2). In some cases, a binder provided herein can have the ability' to target (e.g., target and bind) a PLA2G7 polypeptide and can lack the ability to target to other members of the phospholipase A2 (PLA2) family (e.g., a PLA2Gl polypeptide, a PLA2G2 polypeptide, a PLA2G3 polypeptide, a PLA2G4 polypeptide, a PLA2G5 polypeptide, a PLA2G6 polypeptide, a PLA2G8 polypeptide, a PLA2G9 polypeptide, a PLA2G10 polypeptide, a PLA2Gll polypeptide, a PLA2G12 polypeptide, a PLA2G13 polypeptide, a PLA2G14 polypeptide, a PLA2G15 polypeptide, and a PLA2G16 polypeptide). For example, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein can have the ab i 1 i ty to bind to a human PLA2G7 polypeptide and can lack the ability to bind to one or more other human PLA2 polypeptides (e.g., a human PLA2G1 polypeptide, a human PLA2G2 polypeptide, a human PLA2G3 polypeptide, a human PLA2G4 polypeptide, a human PLA2G5 polypeptide, a human PLA2G6 polypeptide, a human PLA2G8 polypeptide, a human PLA2G9 polypeptide, a human PLA2G10 polypeptide, a human PLA2G11 polypeptide, a human PLA2G12 polypeptide, a human PLA2G13 polypeptide, a human PLA2G14 polypeptide, a human PLA2G15 polypeptide, and a human PLA2G16 polypeptide).

[0046] In some cases, a binder provided herein can have the ability to target (e.g., target and bind) a PLA2G7 polypeptide and can inhibit the activity of the PLA2G7 polypeptide. For example, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein can have the ability to bind to a PLA2G7 polypeptide and can inhibit the activity of the PLA2G7 polypeptide by, for example, 10, 20, 30, 40, 50, 60, 70, Atorney Docket No. 45049-0092W01 / 06870

[0047] 80, 90, 95, or more percent. In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein can have the ability to bind to a PLA2G7 polypeptide and can fully neutralize the activity of the PLA2G7 polypeptide (e.g., can inhibit 100% of the activity of the PLA2G7 polypeptide). In some cases, a binder provided herein can reduce the level of PLA2G7 polypeptide activity within a mammal (e.g., a human). For example, a binder provided herein can reduce the level of PLA2G7 polypeptide activity within a mammal by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.

[0048] The term “increased level’" as used herein with respect to a level of a PLA2G7 polypeptide activity refers to any level that is higher than a reference level of the PLA2G7 polypeptide activity. In some cases, an increased level of PLA2G7 polypeptide activity can be a level that is at least 5% greater than (e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%. at least 60%, at least 70%, at least 80%, or at least 90% greater than) a reference level of the PLA2G7 polypeptide activity.

[0049] The term “reference level” as used herein with respect to PLA2G7 polypeptide activity refers to the level of polypeptide activity typically observed in control samples. Control samples can include, without limitation, samples from one or more mammals that do not have a condition or disease associated with an increased level of PLA2G7 polypeptide activity. In some cases, a reference level of PLA2G7 polypeptide activity can be the level of activity7observed in a population of healthy mammals without a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a random sampling of 25, 50, 100. or more healthy humans without a condition or disease associated with an increased level of PLA2G7 polypeptide activity). It will be appreciated that levels of PLA2G7 polypeptide activity from comparable samples are used when determining whether or not a particular level of activity is an increased level of polypeptide activity.

[0050] The term “antibody domain” as used herein refers to a domain of an antibody such as a heavy chain variable domain (VH domain) or a light chain variable domain (VL domain) in the absence of one or more other domains of an antibody. In some cases, an antibody domain can be a single antibody domain (e.g., a VH domain or a VL domain) having the ability7to bind to an antigen (e.g., a PLA2G7 polypeptide). An antibody Atorney Docket No. 45049-0092W01 / 06870 domain provided herein can include the CDRs as described herein (e.g., as described in Table 13) and can be a human antibody domain (e.g., a human VH domain), a humanized antibody domain (e.g., a humanized VH domain), or a chimeric antibody domain (e.g., a chimeric VH domain). In some cases, an antibody domain provided herein can include the CDRs as described herein (e.g., as described in Table 13) and can be a monoclonal antibody domain. In some cases, an antibody domain provided herein can include the CDRs as described herein (e.g., as described in Table 13) and can be engineered as a single VH domain or a single VL domain.

[0051] The term “antigen binding fragment"’ as used herein refers to a fragment of an antibody (e.g., a fragment of a humanized antibody, a fragment of a human antibody, or a fragment of a chimeric antibody) having the ability to bind to an antigen (e.g., a PLA2G7 polypeptide). Examples of antigen binding fragments include, without limitation, Fab, Fab’, or F(ab’)2 antigen binding fragments. An antigen binding fragment provided herein can include the CDRs as described herein (e.g., as described in Table 13) and can be configured to be a human antigen binding fragment, a humanized antigen binding fragment, or a chimeric antigen binding fragment. In some cases, an antigen binding fragment provided herein can include the CDRs as described herein (e.g., as described in Table 13) and can be a monoclonal antigen binding fragment. In some cases, an antigen binding fragment provided herein can include the CDRs as described herein (e.g., as described in Table 13) and can be configured as a Fab antibody. In some cases, a Fab antibody can include a hinge sequence to allow for disulfide bonding between heavy and light chains of the Fab.

[0052] The term “antibody” as used herein includes polyclonal antibodies, monoclonal antibodies, recombinant antibodies, humanized antibodies, human antibodies, chimeric antibodies, single-domain antibodies (sdAbs; also referred to as nanobodies), multispecific antibodies (e.g., bispecific antibodies) formed from at least two antibodies, diabodies, single-chain variable fragment antibodies (e.g.. scFv antibodies), and tandem single-chain variable fragments antibody (e.g., taFv) having the ability to bind to an antigen (e.g., a PLA2G7 polypeptide). A multi-specific antibody (e.g., a bispecific antibody) is an antibody that can bind either two or more different antigens or two or more different epitopes of the same antigen simultaneously (Ma et al., Front Immunol. , 12:626616 (2021)). A multi-specific antibody (e.g., a bispecific antibody) can have an Atorney Docket No. 45049-0092W01 / 06870

[0053] IgG-like structure (e.g., a structure with two Fab arms and one Fc region) or a non-IgG- like structure (e.g., a structure that lacks an Fc region). Examples of multi-specific antibodies (e.g., bispecific antibodies) that can target (e.g., target and bind) a PLA2G7 polypeptide include, without limitation, those bispecific antibodies set forth in Example 5. A diabody can include two chains, each having a heavy chain variable domain and a light chain variable domain, either from the same or from different antibodies (see, e.g., Homig and Farber-Schwarz, Methods Mol. Biol., 907:713-27 (2012); and Brinkmann and Kontermann, MAbs. , 9(2): 182-212 (2017)). The two variable domains can be directly connected or can be connected using any appropriate linker sequence (e.g., a polypeptide linker such as a polypeptide linker having five to ten residues in length). For example, a heavy chain variable domain can be directly connected to a light chain variable domain, or a heavy chain variable domain can be connected to alight chain variable domain via a linker sequence. In some cases, a linker can be a flexible linker (e.g., such that the linker can function as a hinge). In some cases, an interdomain disulfide bond can be present in one or both of the heavy chain variable domain and light chain variable domain pairs of the diabody. A scFv is a single-chain polypeptide antibody in which the heavy chain variable domain and the light chain variable domain are directly connected or connected via a polypeptide linker. See. also, Chen et al. , A dv. DrugDeliv. Rev., 65(10): 1357-1369 (2013). A scFv can be designed to have an orientation with the heavy chain variable domain being followed by the light chain variable domain or can be designed to have an orientation with the light chain variable domain being followed by the heavy chain variable domain.

[0054] An antibody provided herein can include the CDRs as described herein (e.g., as described in Table 13) and can be configured to be a human antibody, a humanized antibody, or a chimeric antibody. In some cases, an antibody provided herein can include the CDRs as described herein (e.g., as described in Table 13) and can be a monoclonal antibody. In some cases, an antibody provided herein can include the CDRs as described herein (e.g., as described in Table 13) and can be configured as a scFv antibody.

[0055] An anti-PLA2G7 antibody domain, anti-PLA2G7 antigen binding fragment, or anti-PLA2G7 antibody provided herein can be of the IgA-, IgD-, IgE-, IgG-, or IgM-ty pe, including IgG- or IgM-types such as, without limitation, IgGi-, IgGz-, IgG?-. IgG4-, IgMi- , and IgM2-types. In some cases, an antibody domain provided herein (e.g., an anti- Atorney Docket No. 45049-0092W01 / 06870

[0056] PLA2G7 antibody domain) can be a VH domain. In some cases, an antibody domain provided herein (e.g., an anti-PLA2G7 antibody domain) can be a sdAb (a nanobody). In some cases, an antigen binding fragment provided herein (e.g., an anti-PLA2G7 antibody fragment) can be a Fab. In some cases, an antibody provided herein (e.g., an anti- PLA2G7 antibody) can be a scFv antibody. In some cases, an antibody provided herein (e.g., an anti-PLA2G7 antibody) can be a fully intact antibody.

[0057] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein having the ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) can include a heavy chain variable domain having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 1 (or a variant of SEQ ID NO: 1 with one, two, three, or four amino acid modifications), a CDR2 having the amino acid sequence set forth in SEQ ID NO:2 (or a variant of SEQ ID NO:2 with one, two, three, or four amino acid modifications), and a CDR3 having the amino acid sequence set forth in SEQ ID NO:3 (or a variant of SEQ ID NO:3 with one, two. three, or four amino acid modifications). An example of such an antigen binding domain having these CDRs and the abi 1 ity to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) includes, without limitation, the VH domain set forth in SEQ ID NO: 8 (see, e.g., Example 3).

[0058] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein having the ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) and a heavy chain variable domain having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 1 (or a variant of SEQ ID NO: 1 with one, two. three, or four amino acid modifications), a CDR2 having the amino acid sequence set forth in SEQ ID NO:2 (or a variant of SEQ ID NO:2 with one, two, three, or four amino acid modifications), and a CDR3 having the amino acid sequence set forth in SEQ ID NO:3 (or a variant of SEQ ID NO:3 with one, two, three, or four amino acid modifications) can include any appropriate framework regions. For example, such a binder can include a heavy chain variable domain that includes a framework region 1 having the amino acid sequence set forth in SEQ ID NO:4 (or a variant of SEQ ID NO:4 with one, two, three, four, five, six, seven, eight, nine, ten, or more amino acid modifications), a framework region 2 having the amino acid sequence set forth in SEQ ID NO:5 (or a variant of SEQ ID NO:5 with one, two, three, four, five, six, seven, eight. Atorney Docket No. 45049-0092W01 / 06870 nine. ten. or more amino acid modifications), a framework region 3 having the amino acid sequence set forth in SEQ ID NO:6 (or a variant of SEQ ID NO:6 with one, two, three, four, five, six, seven, eight, nine, ten, or more amino acid modifications), and a framework region 4 having the amino acid sequence set forth in SEQ ID NO:7 (or a variant of SEQ ID NO:7 with one. two, three, four, five, six, seven, eight, nine. ten. or more amino acid modifications).

[0059] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein having the ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) can include a heavy chain variable domain that includes an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 8. For example, a binder provided herein can include a heavy chain variable domain that includes an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 8. In some cases, a binder provided herein can include a heavy chain variable domain that includes an amino acid sequence having 100 percent identity to the amino acid sequence set forth in SEQ ID NO: 8

[0060] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein having the ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) can include a heavy chain variable domain that includes an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 8, provided that the heavy chain variable domain includes the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3. For example, a binder provided herein can include a heavy chain variable domain that includes an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 8, provided that the heavy chain variable domain includes the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3.

[0061] In some cases, a binder (e.g.. an antibody domain, an antigen binding fragment, or an antibody) provided herein having the ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) can include a heavy chain variable domain having a CDR1 having the amino acid sequence set forth in SEQ ID NO:9 (or a variant of SEQ ID NO:9 with one, two, three, or four amino acid modifications), a CDR2 having the amino acid sequence set forth in SEQ ID NO: 10 (or a variant of SEQ ID NO: 10 with one, two, three, Atorney Docket No. 45049-0092W01 / 06870 or four amino acid modifications), and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 11 (or a variant of SEQ ID NO: 11 w ith one, two, three, or four amino acid modifications). An example of such an antigen binding domain having these CDRs and the ability- to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) includes, without limitation, the VH domain set forth in SEQ ID NO: 16 (see, e.g., Example 3).

[0062] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein having the abi 1 ity to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) and a heavy chain variable domain having a CDR1 having the amino acid sequence set forth in SEQ ID NO:9 (or a variant of SEQ ID NO:9 with one, two, three, or four amino acid modifications), a CDR2 having the amino acid sequence set forth in SEQ ID NO: 10 (or a variant of SEQ ID NO:10 with one, two, three, or four amino acid modifications), and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 11 (or a variant of SEQ ID NO: 11 with one, two, three, or four amino acid modifications) can include any appropriate framework regions. For example, such a binder can include a heavy chain variable domain that includes a framework region 1 having the amino acid sequence set forth in SEQ ID NO: 12 (or a variant of SEQ ID NO: 12 with one, two, three, four, five. six. seven, eight, nine, ten. or more amino acid modifications), a framework region 2 having the amino acid sequence set forth in SEQ ID NO: 13 (or a variant of SEQ ID NO: 13 with one, two, three, four, five, six, seven, eight, nine, ten, or more amino acid modifications), a framework region 3 having the amino acid sequence set forth in SEQ ID NO: 14 (or a variant of SEQ ID NO: 14 with one, two. three, four, five, six, seven, eight, nine, ten, or more amino acid modifications), and a framework region 4 having the amino acid sequence set forth in SEQ ID NO: 15 (or a variant of SEQ ID NO: 15 with one, two, three, four, five, six, seven, eight, nine, ten, or more amino acid modifications).

[0063] In some cases, a binder (e.g.. an antibody domain, an antigen binding fragment, or an antibody) provided herein having the ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) can include a heavy chain variable domain that includes an amino acid sequence having at least 90 percent identity- to the amino acid sequence set forth in SEQ ID NO: 16. For example, a binder provided herein can include a heavy chain variable domain that includes an amino acid sequence having at least 90. 91, 92, 93, 94, Atorney Docket No. 45049-0092W01 / 06870

[0064] 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 16. In some cases, a binder provided herein can include a heavy chain variable domain that includes an amino acid sequence having 100 percent identity' to the amino acid sequence set forth in SEQ ID NO: 16.

[0065] In some cases, a binder (e.g.. an antibody domain, an antigen binding fragment, or an antibody) provided herein having the ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) can include a heavy chain variable domain that includes an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 16, provided that the heavy chain variable domain includes the amino acid sequences set forth in SEQ ID NOs:9, 10, and 11. For example, a binder provided herein can include a heavy chain variable domain that includes an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity' to the amino acid sequence set forth in SEQ ID NO: 16, provided that the heavy chain variable domain includes the amino acid sequences set forth in SEQ ID NOs:9, 10, and 11.

[0066] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein having the abi 1 ity to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) can include (a) a heavy chain variable domain having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 17 (or a variant of SEQ ID NO: 17 with one, two, three, or four amino acid modifications), a CDR2 having the amino acid sequence set forth in SEQ ID NO: 18 (or a variant of SEQ ID NO: 18 with one, two, three, or four amino acid modifications), and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 19 (or a variant of SEQ ID NO: 19 with one, two. three, or four amino acid modifications), and / or (b) a light chain variable domain having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 25 (or a variant of SEQ ID NO:25 with one, two, three, or four amino acid modifications), a CDR2 having the amino acid sequence set forth in SEQ ID NO:26 (or a variant of SEQ ID NO:26 with one, two, three, or four amino acid modifications), and a CDR3 having the amino acid sequence set forth in SEQ ID NO:27 (or a variant of SEQ ID NO:27 with one, two, three, or four amino acid modifications). An example of an antigen binding domain having the CDRs set forth in SEQ ID NOs: 17-19 (or variants thereof with one, two, three, or four amino acid modifications) and the ability’ to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) includes, without limitation, the VH domain set forth in SEQ ID Atorney Docket No. 45049-0092W01 / 06870

[0067] NO:24 (see, e.g., Example 3), and an example of an antigen binding domain having the CDRs set forth in SEQ ID NOs:25-27 (or variants thereof with one, two, three, or four amino acid modifications) and the ability' to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) includes, without limitation, the VL domain set forth in SEQ ID NO:32 (see, e.g.. Example 3).

[0068] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein having the ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) and (a) a heavy chain variable domain having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 17 (or a variant of SEQ ID NO: 17 with one, two, three, or four ammo acid modifications), a CDR2 having the amino acid sequence set forth in SEQ ID NO: 18 (or a variant of SEQ ID NO: 18 with one, two, three, or four amino acid modifications), and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 19 (or a variant of SEQ ID NO: 19 with one, two, three, or four amino acid modifications), and / or (b) a light chain variable domain having a CDR1 having the amino acid sequence set forth in SEQ ID NO:25 (or a variant of SEQ ID NO:25 wi th one, two, three, or four amino acid modifications), a CDR2 having the amino acid sequence set forth in SEQ ID NO:26 (or a variant of SEQ ID NO:26 with one, two, three, or four amino acid modifications), and a CDR3 having the amino acid sequence set forth in SEQ ID NO:27 (or a variant of SEQ ID NO:27 with one, two, three, or four amino acid modifications) can include any appropriate framework regions. For example, such a binder can include (a) a heavy chain variable domain that includes a framework region 1 having the amino acid sequence set forth in SEQ ID NO:20 (or a variant of SEQ ID NO:20 with one, two. three, four, five, six. seven, eight, nine, ten, or more amino acid modifications), a framework region 2 having the amino acid sequence set forth in SEQ ID NO:21 (or a variant of SEQ ID NO:21 with one, two, three, four, five, six, seven, eight, nine, ten, or more amino acid modifications), a framework region 3 having the amino acid sequence set forth in SEQ ID NO:22 (or a variant of SEQ ID NO:22 with one, two. three, four, five, six, seven, eight, nine, ten, or more amino acid modifications), and a framework region 4 having the amino acid sequence set forth in SEQ ID NO: 23 (or a variant of SEQ ID NO:23 with one, two, three, four, five, six, seven, eight, nine, ten, or more amino acid modifications), and / or (b) a light chain variable domain that includes a framework region 1 having the amino acid sequence set forth in SEQ ID NO: 28 (or a Atorney Docket No. 45049-0092W01 / 06870 variant of SEQ ID NO:28 with one, two, three, four, five, six, seven, eight, nine, ten, or more amino acid modifications), a framework region 2 having the amino acid sequence set forth in SEQ ID NO:29 (or a variant of SEQ ID NO:29 w ith one, two, three, four, five, six, seven, eight, nine, ten, or more amino acid modifications), a framework region 3 having the amino acid sequence set forth in SEQ ID NO:30 (or a variant of SEQ ID NO:30 with one, two, three, four, five, six, seven, eight, nine, ten, or more amino acid modifications), and a framework region 4 having the amino acid sequence set forth in SEQ ID NO:31 (or a variant of SEQ ID NO:31 with one, two, three, four, five, six, seven, eight, nine, ten, or more amino acid modifications).

[0069] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein having the ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) can include (a) a heavy chain variable domain that includes an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 24, and / or (b) a light chain variable domain that includes an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:32. For example, a binder provided herein can include (a) a heavy chain variable domain that includes an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO:24, and / or (b) a light chain variable domain that includes an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 32. In some cases, a binder provided herein can include (a) a heavy chain variable domain that includes an amino acid sequence having 100 percent identity to the amino acid sequence set forth in SEQ ID NO: 24. and / or (b) a light chain variable domain that includes an amino acid sequence having 100 percent identity to the amino acid sequence set forth in SEQ ID NO:32.

[0070] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein having the ability to bind to a PLA2G7 polypeptide (e.g.. a human PLA2G7 polypeptide) can include (a) a heavy chain variable domain that includes an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 24, provided that the heavy chain variable domain includes the amino acid sequences set forth in SEQ ID NOs: 17, 18, and 19, and / or (b) a light chain variable domain that includes an amino acid sequence having at least 90 percent identity Atorney Docket No. 45049-0092W01 / 06870 to the amino acid sequence set forth in SEQ ID NO: 32, provided that the light chain variable domain includes the amino acid sequences set forth in SEQ ID NOs:25, 26, and 27. For example, a binder provided herein can include (a) a heavy chain variable domain that includes an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO:24, provided that the heavy chain variable domain includes the amino acid sequences set forth in SEQ ID NOs: 17, 18, and 19, and / or (b) a light chain variable domain that includes an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent identity to the amino acid sequence set forth in SEQ ID NO: 32, provided that the heavy chain variable domain includes the amino acid sequences set forth in SEQ ID NOs: 25, 26, and 27.

[0071] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) having any set of three CDRs set forth in Example 3 can be designed to include framework regions as set forth in Example 3 or can be designed to include one or more framework regions from another antibody, antibody fragment, or antibody domain. For example, a sdAb can be designed to include one set of three CDRs (e.g., CDR1, CDR2, and CDR3) set forth in Example 3 and the framework regions set forth in Example 3. For example, a sdAb can be designed to include one set of three CDRs (e.g., CDR1, CDR2, and CDR3) set forth in Example 3 and the framework regions set forth in Example 3 except that framework region 1 having the amino acid set forth in SEQ ID NO: 4 is replaced with a framework region 1 having the amino acid set forth in SEQ ID NO:20.

[0072] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein having the ability to bind to a PLA2G7 polypeptide (e.g.. a human PLA2G7 polypeptide) can include a heavy chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO: 1, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:2, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO: 3. As used herein, a “CDR1 that consists essentially of the amino acid sequence set forth in SEQ ID NO: F' is a CDR1 that has zero, one, or two amino acid substitutions within SEQ ID NO: 1. that has zero, one, two, three, four, or five amino acid residues directly preceding SEQ ID NO: 1, and / or that has zero, one, two, three, four, or five amino acid Atorney Docket No. 45049-0092W01 / 06870 residues directly following SEQ ID NO: 1, provided that the binder maintains its basic ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide). Examples of a CDR1 that consists essentially of the amino acid sequence set forth in SEQ ID NO: 1 include, without limitation, those set forth in Table 1. Table 1. Exemplar}' CDRls that consist essentially of the amino acid sequence set forth in

[0073] SEQ ID NOT.

[0074] As used herein, a “CDR2 that consists essentially of the amino acid sequence set forth in SEQ ID NO:2” is a CDR2 that has zero, one, or two amino acid substitutions within SEQ ID NO:2, that has zero, one. two, three, four, or five amino acid residues directly preceding SEQ ID NO:2, and / or that has zero, one, two, three, four, or five amino acid residues directly following SEQ ID NO:2, provided that the binder (e g., the antibody domain, the antigen binding fragment, or the antibody) maintains its basic ability' to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide). Examples of a CDR2 that consists essentially of the amino acid sequence set forth in SEQ ID NO:2 include, without limitation, those set forth in Table 2.

[0075] Table 2. Exemplar ' CDR2s that consist essentially of the amino acid sequence set forth in SEQ ID NO:2. Atorney Docket No. 45049-0092W01 / 06870

[0076] As used herein, a “CDR3 that consists essentially of the amino acid sequence set forth in SEQ ID NO:3” is a CDR3 that has zero, one, or two amino acid substitutions within SEQ ID NO: 3, that has zero, one, two, three, four, or five amino acid residues directly preceding SEQ ID NO:3, and / or that has zero, one, two, three, four, or five amino acid residues directly following SEQ ID NO:3, provided that the binder (e.g., the antibody domain, the antigen binding fragment, or the antibody) maintains its basic ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide). Examples of a CDR3 that consists essentially of the amino acid sequence set forth in SEQ ID NO: 3 include, without limitation, those set forth in Table 3.

[0077] Table 3. Exemplary' CDR3s that consist essentially of the amino acid sequence set forth in SEQ ID NO:3.

[0078] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein having the ability' to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 poly peptide) can include a heavy chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:9, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NOTO, and (iii) a CDR3 that comprises, Atorney Docket No. 45049-0092W01 / 06870 consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO: 11. As used herein, a “CDR1 that consists essentially of the amino acid sequence set forth in SEQ ID NO: 9’" is a CDR1 that has zero, one, or two amino acid substitutions within SEQ ID NO: 9, that has zero, one, two, three, four, or five amino acid residues directly preceding SEQ ID NO:9, and / or that has zero, one, two. three, four, or five amino acid residues directly following SEQ ID NO:9, provided that the binder maintains its basic ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide). Examples of a CDR1 that consists essentially of the amino acid sequence set forth in SEQ ID NO: 9 include, without limitation, those set forth in Table 4.

[0079] Table 4. Exemplar}' CDR1 s that consist essentially of the amino acid sequence set forth in SEQ ID NO:9.

[0080] As used herein, a “CDR2 that consists essentially of the amino acid sequence set forth in SEQ ID NOTO” is a CDR2 that has zero, one, or two amino acid substitutions within SEQ ID NOTO, that has zero, one, two, three, four, or five amino acid residues directly preceding SEQ ID NOTO, and / or that has zero, one, two, three, four, or five amino acid residues directly following SEQ ID NOTO, provided that the binder (e.g., the antibody domain, the antigen binding fragment, or the antibody) maintains its basic ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide). Examples of a CDR2 that consists essentially of the amino acid sequence set forth in SEQ ID NO: 10 include, without limitation, those set forth in Table 5. Atorney Docket No. 45049-0092W01 / 06870

[0081] Table 5. Exemplars' CDR2s that consist essentially of the amino acid sequence set forth in SEQ ID NOTO.

[0082] As used herein, a “CDR3 that consists essentially of the amino acid sequence set forth in SEQ ID NO: 11” is a CDR3 that has zero, one, or two amino acid substitutions within SEQ ID NO: 11, that has zero, one, two, three, four, or five amino acid residues directly preceding SEQ ID NO: 11. and / or that has zero, one, two, three, four, or five amino acid residues directly following SEQ ID NO: 11, provided that the binder (e.g., the antibody domain, the antigen binding fragment, or the antibody) maintains its basic ability' to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide). Examples of a CDR3 that consists essentially of the amino acid sequence set forth in SEQ ID NO: 11 include, without limitation, those set forth in Table 6.

[0083] Table 6. Exemplar}' CDR3s that consist essentially of the amino acid sequence set forth in SEQ ID NOTE Atorney Docket No. 45049-0092W01 / 06870

[0084] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein having the ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) can include (a) a heavy chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO: 17, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO: 18, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO: 19, and / or (b) a light chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:25. (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:26, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:27. As used herein, a "CDR I that consists essentially of the amino acid sequence set forth in SEQ ID NO: 17” is a CDR1 that has zero, one, or two amino acid substitutions within SEQ ID NO: 17. that has zero, one, two, three, four, or five amino acid residues directly preceding SEQ ID NO: 17, and / or that has zero, one, two, three, four, or five amino acid residues directly following SEQ ID NO: 17, provided that the binder maintains its basic ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide). Examples of a CDR1 that consists essentially of the amino acid sequence set forth in SEQ ID NO: 17 include, without limitation, those set forth in Table 7.

[0085] Table 7. Exemplary’ CDRls that consist essentially of the amino acid sequence set forth in SEQ ID NO: 17. Atorney Docket No. 45049-0092W01 / 06870

[0086] As used herein, a ‘CDR2 that consists essentially of the amino acid sequence set forth in SEQ ID NO: 18” is a CDR2 that has zero, one, or two amino acid substitutions within SEQ ID NO: 18, that has zero, one, two, three, four, or five amino acid residues directly preceding SEQ ID NO: 18. and / or that has zero, one, two, three, four, or five amino acid residues directly following SEQ ID NO: 18, provided that the binder (e.g., the antibody domain, the antigen binding fragment, or the antibody) maintains its basic ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide). Examples of a CDR2 that consists essentially of the amino acid sequence set forth in SEQ ID NO: 18 include, without limitation, those set forth in Table 8.

[0087] Table 8. Exemplar}' CDR2s that consist essentially of the amino acid sequence set forth in SEQ ID NO: 18.

[0088] As used herein, a “CDR3 that consists essentially of the amino acid sequence set forth in SEQ ID NO: 19” is a CDR3 that has zero, one, or two amino acid substitutions within SEQ ID NO: 19. that has zero, one, two, three, four, or five amino acid residues directly preceding SEQ ID NO: 19, and / or that has zero, one, two, three, four, or five amino acid residues directly following SEQ ID NO: 19, provided that the binder (e.g., the antibody domain, the antigen binding fragment, or the antibody) maintains its basic ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide). Examples of a CDR3 that consists essentially of the amino acid sequence set forth in SEQ ID NO: 19 include, without limitation, those set forth in Table 9. Atorney Docket No. 45049-0092W01 / 06870

[0089] Table 9. Exemplars' CDR3s that consist essentially of the amino acid sequence set forth in SEQ ID NO: 19.

[0090] As used herein, a “CDR1 that consists essentially of the amino acid sequence set forth in SEQ ID NO:25” is a CDR1 that has zero, one, or two amino acid substitutions within SEQ ID NO:25, that has zero, one, two, three, four, or five amino acid residues directly preceding SEQ ID NO:25. and / or that has zero, one, two, three, four, or five amino acid residues directly following SEQ ID NO: 25, provided that the binder maintains its basic ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide). Examples of a CDR1 that consists essentially of the amino acid sequence set forth in SEQ ID NO:25 include, without limitation, those set forth in Table 10.

[0091] Table 10. Exemplary CDRls that consist essentially of the amino acid sequence set forth in SEQ ID NO:25. Atorney Docket No. 45049-0092W01 / 06870

[0092] As used herein, a ‘CDR2 that consists essentially of the amino acid sequence set forth in SEQ ID NO:26” is a CDR2 that has zero, one, or two amino acid substitutions within SEQ ID NO:26, that has zero, one, two, three, four, or five amino acid residues directly preceding SEQ ID NO:26. and / or that has zero, one, two, three, four, or five amino acid residues directly following SEQ ID NO:26, provided that the binder (e.g., the antibody domain, the antigen binding fragment, or the antibody) maintains its basic ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide). Examples of a CDR2 that consists essentially of the amino acid sequence set forth in SEQ ID NO:26 include, without limitation, those set forth in Table 11.

[0093] Table 11. Exemplary CDR2s that consist essentially of the amino acid sequence set forth in SEQ ID NO: 26.

[0094] As used herein, a “CDR3 that consists essentially of the amino acid sequence set forth in SEQ ID NO:27” is a CDR3 that has zero, one, or two amino acid substitutions within SEQ ID NO:27. that has zero, one, two, three, four, or five amino acid residues directly preceding SEQ ID NO:27, and / or that has zero, one, two, three, four, or five amino acid residues directly following SEQ ID NO:27, provided that the binder (e.g., the antibody domain, the antigen binding fragment, or the antibody) maintains its basic ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide). Examples of a CDR3 that consists essentially of the amino acid sequence set forth in SEQ ID NO:27 include, without limitation, those set forth in Table 12. Atorney Docket No. 45049-0092W01 / 06870

[0095] Table 12. Exemplary CDR3s that consist essentially of the amino acid sequence set forth in SEQ ID NO 27.

[0096] As indicated herein, the amino acid sequences described herein can include amino acid modifications (e.g., the articulated number of amino acid modifications). Such amino acid modifications can include, without limitation, amino acid substitutions, amino acid deletions, amino acid additions, and combinations thereof. In some cases, an amino acid modification can be made to improve the binding and / or contact with an antigen and / or to improve a functional activity of a binder (e g., an antibody domain, an antigen binding fragment, or an antibody) provided herein. In some cases, an amino acid substitution within an articulated sequence identifier can be a conservative amino acid substitution. For example, conservative amino acid substitutions can be made by substituting one amino acid residue for another amino acid residue having a similar side chain. Families of amino acid residues having similar side chains can include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., ty rosine, phenylalanine, tryptophan, histidine).

[0097] In some cases, an amino acid substitution within an articulated sequence identifier can be a non-conservative amino acid substitution. Non-conservative amino acid substitutions can be made by substituting one amino acid residue for another amino acid residue having a dissimilar side chain. Examples of non-conservative substitutions Atorney Docket No. 45049-0092W01 / 06870 include, without limitation, substituting (a) a hydrophilic residue (e.g., serine or threonine) for a hydrophobic residue (e.g., leucine, isoleucine, phenylalanine, valine, or alanine); (b) a cysteine or proline for any other residue; (c) a residue having a basic side chain (e.g., lysine, arginine, or histidine) for a residue having an acidic side chain (e.g., aspartic acid or glutamic acid); and (d) a residue having a bulky side chain (e.g., phenylalanine) for glycine or other residue having a small side chain.

[0098] Methods for generating an amino acid sequence variant (e.g., an amino acid sequence that includes one or more modifications with respect to an articulated sequence identifier) can include site-specific mutagenesis or random mutagenesis (e.g.. by PCR) of a nucleic acid encoding the antibody or fragment thereof. See, for example, Zoller, Curr. Opin. Biotechnol. 3:348-354 (1992). Both naturally occurring and non-naturally occurring amino acids (e.g., artificially-derivatized amino acids) can be used to generate an amino acid sequence variant provided herein.

[0099] A representative number of binders (e.g., antibody domains, antigen binding fragments, and / or antibodies) having the ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) are further described in Table 13.

[0100] Table 13. Representative binders having the ability to bind to a PLA2G7 polypeptide.

[0101] Table 14 includes an alternative designation that can be used to refer to each of Clones #1 - #3.

[0102] Table 14. Alternative nomenclature for Clones #1 - #3. Atorney Docket No. 45049-0092W01 / 06870

[0103] In some cases, an antigen binding fragment or antibody domain provided herein can be produced by proteolytic digestion of an intact antibody. For example, an antigen binding fragment can be obtained by treating an antibody with an enz me such as papain or pepsin. Papain digestion of whole antibodies can be used to produce F(ab)2 or Fab fragments, while pepsin digestion of whole antibodies can be used to produce F(ab')2 or Fab’ fragments.

[0104] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein can be substantially pure. The term ‘‘substantially pure” as used herein with reference to a binder refers to the binder as being substantially free of other polypeptides, lipids, carbohydrates, and nucleic acid with which it is naturally associated. Thus, a substantially pure binder provided herein is any binder that is removed from its natural environment and is at least 60 percent pure. A substantially pure binder provided herein can be at least about 65, 70, 75, 80, 85, 90, 95, or 99 percent pure.

[0105] This document also provides bispecific binders (e.g., bispecific antibody domains, bispecific antigen binding fragments, and / or bispecific antibodies) that bind to two different epitopes with at least one being an epitope of a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide). In some cases, a bispecific binder provided herein can be designed to bind to two different epitopes of the same PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide). In some cases, a bispecific binder provided herein can bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) and can bind to an epitope on a different polypeptide. For example, a bispecific binder provided herein can be designed to have a structure set forth in Example 5. In some cases, a bispecific binder provided herein can be designed to include an antigen binding domain described herein. For example, a bispecific binder provided herein can be designed to include an antigen binding domain that includes at least one set of three CDRs (e.g., CDR1, CDR2, and CDR3) of an antigen binding domain provided herein (e.g., SEQ ID NOs:l-3, SEQ ID NOs:9-ll, SEQ ID NOs: 17-19, or SEQ ID NOs:25-27). In some cases, a bispecific binder provided herein can be designed to include two antigen binding domains described herein. For example, a bispecific binder provided herein can be designed to include an antigen binding domain that includes a first set of three CDRs (e.g., CDR1, CDR2, and CDR3) of a first antigen binding domain provided herein (e.g., SEQ ID NOs: 1-3) and a second set of three CDRs (e.g., CDR1, CDR2, and CDR3) of a second antigen binding Atorney Docket No. 45049-0092W01 / 06870 domain provided herein (e.g., SEQ ID NOs: 9- 11). In some cases, a bispecific binder provided herein can be designed to include an antigen binding domain that includes a first antigen binding domain including SEQ ID NOs: 17-19 and a second antigen binding domain including SEQ ID NOs: 1-3 or SEQ ID NOs:9-ll. Bispecific binders can be produced by chemically conjugating two different binders together. Bispecific binders also can be produced by fusing two antibody-producing cells, e.g., hybridomas, to make a hybrid cell line that produces two different heavy and two different light chains within the same cell, which can result in, for example, bispecific IgG molecules. See, Brinkmann and Kontermann. MAbs.. 9(2): 182-212 (2017). In some cases, a bispecific bind can be produced as described in Example 1.

[0106] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein can be fused or conjugated (e.g., covalently or non- covalently attached) to another polypeptide or other moiety to provide a fusion protein or conjugate. For example, a binder provided herein can be conjugated (e.g., covalently or non-covalently attached) to a polymer (e.g., polyethylene glycol (PEG), polyethylenimine (PEI) modified with PEG (PEI-PEG), and / or polyglutamic acid (PGA) (N-(2- Hydroxypropyl) methacrylamide (HP MA) copolymers), hyaluronic acid, a fluorescent substance, a luminescent substance, a hapten, an enzyme, a metal chelate, a drug, a radioisotope, and / or a cytotoxic agent. Any appropriate method can be used to conjugate (e.g., covalently or non-covalently attach) another polypeptide or other moiety to a binder provided herein. For example, another polypeptide or other moiety7can be conjugated to a binder provided herein using the methods described in U.S. Patent No. 8,021.661.

[0107] In some cases, a binder (e.g.. an antibody domain, an antigen binding fragment, or an antibody) provided herein can be modified with a moiety7that improves its stabilization and / or retention in circulation, for example, in blood, serum, or other tissues by, for example, at least 1.5-, 2-, 5-, 10-, or 50-fold. For example, a binder provided herein can be attached (e.g.. covalently or non-covalently attached) to a polymer such as a substantially non-antigenic polymer. Examples of substantially non-antigenic polymers that can be used as described herein include, without limitation, polyalkylene oxides, and polyethylene oxides. In some cases, a polymer used herein can have any appropriate molecule weight. For example, a polymer having an average molecular weight from about 200 Daltons to about 35,000 Daltons (e.g., from about 1,000 to about 15,000 Daltons or Atorney Docket No. 45049-0092W01 / 06870 from about 2,000 to about 12,500 Daltons) can be used. In some cases, a binder provided herein can be attached (e.g., covalently or non-covalently) to a water-soluble polymer. Examples of water-soluble polymers that can be used as described herein include, without limitation, hydrophilic polyvinyl polymers, polyvinylalcohol, polyvinylpyrrolidone, polyalkylene oxide homopolymers, polyethylene glycol (PEG), polypropylene glycols, polyoxy ethylenated polyols and copolymers thereof and / or block copolymers thereof provided that the water solubility of the copolymer or block copolymers is maintained.

[0108] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein can be attached (e.g., covalently or non-covalently attached) to one or more polyoxyalkylenes (e.g., polyoxyethylene, poly oxy propylene, or block copolymers of polyoxyethylene and polyoxypropylene), polymethacrylates, carbomers, branched or unbranched polysaccharides, or combinations thereof. For example, a binder provided herein can be covalently attached to polyoxyethylene.

[0109] This document also provides nucleic acid molecules (e.g.. isolated nucleic acid molecules) having a nucleic acid sequence encoding at least part of a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein. For example, an isolated nucleic acid molecule provided herein can include a nucleic acid sequence encoding a heavy chain variable domain such as a heavy chain variable domain as set forth in Example 3. In another example, an isolated nucleic acid molecule provided herein can include a nucleic acid sequence set forth in Example 4. A nucleic acid provided herein (e.g., an isolated nucleic acid molecule) can be single stranded or double stranded nucleic acid of any appropriate type (e.g., DNA, RNA. or DNA / RNA hybrids).

[0110] This document also provides vectors (e.g.. plasmid vectors or viral vectors) containing one or more nucleic acids provided herein. An example of a plasmid vector that can be designed to include one or more nucleic acids having a nucleic acid sequence encoding at least part of a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein includes, without limitation, phagemids. Examples of viral vectors that can be designed to include one or more nucleic acids having a nucleic acid sequence encoding at least part of a binder provided herein include, without limitation, retroviral vectors, parvovirus-based vectors (e.g., adenoviral -based vectors and adeno-associated virus (AAV)-based vectors), lentiviral vectors (e.g., herpes simplex (HSV)-based vectors), poxviral vectors (e.g., vaccinia virus-based vectors and fowlpox Atorney Docket No. 45049-0092W01 / 06870 virus-based vectors), and hybrid or chimeric viral vectors. For example, a viral vector having an adenoviral backbone with lentiviral components such as those described elsewhere (Zheng etal., Nat. Biotech., 18(2): 176-80 (2000); WO 98 / 22143; WO 98 / 46778; and WO 00 / 17376) or viral vectors having an adenoviral backbone with AAV components such as those described elsewhere (Fisher et al., Hum. Gene Ther.. 7:2079- 2087 (1996)) can be designed to include one or more nucleic acids having a nucleic acid sequence encoding at least part of a binder provided herein.

[0111] In some cases, a vector (e.g., a plasmid vector or a viral vector) provided herein can include a nucleic acid sequence encoding an antibody domain (e.g.. a VH domain) provided herein.

[0112] A vector provided herein (e.g., a plasmid vector or viral vector provided herein) can include any appropriate promoter and other regulatory' sequence (e.g., transcription and translation initiation and termination codons) operably linked the nucleic acid sequence encoding at least part of a binder (e.g.. an antibody domain, an antigen binding fragment, or an antibody) provided herein. In some cases, a promoter used to drive expression can be a constitutive promotor or a regulatable promotor. Examples of regulatable promoters that can be used as described herein include, without limitation, inducible promotors, repressible promotors, and tissue-specific promoters. Examples of promoters that can be used as described herein include, without limitation, adenoviral promotors, vaccinia virus promotors, CMV promoters (e.g., immediate early CMV promotors), and AAV promoters.

[0113] Any appropriate method can be used to make a nucleic acid molecule (or vector such as a plasmid vector or viral vector) having a nucleic acid sequence encoding at least part of a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein. For example, molecule cloning techniques can be used to make a nucleic acid molecule (or vector such as a plasmid vector or viral vector) having a nucleic acid sequence encoding at least part of a binder provided herein as described elsewhere (see, e.g., Sambrook et al. , Molecular Cloning: A Laboratory Manual, 2nd edition, Cold Spring Harbor Laboratory. NY (1989); and Ausubel et al., Current Protocols in Molecular Biology', Green Publishing Associates and John Wiley & Sons, New York, N.Y. (1994)).

[0114] This document also provides host cells that include a nucleic acid provided herein (e.g., a nucleic acid having anucleic acid sequence encoding at least part of a binder (e.g., Atorney Docket No. 45049-0092W01 / 06870 an antibody domain, an antigen binding fragment, or an antibody) provided herein). Host cells that can be designed to include one or more nucleic acids provided herein can be prokaryotic cells or eukaryotic cells. Examples of prokaryotic cells that can be designed to include a nucleic acid provided herein include, without limitation, E. coli (e.g, Tb-1, TG-1, DH5a. XL-Blue MRF (Stratagene). SA2821. or Y1090 cells), Bacillus subtilis, Salmonella typhimurium, Serratia marcescens. ox Pseudomonas (e.g., P. aeruginosa) cells. Examples of eukaryotic cells that can be designed to include a nucleic acid provided herein include, without limitation, insect cells (e.g., Sf9 or Ea4 cells), yeast cells (e.g., S'. cerevisiae cells), and mammalian cells (e.g.. mouse, rat. hamster, monkey, or human cells). For example, VERO cells, HeLa cells, 3T3 cells, Chinese hamster ovary (CHO) cells, W138 BHK cells, COS-7 cells, and MDCK cells can be designed to include a nucleic acid provided herein. Any appropriate method can be used to introduce one or more nucleic acids provided herein (e.g., a vector such as a plasmid vector or viral vector having a nucleic acid sequence encoding at least part of a binder provided herein) into a host cell. For example, calcium chloride-mediated transformation, transduction, conjugation, triparental mating, DEAE, dextran-mediated transfection, infection, membrane fusion w ith liposomes, high velocity bombardment with DNA-coated microprojectiles, direct microinjection into single cells, electroporation, or combinations thereof can be used to introduce a nucleic acid provided herein into a host cell (see, e.g., Sambrook et al., Molecular Biology: A Laboratory Manual, Cold Spring Harbor Laboratory, NY (1989); Davis et al., Basic Methods in Molecular Biology (1986); and Neumann et al., EMBO J., 1:841 (1982)).

[0115] In some cases, a binder (e.g.. an antibody domain, an antigen binding fragment, or an antibody) provided herein can be produced using a method that includes (a) introducing nucleic acid encoding the binder into a host cell; (b) culturing the host cell in culture medium under conditions sufficient to express the polypeptide; (c) harvesting the polypeptide from the cell or culture medium; and (d) purifying the polypeptide (e.g., to reach at least 50, 60, 70, 80, 90, 95, 97, 98, or 99 percent purity). Example 4 is a sequence listing of nucleic acid sequences encoding exemplary binders described herein.

[0116] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein, a nucleic acid provided herein (e.g., nucleic acid encoding an antibody domain, an antigen binding fragment, or an antibody), a vector provided Atorney Docket No. 45049-0092W01 / 06870 herein (e.g., a viral vector designed to express an antibody domain, an antigen binding fragment, or an antibody), and / or a host cell provided herein (e.g., a host cell designed to express an antibody domain, an antigen binding fragment, or an antibody) can be formulated as a pharmaceutical composition for administration to a mammal (e.g., a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity)- In some cases, a binder provided herein, a nucleic acid provided herein, a vector provided herein, and / or a host cell provided herein can be formulated as a pharmaceutical composition for administration to a mammal (e.g., a human) to inhibit the activity of a PLA2G7 polypeptide in the mammal having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity). For example, a binder provided herein having the ability to bind to a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) can be formulated as a pharmaceutical composition for administration to a mammal (e.g., a human). In some cases, a pharmaceutical composition provided herein can include a pharmaceutically acceptable carrier such as a buffer, a salt, a surfactant, a sugar, a tonicity modifier, or combinations thereof as, for example, described elsewhere (Gervasi, et al. , Eur. J. Pharmaceutics and Biopharmaceutics, 131 :8-24 (2018)). Examples of pharmaceutically acceptable carriers that can be used to make a pharmaceutical composition provided herein include, without limitation, water, lactic acid, citric acid, sodium chloride, sodium citrate, sodium succinate, sodium phosphate, a surfactant (e.g., polysorbate 20, polysorbate 80. or poloxamer 188), dextran 40, or a sugar (e.g., sorbitol, mannitol, sucrose, dextrose, or trehalose), or combinations thereof. For example, a pharmaceutical composition designed to include a binder provided herein (or a nucleic acid, a vector, or a host cell provided herein) can be formulated to include a buffer (e.g., an acetate, citrate, histidine, succinate, phosphate, or hydroxymethylaminomethane (Tris) buffer), a surfactant (e.g., polysorbate 20, polysorbate 80, or poloxamer 188), and a sugar such as sucrose. Other ingredients that can be included within a pharmaceutical composition provided herein include, without limitation, amino acids such as glycine or arginine, and antioxidants such as ascorbic acid, methionine, or ethylenediaminetetraacetic acid (EDTA). Atorney Docket No. 45049-0092W01 / 06870

[0117] In some cases, when a pharmaceutical composition is formulated to include one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, or host cell provided herein), any appropriate amount of the binder can be used. For example, a pharmaceutical composition provided herein can be formulated to be a liquid that includes from about 10 mg to about 100 mg (e g., from about 10 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 70 mg, about 10 mg to about 60 mg, about 10 mg to about 50 mg, about 10 mg to about 42 mg, about 10 mg to about 34 mg, about 10 mg to about 26 mg. about 10 mg to about 18 mg, about 18 mg to about 100 mg. about 26 mg to about 100 mg, about 34 mg to about 100 mg, about 42 mg to about 100 mg, about 50 mg to about 100 mg, about 60 mg to about 100 mg, about 70 mg to about 100 mg, about 80 mg to about 100 mg, about 90 mg to about 100 mg, about 18 mg to about 90 mg, about 26 mg to about 80 mg. about 34 mg to about 70 mg, about 42 mg to about 60 mg. about 10 mg to about 26 mg. about 18 mg to about 34 mg, about 26 mg to about 42 mg, about 34 mg to about 50 mg, about 42 mg to about 60 mg, about 50 mg to about 70 mg, about 60 mg to about 80 mg, about 70 mg to about 90 mg, or about 80 mg to about 100 mg) of a binder provided herein per mL. In another example, a pharmaceutical composition provided herein can be formulated to be a solid or semi -solid that includes from about 10 mg to about 100 mg of a binder provided herein. For example, a pharmaceutical composition provided herein can be formulated to be a solid or semi-solid that includes from about 10 mg to about 100 mg (e.g., from about 10 mg to about 90 mg, about 10 mg to about 80 mg. about 10 mg to about 70 mg, about 10 mg to about 60 mg. about 10 mg to about 50 mg. about 10 mg to about 42 mg, about 10 mg to about 34 mg, about 10 mg to about 26 mg, about 10 mg to about 18 mg, about 18 mg to about 100 mg, about 26 mg to about 100 mg, about 34 mg to about 100 mg, about 42 mg to about 100 mg, about 50 mg to about 100 mg, about 60 mg to about 100 mg, about 70 mg to about 100 mg, about 80 mg to about 100 mg, about 90 mg to about 100 mg, about 18 mg to about 90 mg, about 26 mg to about 80 mg, about 34 mg to about 70 mg, about

[0118] 42 mg to about 60 mg, about 10 mg to about 26 mg, about 18 mg to about 34 mg, about

[0119] 26 mg to about 42 mg, about 34 mg to about 50 mg, about 42 mg to about 60 mg, about

[0120] 50 mg to about 70 mg, about 60 mg to about 80 mg. about 70 mg to about 90 mg, or about 80 mg to about 100 mg) of a binder provided herein. In some cases, a Atorney Docket No. 45049-0092W01 / 06870 pharmaceutical composition containing a binder provided herein can be formulated as a dosage form with a titer of the binder being from about 10 mg per kg body weight (mg / kg) to about 100 mg / kg (e.g., from about 10 mg / kg to about 90 mg / kg, about 10 mg / kg to about 80 mg / kg, about 10 mg / kg to about 70 mg / kg, about 10 mg / kg to about 60 mg / kg, about 10 mg / kg to about 50 mg / kg, about 10 mg / kg to about 42 mg / kg, about 10 mg / kg to about 34 mg / kg, about 10 mg / kg to about 26 mg / kg, about 10 mg / kg to about 18 mg / kg, about 18 mg / kg to about 100 mg / kg, about 26 mg / kg to about 100 mg / kg, about 34 mg / kg to about 100 mg / kg, about 42 mg / kg to about 100 mg / kg, about 50 mg / kg to about 100 mg / kg, about 60 mg / kg to about 100 mg / kg, about 70 mg / kg to about 100 mg / kg, about 80 mg / kg to about 100 mg / kg, about 90 mg / kg to about 100 mg / kg, about 18 mg / kg to about 90 mg / kg, about 26 mg / kg to about 80 mg / kg, about 34 mg / kg to about 70 mg / kg, about 42 mg / kg to about 60 mg / kg, about 10 mg / kg to about 26 mg / kg, about 18 mg / kg to about 34 mg / kg. about 26 mg / kg to about 42 mg / kg, about 34 mg / kg to about 50 mg / kg, about 42 mg / kg to about 60 mg / kg. about 50 mg / kg to about 70 mg / kg, about 60 mg / kg to about 80 mg / kg, about 70 mg / kg to about 90 mg / kg, or about 80 mg / kg to about 100 mg / kg). In some cases, when a pharmaceutical composition is formulated to include one or more nucleic acids (e g., vectors such as viral vectors) encoding at least part of a binder provided herein, any appropriate concentration of the nucleic acid can be used. For example, a pharmaceutical composition provided herein can be formulated to be a liquid that includes from about 10 mg / kg to about 100 mg / kg (e.g., from about 10 mg / kg to about 90 mg / kg, about 10 mg / kg to about 80 mg / kg, about 10 mg / kg to about 70 mg / kg, about 10 mg / kg to about 60 mg / kg, about 10 mg / kg to about 50 mg / kg, about 10 mg / kg to about 42 mg / kg, about 10 mg / kg to about 34 mg / kg. about 10 mg / kg to about 26 mg / kg, about 10 mg / kg to about 18 mg / kg, about 18 mg / kg to about 100 mg / kg, about 26 mg / kg to about 100 mg / kg, about 34 mg / kg to about 100 mg / kg, about 42 mg / kg to about 100 mg / kg, about 50 mg / kg to about 100 mg / kg. about 60 mg / kg to about 100 mg / kg, about 70 mg / kg to about 100 mg / kg. about 80 mg / kg to about 100 mg / kg. about 90 mg / kg to about 100 mg / kg, about 18 mg / kg to about 90 mg / kg, about 26 mg / kg to about 80 mg / kg, about 34 mg / kg to about 70 mg / kg, about 42 mg / kg to about 60 mg / kg, about 10 mg / kg to about 26 mg / kg, about 18 mg / kg to about 34 mg / kg, about 26 mg / kg to about 42 mg / kg, about 34 mg / kg to about 50 mg / kg, about 42 mg / kg to about 60 mg / kg, about 50 mg / kg to about 70 mg / kg, about 60 mg / kg to about 80 mg / kg, about 70 mg / kg to about 90 Atorney Docket No. 45049-0092W01 / 06870 mg / kg. or about 80 mg / kg to about 100 mg / kg) of a nucleic acid provided herein per mL. In another example, a pharmaceutical composition provided herein can be formulated to be a solid or semi-solid that includes from about 10 mg / kg to about 100 mg / kg (e.g., from about 10 mg / kg to about 90 mg / kg, about 10 mg / kg to about 80 mg / kg, about 10 mg / kg to about 70 mg / kg, about 10 mg / kg to about 60 mg / kg. about 10 mg / kg to about 50 mg / kg, about 10 mg / kg to about 42 mg / kg, about 10 mg / kg to about 34 mg / kg, about 10 mg / kg to about 26 mg / kg, about 10 mg / kg to about 18 mg / kg, about 18 mg / kg to about 100 mg / kg, about 26 mg / kg to about 100 mg / kg, about 34 mg / kg to about 100 mg / kg, about 42 mg / kg to about 100 mg / kg, about 50 mg / kg to about 100 mg / kg, about 60 mg / kg to about 100 mg / kg, about 70 mg / kg to about 100 mg / kg, about 80 mg / kg to about 100 mg / kg, about 90 mg / kg to about 100 mg / kg, about 18 mg / kg to about 90 mg / kg, about 26 mg / kg to about 80 mg / kg, about 34 mg / kg to about 70 mg / kg, about 42 mg / kg to about 60 mg / kg, about 10 mg / kg to about 26 mg / kg, about 18 mg / kg to about 34 mg / kg, about 26 mg / kg to about 42 mg / kg, about 34 mg / kg to about 50 mg / kg. about 42 mg / kg to about 60 mg / kg, about 50 mg / kg to about 70 mg / kg, about 60 mg / kg to about 80 mg / kg, about 70 mg / kg to about 90 mg / kg, or about 80 mg / kg to about 100 mg / kg) of a nucleic acid provided herein.

[0121] In some cases, a pharmaceutical composition designed to include one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, or host cell provided herein) can be formulated to include one or more agents capable of reducing aggregation of the binder when formulated. Examples of such agents that can be used as described herein include, without limitation, methionine, arginine, lysine, aspartic acid, glycine, glutamic acid, and combinations thereof. In some cases, one or more of these amino acids can be included within the formulation at a concentration from about 0.5 mM to about 145 mM (e.g., from about 1 mM to about 145 mM, from about 10 mM to about 145 mM. from about 100 mM to about 145 mM, from about 0.5 mM to about 125 mM, from about 0.5 mM to about 100 mM, from about 0.5 mM to about 75 mM, or from about 10 mM to about 100 mM).

[0122] A pharmaceutical composition provided herein can be in any appropriate form. For example, a pharmaceutical composition provided herein can designed to be a liquid, a semi-solid, or a solid. In some cases, a pharmaceutical composition provided herein can Atorney Docket No. 45049-0092W01 / 06870 be a liquid solution (e.g., an injectable and / or infusible solution), a dispersion, a suspension, a tablet, a pill, a powder, a microemulsion, a liposome, or a suppository. In some cases, a pharmaceutical composition provided herein can be lyophilized. In some cases, a pharmaceutical composition provided herein (e.g., a pharmaceutical composition that includes one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, or host cell provided herein)) can be formulated with a carrier or coating designed to protect against rapid release. For example, a pharmaceutical composition provided herein can be formulated as a controlled release formulation or as a regulated release formulation as described elsewhere (U.S. Patent Application Publication Nos. 2019 / 0241667; 2019 / 0233522; and 2019 / 0233498).

[0123] This document also provides methods for administering a composition (e.g., a pharmaceutical composition provided herein) containing one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, or host cell provided herein) to a mammal (e.g., a human). For example, a composition (e.g., a pharmaceutical composition provided herein) containing one or more binders provided herein (or a nucleic acid, vector, and / or host cell provided herein) can be administered to a mammal (e.g., a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) to treat that mammal.

[0124] In some cases, a composition (e.g.. a pharmaceutical composition provided herein) containing one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, and / or host cell provided herein) can be administered to a mammal (e.g., a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g.. a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) and in need of treatment thereof to reduce the level of PLA2G7 polypeptide activity in the mammal. In some cases, a composition (e.g., a pharmaceutical composition provided herein) containing one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, and / or host cell provided herein) Atorney Docket No. 45049-0092W01 / 06870 can be effective to reduce the level PLA2G7 polypeptide activity in a mammal having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) by, for example, 10, 20, 30, 40, 50, 60, 70, 80. 90, 95, or more percent.

[0125] In some cases, a composition (e g., a pharmaceutical composition provided herein) containing one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, and / or host cell provided herein) can be administered to a mammal (e.g., a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity7(e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity7) and in need of treatment thereof, to reduce or eliminate hydrolyzation of an oxidized low-density7lipoprotein (oxLDL) by a PLA2G7 polypeptide in the mammal. In some cases, a composition (e.g., a pharmaceutical composition provided herein) containing one or more binders (e g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, and / or host cell provided herein) can be effective to reduce hydrolyzation an oxLDL by a PLA2G7 polypeptide in a mammal having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.

[0126] In some cases, a composition (e.g.. a pharmaceutical composition provided herein) containing one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, and / or host cell provided herein) can be administered to a mammal (e.g., a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g.. a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) and in need of treatment thereof, to reduce or eliminate the amount of bioactive lysophosphatidylcholine (lysoPC) and / or oxideized non-esterfied fatty acids (oxNEFAs) in the mammal. In some cases, a composition (e.g., a pharmaceutical composition provided herein) containing one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more Atorney Docket No. 45049-0092W01 / 06870 antibodies) provided herein (or a nucleic acid, vector, and / or host cell provided herein) can be effective to reduce the amount of bioactive lysophosphatidylcholine (lysoPC) and / or oxideized non-esterfied fatty7acids (oxNEFAs) in a mammal having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.

[0127] In some cases, a composition (e.g., a pharmaceutical composition provided herein) containing one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, and / or host cell provided herein) can be administered to a mammal (e.g., a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity7(e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity ) and in need of treatment thereof, to reduce or eliminate inflammation of blood vessels in the mammal. In some cases, a composition (e.g., a pharmaceutical composition provided herein) containing one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, and / or host cell provided herein) can be effective to reduce or eliminate inflammation of blood vessels in a mammal having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity ) by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.

[0128] In some cases, a composition (e.g.. a pharmaceutical composition provided herein) containing one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies ) provided herein (or a nucleic acid, vector, and / or host cell provided herein) can be administered to a mammal (e.g., a human) having cancer (e.g., a cancer characterized by an increased level of PLA2G7 polypeptide activity) and in need of treatment thereof, to reduce or eliminate tumor cell migration, invasion, and / or metastasis in the mammal. In some cases, a composition (e.g., a pharmaceutical composition provided herein) containing one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, and / or host cell provided herein) Atorney Docket No. 45049-0092W01 / 06870 can be effective to reduce tumor cell migration, invasion, and / or metastasis in a mammal having cancer (e.g., a cancer characterized by an increased level of PLA2G7 polypeptide activity ) by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.

[0129] In some cases, a composition (e.g., a pharmaceutical composition provided herein) containing one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, and / or host cell provided herein) can be administered to a mammal (e.g., a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g.. a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) to improve survival of the mammal. For example, a mammal having a condition or disease associated with an increased level of PLA2G7 polypeptide activity7(e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) and in need of treatment thereof can be administered one or more binders provided herein (or a nucleic acid, vector, and / or host cell provided herein) to improve the survival of the mammal by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In another example, a mammal having a condition or disease associated with an increased level of PLA2G7 polypeptide activity7(e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) and in need of treatment thereof can be administered one or more binders provided herein (or a nucleic acid, vector, and / or host cell provided herein) to improve the survival of a the mammal by, for example, at least 6 months (e.g., about 6 months, about 8 months, about 10 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 4 years, about 5 years, or more).

[0130] Any appropriate mammal having a condition or disease associated with an increased level of PLA2G7 polypeptide activity7(e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 poly peptide activity) can be treated as described herein (e.g., by administering a composition (e.g., a pharmaceutical composition provided herein) containing one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, and / or host cell provided herein)). Examples of mammals that can have a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by Atorney Docket No. 45049-0092W01 / 06870 an increased level of PLA2G7 polypeptide activity) and can be treated as described herein include, without limitation, humans, non-human primates (e.g., monkeys), horses, bovine species, porcine species, dogs, cats, mice, and rats. In some cases, a human having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) can be treated by administering one or more binders provided herein (or a nucleic acid, vector, and / or host cell provided herein) to the human.

[0131] Any ty pe of condition or disease associated with an increased level of PLA2G7 polypeptide activity can be treated using a composition (e.g., a pharmaceutical composition provided herein) containing one or more binders (e.g., one or more antibodydomains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, or host cell provided herein). For example, a mammal having a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity can be treated by administering a composition (e.g., a pharmaceutical composition) containing one or more binders provided herein to that mammal. In some cases, a condition or disease associated with an increased level of PLA2G7 polypeptide activity- that can be treated as described herein can be a cancer. Examples of cancers that can be associated with an increased level of PLA2G7 polypeptide activity and that can be treated as described herein include, without limitation, colorectal cancers, colon cancers, gastric cancers, gastrointestinal cancers, and pancreatic cancers. In some cases, a condition or disease associated with an increased level of PLA2G7 polypeptide activity that can be treated as described herein can be a cardiovascular disease. Examples of cardiovascular diseases that can be associated with an increased level of PLA2G7 polypeptide activity and that can be treated as described herein include, without limitation, atherosclerosis, coronary- heart disease, and ischemic stroke.

[0132] Any appropriate method can be used to administer a composition (e.g., a pharmaceutical composition) provided herein to a mammal (e.g., a human). For example, a composition provided herein (e.g., a pharmaceutical composition containing one or more binders provided herein such as one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies provided herein) can be administered to a mammal (e.g., a human) intravenously (e.g., via an intravenous injection or infusion), Atorney Docket No. 45049-0092W01 / 06870 subcutaneously (e.g., via a subcutaneous injection), intraperitoneally (e.g., via an intraperitoneal injection), orally, via inhalation, or intramuscularly (e.g., via intramuscular injection). In some cases, the route and / or mode of administration of a composition (e.g., a pharmaceutical composition provided herein) can be adjusted for the mammal being treated.

[0133] In some cases, an effective amount (e g., an effective dose) of a composition containing one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, or host cell provided herein) (e.g., a pharmaceutical composition provided herein) can be an amount that reduces the level of PLA2G7 polypeptide activity within a mammal having a condition or disease associated with an increased level of PLA2G7 polypeptide activity7(e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) without producing significant toxicity to the mammal. For example, an effective amount of a binder provided herein can be from about 10 mg / kg to about 100 mg / kg (e.g., from about 10 mg / kg to about 90 mg / kg, about 10 mg / kg to about 80 mg / kg, about 10 mg / kg to about 70 mg / kg, about 10 mg / kg to about 60 mg / kg, about 10 mg / kg to about 50 mg / kg, about 10 mg / kg to about 42 mg / kg, about 10 mg / kg to about 34 mg / kg. about 10 mg / kg to about 26 mg / kg, about 10 mg / kg to about 18 mg / kg, about 18 mg / kg to about 100 mg / kg, about 26 mg / kg to about 100 mg / kg, about 34 mg / kg to about 100 mg / kg, about 42 mg / kg to about 100 mg / kg, about 50 mg / kg to about 100 mg / kg, about 60 mg / kg to about 100 mg / kg, about 70 mg / kg to about 100 mg / kg, about 80 mg / kg to about 100 mg / kg, about 90 mg / kg to about 100 mg / kg, about 18 mg / kg to about 90 mg / kg. about 26 mg / kg to about 80 mg / kg, about 34 mg / kg to about 70 mg / kg, about 42 mg / kg to about 60 mg / kg, about 10 mg / kg to about 26 mg / kg, about 18 mg / kg to about 34 mg / kg, about 26 mg / kg to about 42 mg / kg, about 34 mg / kg to about 50 mg / kg, about 42 mg / kg to about 60 mg / kg, about 50 mg / kg to about 70 mg / kg, about 60 mg / kg to about 80 mg / kg. about 70 mg / kg to about 90 mg / kg, or about 80 mg / kg to about 100 mg / kg). The effective amount can remain constant or can be adjusted as a sliding scale or variable dose depending on the mammal’s response to treatment. Various factors can influence the actual effective amount used for a particular application. For example, the severity of a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by Atorney Docket No. 45049-0092W01 / 06870 an increased level of PLA2G7 polypeptide activity) when treating a mammal having a condition or disease associated with an increased level of PLA2G7 polypeptide activity, the route of administration, the age and general health condition of the mammal, excipient usage, the possibility of co-usage with other therapeutic or prophylactic treatments such as use of other agents (e.g., checkpoint inhibitors), and the judgment of the treating physician may require an increase or decrease in the actual effective amount of a composition provided herein (e.g., a pharmaceutical composition containing one or more binders provided herein) that is administered.

[0134] In some cases, an effective frequency of administration of a composition containing one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, or host cell provided herein) (e.g., a pharmaceutical composition provided herein) can be a frequency that reduces the level of PLA2G7 polypeptide activity within a mammal having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) without producing significant toxicity to the mammal. For example, an effective frequency of administration of a pharmaceutical composition provided herein such as a pharmaceutical composition containing one or more binders provided herein can be from about twice daily to about once a year (e.g., from about twice daily to about once a month, from about twice daily to about once a week, from about once daily to about once a month, or from one once daily to about once a week). In some cases, the frequency of administration of a pharmaceutical composition provided herein such as a pharmaceutical composition containing one or more binders provided herein can be daily. The frequency of administration of a pharmaceutical composition provided herein such as a pharmaceutical composition containing one or more binders provided herein can remain constant or can be variable during the duration of treatment. Various factors can influence the actual effective frequency used for a particular application. For example, the severity of the condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity), the route of administration, the age and general health condition of the mammal, excipient usage, the possibility of co-usage with other therapeutic or prophylactic treatments such as use of Atorney Docket No. 45049-0092W01 / 06870 other agents (e.g., checkpoint inhibitors), and the judgment of the treating physician may require an increase or decrease in the actual effective frequency of administration of a composition provided herein (e.g., a pharmaceutical composition containing one or more binders provided herein).

[0135] In some cases, an effective duration of administration of a composition containing one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, or host cell provided herein) (e.g., a pharmaceutical composition provided herein) can be a duration that reduces the level of PLA2G7 polypeptide activity within a mammal having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity7) without producing significant toxicity to the mammal. For example, an effective duration of administration of a pharmaceutical composition provided herein such as a pharmaceutical composition containing one or more binders provided herein can vary from a single time point of administration to several weeks to several months (e g., 4 to 12 weeks). Multiple factors can influence the actual effective duration used for a particular application. For example, the severity of the condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity ), the route of administration, the age and general health condition of the mammal, excipient usage, the possibility of co-usage with other therapeutic or prophylactic treatments such as use of other agents (e.g., checkpoint inhibitors), and the judgment of the treating physician may require an increase or decrease in the actual effective duration of administration of a composition provided herein (e.g., a pharmaceutical composition containing one or more binders provided herein).

[0136] In some cases, one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, or host cell provided herein can be administered to a mammal (e.g., a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) as the sole active agent(s) to treat the condition. Atorney Docket No. 45049-0092W01 / 06870

[0137] In some cases, methods for treating a mammal (e.g., a human) as described herein (e.g., by administering a composition containing one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, or host cell provided herein)) also can include administering to the mammal one or more (e.g., one, two. three, or more) additional agents used to treat a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity). For example, a combination therapy used to treat a mammal (e.g.. a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) can include administering to the mammal one or more binders provided herein (or a nucleic acid, vector, or host cell provided herein) and administering to the mammal one or more (e.g., one, two. three, or more) additional inhibitors of PLA2G7 activity. Examples of additional inhibitors of PLA2G7 activity that can be administered to a mammal (e g., a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) to treat the mammal include, without limitation, darapladib, varepladib, rilapladib, and GSK2647544. In some cases, a combination therapy used to treat a mammal (e.g., a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer characterized by an increased level of PLA2G7 polypeptide activity) can include administering to the mammal one or more binders provided herein (or a nucleic acid, vector, or host cell provided herein) and administering to the mammal one or more (e.g., one, two, three, or more) agents used to treat cancer. For example, an anti-cancer agent that can be administered to a mammal can be a chemotherapeutic agent. For example, an anti-cancer agent that can be administered to a mammal can be a cytotoxic agent. In some cases, an anti-cancer agent that can be administered to a mammal can be an immune- checkpoint inhibitor (e.g., anti-PD-1 antibodies, PD-1 inhibitors, anti-PD-Ll antibodies, PD-L1 inhibitors and anti-CTLA-4 antibodies). Examples of anti-cancer agents that can be administered to a mammal (e.g., a human) having a cancer characterized by an increased level of PLA2G7 polypeptide activity to treat the mammal include, without Atorney Docket No. 45049-0092W01 / 06870 limitation, enzalutamide, imanitib, gefitinib, erlotini, sunitinib, lapatinib, nilotinib, sorafenib, temsirolimus, everolimus, pazopanib, crizotinib, ruxolitinib, axitinib, bosutinib, cabozantinib, ponatinib, regorafenib, ibrutinib, trametinib, perifosine, bortezomib, carfilzomib, batimastat, ganetespib, obatoclax, navitoclax, taxol, paclitaxel, bevacizumab, cemiplimab, nivolumab, pembrolizumab, JTX-4014, spartalizumab, camrelizumab. sintilimab, tislelizumab, toripalimab, dostarlimab, INCMGA00012, AMP -224, AMP-514, avelumab, durvalumab, atezolizumab, KN035, CK-301, AUNP12, CA-170, BMS- 986189, ipilimumab and any combinations thereof. In some cases, a combination therapy used to treat a mammal (e.g.. a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) can include administering to the mammal one or more binders provided herein (or a nucleic acid, vector, or host cell provided herein) and administering to the mammal one or more (e.g., one, two. three, or more) agents used to treat cardiovascular disease. Examples of agents used to treat cardiovascular disease that can be administered to a mammal (e.g., a human) having a cardiovascular disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cardiovascular disease (e.g., atherosclerosis)) to treat the mammal include, without limitation, atorvastatin, simvastatin, and fluvastatin.

[0138] In cases where one or more binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, or host cell provided herein) are used in combination wi th one or more additional agents, the one or more additional agents can be administered at the same time (e.g., in a single composition containing one or more binders provided herein (or a nucleic acid, vector, or host cell provided herein) and containing the one or more additional agents) or independently. For example, a composition including one or more binders provided herein (or a nucleic acid, vector, or host cell provided herein) can be administered first, and the one or more additional agents administered second, or vice versa.

[0139] In some cases, a combination therapy used to treat a mammal (e.g., a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity) can include administering to the mammal one or more Atorney Docket No. 45049-0092W01 / 06870 binders (e.g., one or more antibody domains, one or more antigen binding fragments, and / or one or more antibodies) provided herein (or a nucleic acid, vector, or host cell provided herein) (e.g., a pharmaceutical composition provided herein), and can include performing one or more (e g., one, two, three, or more) therapies used to treat the condition. In some cases, a combination therapy used to treat a mammal (e.g., a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer characterized by an increased level of PLA2G7 polypeptide activity) can include administering to the mammal one or more binders provided herein (or a nucleic acid, vector, or host cell provided herein) and subjecting the mammal to one or more (e.g., one, two, three, or more) therapies used to treat cancer. Examples of additional therapies that can be used to treat a mammal (e.g., a human) having a cancer associated with an increased level of PLA2G7 polypeptide activity include, without limitation radiation therapies and / or surgeries (e.g., tumor resection surgeries). In some cases, a combination therapy used to treat a mammal (e.g., a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity7(e.g., a cardiovascular characterized by an increased level of PLA2G7 polypeptide activity) can include administering to the mammal one or more binders provided herein (or a nucleic acid, vector, or host cell provided herein) and subjecting the mammal to one or more (e.g., one, two, three, or more) therapies used to treat cardiovascular disease. Examples of additional therapies that can be used to treat a mammal (e.g., a human) having a cardiovascular disease associated with an increased level of PLA2G7 polypeptide activity7include, without limitation, surgeries (e.g.. coronary bypass surgery, angioplasty, and / or endarterectomy) and / or fibrinolytic therapy. In cases where one or more binders provided herein (or a nucleic acid, vector, or host cell provided herein) and containing the one or more additional agents) are used in combination with one or more therapies used to treat a mammal (e.g., a human) having a condition or disease associated with an increased level of PLA2G7 polypeptide activity (e.g., a cancer or a cardiovascular disease characterized by an increased level of PLA2G7 polypeptide activity), the one or more additional therapies can be performed at the same time or independently of the administration of the one or more binders provided herein (or a nucleic acid, vector, or host cell provided herein). For example, one or more binders provided herein (or a nucleic acid, vector, or host cell provided herein) and containing the one or more additional agents) can be Atorney Docket No. 45049-0092W01 / 06870 administered before, during, and / or after the one or more additional therapies are performed.

[0140] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein can be used to detect the presence or absence of a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) in vitro, in situ, or m vivo. For example, a binder provided herein can be designed to include a label (e g., a covalently attached radioactive, enzy matic, colorimetric, or fluorescent label). In some cases, a labelled binder can be used to detect the presence or absence of a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) within a biological sample in vitro. Examples of biological samples that can be assessed using a binder provided herein include, without limitation, serum samples, plasma samples, tissue samples, biopsy samples, cell line samples, and tissue culture samples. In some cases, a biological sample that can be assessed as described herein can include mammalian body tissues and / or cells such as leukocytes, ovary tissue or cells, prostate tissue or cells, heart tissue or cells, placenta tissue or cells, pancreas tissue or cells, liver tissue or cells, spleen tissue or cells, lung tissue or cells, breast tissue or cells, head and neck tissue or cells, endometrium tissue or cells, colon tissue or cells, colorectal tissue or cells, cervix tissue or cells, stomach tissue or cells, or umbilical tissue or cells that may express a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide). In some cases, a binder provided herein can be immobilized, e.g., on a support, and retention of a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) from a biological sample on the support can be detected, and / or vice versa. In some cases, a binder provided herein can be used in applications such as fluorescence polarization, microscopy, ELISA, centrifugation, chromatography, and / or cell sorting (e.g., fluorescence activated cell sorting).

[0141] In some cases, a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein containing a label (e.g., a covalently attached radioactive label) can be used to detect the presence or absence of a PLA2G7 polypeptide (e.g., a human PLA2G7 polypeptide) in vivo (e.g., within a mammal such as a human). For example, a labelled binder can be used in an in vivo imaging technique to detect the presence or absence of the PLA2G7 polypeptide w ithin a mammal (e.g., a human). For example, a binder provided herein that is labelled (e.g., covalently labelled) with a radiolabel or an MR1 detectable label can be administered to a mammal (e.g., a human), Atorney Docket No. 45049-0092W01 / 06870 and that mammal can be assessed using a means for detecting the detectable label. In some cases, a mammal can be scanned to evaluate the location(s) of a labelled binder provided herein within the mammal. For example, the mammal can be imaged using NMR or other tomographic techniques. Examples of labels that can be attached (e.g., covalently or non-covalently attached) to a binder (e.g., an antibody domain, an antigen binding fragment, or an antibody) provided herein include, without limitation, radiolabels such as131I,mIn,123I,99mTc,32P,33P,1251,3H,14C, and188Rh, fluorescent labels such as fluorescein and rhodamine, nuclear magnetic resonance active labels, positron emitting isotopes detectable by a positron emission tomography (“PET”) scanner, chemiluminescers such as luciferin, and enzymatic markers such as a peroxidase or a phosphatase. In some cases, short-range radiation emitters such as isotopes detectable by short-range detector probes can be used.

[0142] The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.

[0143] EXAMPLES

[0144] Example 1: Generating fully human Fab and VH antibodies binding to PLA2G7

[0145] This Example describes the design and generation of antibodies that can target (e.g., target and bind) a PLA2G7 polypeptide.

[0146] Methods

[0147] Preparation of recombinant human PLA2G7

[0148] A human PLA2G7 polypeptide (residues 22-441) was synthesized in GenScript, and then cloned into pCATDS-Fc plasmid viaNotl and Asci restriction enzyme sites. The constructed plasmid DNA was amplified from One Shot™ TOP 10F’ E. coli strain in the presence of 100 pg / mL ampicillin and prepared by Midi DNA-prep kit (Macherey -Nagel, 740410) for the transient transfection. Purified DNA was complexed with PEI-Max " (Polysciences, 24765-1) and supplied to culture of the FreeStyle™ human embryonic kidney cell line (Gibco, Al 4527). Six days post-transfection, PLA2G7-Fc was purified by affinity chromatography with protein A resin (Captiva, NC0997253). Elution of bound proteins to protein A was done by adding 100 mM glycine buffer pH 3.0. Buffer was then changed to phospho-buffered saline pH 7.4 (PBS) using a PD-10 desalting column (GE, Atorney Docket No. 45049-0092W01 / 06870

[0149] 45-000-148). Protein purity was estimated in either SDS-PAGE or size exclusion chromatography (SEC). The concentration of protein was determined by NanoDrop spectrophotometer 2000C (Thermo, ND2000C).

[0150] Fab and VH libraries panning against PLA2G7

[0151] Recombinant PLA2G7-Fc was biotinylated using EZ-Link™ Sulfo-NHS-SS- Biotin (Thermo, A39258). Phage libraries were pre-blocked with 3% nonfat dry milk (Bio-Rad, 1706404) in PBS (w / v) for 1 hour at 25°C. Blocked phages were incubated with 100 nM biotinylated PLA2G7-Fc in the presence of 10-fold excess anti-HER2 IgG pertuzumab (Selleckchem, A2008) for excluding human IgGl Fc binder for 1 hour at 25°C. Bound phages were separated by streptavidin-coated magnetic beads (Invitrogen, 11-205-D) and washed 10 times with 0. 1% Tween® 20 (v / v) in PBS pH 7.4. Elution of bound phages was conducted by adding 0. 1 M glycine pH 2.5. For second and third rounds of panning, reduced concentration of biotinylated antigens ( 10 nM and 1 nM, respectively) and an increased level of competitor ratio of anti-HER2 IgG were applied. After 3 rounds of panning, the binding of 192 individual clones was analyzed in ELISA, and then selected clones were sequenced after plasmid rescue (Beck et al., Cancer Lett, 525:97-107 (2022)).

[0152] Purification of Fab, VH and IgG

[0153] The plasmid of positive clones was transformed into HB2151 E. coli competent cells, and colonies were selected in ampicillin containing 2x TY plate for overnight incubation at 37°C. The next day, a colony was inoculated in ampicillin containing 2x TY media and cultured in a 37°C shaking incubator. Isopropyl f>-D- 1 -thiogal actopyranoside (IPTG) was added to the culture at an ODeoo of 0.4-0.6. The culture was relocated to a shaking incubator set at 30°C, 200 rpm and incubated overnight. The next day, E. coli cells were harvested, resuspended in 1 / 10 volume of 0.5 mg / mL polymyxin B in PBS pH 7.4, and incubated on ice for an hour. Supernatant was collected by centrifugation at 12,000xg for 10 minutes and loaded into pre-packed Ni-NTA resin. The bound Fab or VH were eluted by adding 300 mM imidazole in PBS pH 7.4. The buffer was then changed to PBS pH 7.4 using a PD-10 desalting column. For IgG purification, the 1H8 VH and 1H8 VL were cloned into pCATDS-HC and pCATDS-LC plasmid via Notl / Apal and Notl / BsiWI restriction enzyme sites. The 1A9 VH was cloned into pCATDS-Fc plasmid Atorney Docket No. 45049-0092W01 / 06870 via Notl and Asci restriction enzyme sites. The plasmid DNA was transfected to Expi293™ cells and expressed for 6 days post-transfection. Expressed IgG was purified by affinity chromatography with protein A resin. IgG was eluted by adding 100 mM glycine buffer pH 3.0 and buffer was changed to PBS pH 7.4 by PD-10 desalting column.

[0154] Enzyme-linked immunosorbent assay (ELISA)

[0155] PLA2G7 proteins were coated on a 96 well plate (Coming, 3690) at 4 pg / mL in PBS overnight at 4°C. The next day, plates were blocked with 3% nonfat dry milk in PBS for 2 hours at room temperature. Fab, VH or IgG were incubated for 2 hours at room temperature. Anti-FLAG mouse antibody (M2 clone)-HRP conjugated (Sigma, A8592, 1:2000 dilution) or anti -human kappa goat antibody -HRP conjugated (Invitrogen, A18853, 1 :3000 dilution) was added to detect binding of either Fab / VH or IgG. 3, 3', 5,5'- Tetramethylbenzidine (TMB) (Thermo, PI34028) was added as a substrate and the enzymatic reaction was stopped by adding 2N sulfonic acid. Absorbance was read at 450 nm on an iMark™ microplate reader (Bio-Rad).

[0156] Biolayer Interferometry (BLI)

[0157] The affinities of Fab, VH, IgG, or VH-Fc were analyzed using the biolayer interferometry BLItz (ForteBio). Biotinylated- PLA2G7-Fc was mounted on the SA Biosensor (Satorius, 18-5019) for two min and equilibrated with PBS (pH 7.4) to establish baselines. Anti-PLA2G7 antibodies (125, 250, or 500 nM) w ere used for association for two minutes and then the antibody was allowed to dissociate in PBS for two minutes. Background was established by running PBS instead of antibody in the association process, and the background curve was subtracted from the antibody sensorgram. The kon and koff were derived from sensorgram fittings and used for KD calculation.

[0158] Cell lines

[0159] U937, HCT116, and HT29 cells were purchased from ATCC. U937 and HT29 cells were maintained in RPMI medium (ATCC) supplemented with 10% (v / v) FBS (Gibco) and 1% (v / v) penicillin-streptomycin (P / S, Gibco). HCT116 cells were maintained in DMEM (ATCC) supplemented with 10% (v / v) FBS and 1 % (v / v) P / S. Primary NK cells were cultured in X-Vivo™ 10 medium (Lonza, 04-380Q), 5% (v / v) human AB serum (Coming), and human M-CSF (25 ng / ml, Biolegend). Atorney Docket No. 45049-0092W01 / 06870

[0160] PLA2G7 activity assay

[0161] The blocking ability of PLA2G7 mAbs against PLA2G7 enzymatic activity was determined by using a platelet-activating factor (PAF) acetylhydrolase assay kit (Abeam, Abl33088). The reaction buffer (0.1 M Tris, pH 7.2), 2-thio PAF and dose dependent PLA2G7 mAbs were added into 96 well plate. The mixture was incubated for 20 minutes at room temperature. The 5,5'-dithiobis-(2-nitrobenzoic acid) (DNTB) was added for the developing reaction and incubated for 1 minute at room temperature. Absorbance was read at 415 nm on an iMark™ microplate reader (Bio-Rad).

[0162] Cell migration assay

[0163] The cells were plated on the upper chamber of a trans well plate (Coming, 3422) in 0% FBS media. The medium with 1% FBS was added to the bottom chamber. The recombinant PLA2G7 and PLA2G7 mAbs were added to the upper chamber. The media was discarded and gently washed with PBS pH 7.4. The cells were stained and fixed by 0.5% crystal violet in 20% MeOH for 30 minutes at room temperature. The stained cells were washed by distilled water, dried, and dissolved by 10% acetic acid solution. Absorbance was read at 590 nm.

[0164] Results

[0165] Identification of two PLA2G7 antibodies with non-overlapping epitopes and engineering of a bispecific antibody based thereon

[0166] To identify PLA2G7 antibodies, a fusion protein comprising PLA2G7 (Phe22- Asn441) linked to the N-terminus of human IgGl Fc with a polypeptide linker (residues; Gly -Ala-Pro) was constructed. First, the quality of this recombinant protein was validated by demonstrating its binding to a commercial monoclonal human PLA2G7-specific mouse antibody, 2A1B6 (Figure 1A). After three rounds of panning using phage- displayed Fab library and VH library, 1H8 Fab (EC5o = 17 nM and KD = 24.5 nM) and 1A9 VH (ECso = 5.8 nM and KD = 13.7 nM) clones were isolated, both exhibiting high affinity to the recombinant PLA2G7 antigen in ELISA and BLI (Figures IB and IE). Fab 1H8 was then reformatted into the IgG. The bivalent IgG 1H8 exhibited higher binding potency than Fab 1H8. as tested by ELISA (ECso = 2.0 nM vs. 17 nM). As 1A9 VH did not competitively bind to PLA2G7 with 1H8 IgG (Figure 1C), a bispecific antibody was engineered by fusing 1 A9 VH to the C-terminus of 1H8 IgG heavy chain (HC) with a Atorney Docket No. 45049-0092W01 / 06870

[0167] (GiSty polypeptide linker, termed 1H8 lgG-lA9. This bispecific antibody showed enhanced affinity' (EC50 = 0.05 nM) against PLA2G7 compared to the individual antibody (Figures IB and IE, Table 15). Furthermore, it was demonstrated that the epitopes of 1H8 IgG and 1A9 VH did not overlap with that of the PLA2G7 inhibitor, darapladib, which binds to the catalytic triad of PLA2G7 (Figure ID). In summary, 1H8 and 1A9 specifically bind to PLA2G7 at distinct epitopes, both of which are separate from the catalytic triad.

[0168] Table 15. Affinity of anti-PLA2G7 binders against PLA2G7

[0169] Mono- and bi-specific antibodies inhibited the PLA2G7 enzymatic activity and blocked PLA2G7- mediated tumor cell migration

[0170] PLA2G7 hydrolyzes oxidized phospholipids in low-density lipoprotein (LDL) particles. PLA2G7 enzymatic activity is associated with risk of coronary heart disease and ischemic stroke (Oei et al., Circulation, 111 :570-75 (2005)). PLA2G7 activity has also been linked to enhanced tumor cell migration and invasion (Vainio et al., Oncotarget, 2: 1176-90 (2011)). A PAF acetylhydrolase assay was conducted to assess the blocking activity of PLA2G7 mAbs against PLA2G7 enzy matic function. 1H8 IgG effectively blocked PLA2G7 enzymatic activity despite not competing with darapladib for binding to PLA2G7 (Figures ID and 2A), while 1 A9 VH-Fc showed no inhibitory effect. Moreover, the bispecific antibody 1H8 IgG-1 A9 (IC50 = 2.2 nM) exhibited slightly enhanced blocking activity compared to 1H8 IgG alone (IC50 = 4.8 nM) (Figure 2A). Given that PLA2G7 has been reported to increase cancer cell migration, and PLA2G7 knockdown by siRNA led to reduced cancer cell migration (Low et al.. Oncotarget, 5:55473-90 (2016)), the inhibition of PLA2G7 -mediated cell migration by PLA2G7 antibodies was evaluated in both HCT116 and HT29 cells. Both 1H8 IgG and the bispecific antibody, 1H8 IgG-lA9 effectively inhibited cell migration, whereas 1A9 VH- Atorney Docket No. 45049-0092W01 / 06870

[0171] Fc did not (Figures 2B-2D). The bispecific antibody 1H8 IgG-1 A9 exhibited higher blocking activity than 1H8 IgG, consistent with of its higher binding affinity to PLA2G7 and enhanced enzy matic inhibition (Figures IB and 2A).

[0172] Taken together, the PLA2G7 mAbs (1H8 IgG and 1H8 IgG-1 A9) specifically bound to PLA2G7 and inhibited its enzymatic activity. Although 1A9 VH alone did not exhibit blocking activity, its incorporation into the bispecific antibody enhanced both the affinity' and activity of 1H8 IgG.

[0173] Example 2: Exemplary PLA2G7 Polypeptides

[0174] This Example provides an amino acid sequence of a human PLA2G7 polypeptide (SEQ ID NO 33).

[0175] MVPPKLHVLFCLCGCLAVVYPFDWQYINPVAHMKSSAWVNKIQVLMAAASFGQ TKIPRGNGPYSVGCTDLMFDHTNKGTFLRLYYPSQDNDRLDTLWIPNKEYFWGL SKFLGTHWLMGNILRLLFGSMTTPANWNSPLRPGEKYPLVVFSHGLGAFRTLYS AIGIDLASHGFIVAAVEHRDRSASATYYFKDQSAAEIGDKSWLYLRTLKQEEETHI RNEQVRQRAKECSQALSL1LDIDHGKPVKNALDLKFDMEQLKDS1DREK1AVIGH SFGGATVIQTLSEDQRFRCGIALDAWMFPLGDEVYSRIPQPLFFINSEYFQYPANII KMKKCYSPDKERKMITIRGSVHQNFADFTFATGKIIGHMLKLKGDIDSNV AIDES NKASLAFLQKHLGLHKDFDQWDCLIEGDDENLIPGTNINTTNQHIMLQNSSGIEK YN (SEQ ID NO:33)

[0176] Example 3: Exemplary PLA2G7 -Binding Molecules

[0177] This Example provides the amino acid sequences of exemplary binders (e.g., sdAbs and Fabs) having the ability to bind a PLA2G7 polypeptide. The |CDRs| and framework sequences of each also are provided and delineated.

[0178] Anti-PLA2G7 clone #1 (also referred to as 1A9)

[0179] VH domain: Atorney Docket No. 45049-0092W01 / 06870

[0180] Framework Region 1 of VH domain:

[0181] QVQLQESGGGLVQPGGSLRLSCAAS (SEQ ID NO:4)

[0182] CDR1 of VH domain:

[0183] GFTFSSYA (SEQ ID NO: 1)

[0184] Framework Region 2 of VH domain:

[0185] MGWFRQAPGKEREWVAA (SEQ ID NO: 5)

[0186] CDR2 of VH domain:

[0187] ISGGGTT (SEQ ID NO:2)

[0188] Framework Region 3 of VH domain:

[0189] YYADSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYC (SEQ ID NO: 6)

[0190] CDR3 of VH domain:

[0191] ATGRQLKVYNWFDP (SEQ ID NO: 3)

[0192] Framework Region 4 of VH domain:

[0193] WGQGTLVTVSS (SEQ ID NO:7)

[0194] Anti-PLA2G7 clone #2 (also referred to as 1G4)

[0195] VH domain:

[0196] Framework Region 1 of VH domain:

[0197] QVQLQESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 12)

[0198] CDR1 of VH domain:

[0199] GFTFSSYA (SEQ ID NO:9)

[0200] Framework Region 2 of VH domain:

[0201] MGWFRQAPGKEREWVAA (SEQ ID NO: 13) Atorney Docket No. 45049-0092W01 / 06870

[0202] CDR2 of VH domain:

[0203] ISGGGTT (SEQ ID NO: 10)

[0204] Framework Region 3 of VH domain:

[0205] YYADSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYC (SEQ ID NO: 14)

[0206] CDR3 of VH domain:

[0207] VTGYLWWDHSWDAFDI (SEQ ID NO: 11)

[0208] Framework Region 4 of VH domain:

[0209] WGQGTMVTVSS (SEQ ID NO:15)

[0210] Anti-PLA2G7 clone #3 (also referred to as 1H8) F ab VH domain

[0211] VH domain:

[0212] Framework Region 1 of VH domain:

[0213] QVQLVESGGGLVKPGGSLRLSCAAS (SEQ ID NO:20)

[0214] CDR1 of VH domain:

[0215] GFTFSDYY (SEQ ID NO: 17)

[0216] Framework Region 2 of VH domain:

[0217] MSWIRQAPGKGLEWVSY (SEQ ID NO:21)

[0218] CDR2 of VH domain:

[0219] ISSSGSTI (SEQ ID NO: 18)

[0220] Framework Region 3 of VH domain:

[0221] YYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAMYYC (SEQ ID NO:22)

[0222] CDR3 of VH domain:

[0223] ARDRKFRFGGYYYGMDV (SEQ ID NO: 19) Atorney Docket No. 45049-0092W01 / 06870

[0224] Framework Region 4 of VH domain:

[0225] WGQGTTVTVSS (SEQ ID NO:23)

[0226] Anti-PLA2G7 clone #3 (also referred to as 1H8) Fab VL domain

[0227] VL domain:

[0228] DIQMTQSPSSLSASVGDRVTITCRAS|QSISSY|LNWYQQKPGKAPKLLIY|AAS|S LQSGVPSRFSGSGSGTDFTLTISSLQPEDAATYYC|MQGTHWPWT|FGQGTKVEI K (SEQ ID NO: 32)

[0229] Framework Region 1 of VL domain:

[0230] DIQMTQSPSSLSASVGDRVT1TCRAS (SEQ ID NO:28)

[0231] CDR1 of VL domain:

[0232] QSISSY (SEQ ID NO:25)

[0233] Framework Region 2 of VL domain:

[0234] LNWYQQKPGKAPKLLIY (SEQ ID NO:29)

[0235] CDR2 of VL domain:

[0236] AAS (SEQ ID NO:26)

[0237] Framework Region 3 of VL domain:

[0238] SLQSGVPSRFSGSGSGTDFTLTISSLQPEDAATYYC (SEQ ID NO:30)

[0239] CDR3 of VL domain:

[0240] MQGTHWPWT (SEQ ID NO: 27)

[0241] Framework Region 4 of VL domain:

[0242] FGQGTKVEIK (SEQ ID NO: 31)

[0243] Example 4: Nucleic Acids Encoding Exemplary PLA2G7-Binding Molecules

[0244] This Example provides the nucleic acid sequences encoding anti-PLA2G7 clone #1, anti-PLA2G7 clone #2, and anti-PLA2G7 clone #3. Atorney Docket No. 45049-0092W01 / 06870

[0245] Nucleic acid sequence encoding anti-PLA2G7 clone #1 (IA9)

[0246] CAGGTACAATTGCAGGAGAGCGGTGGTGGGCTCGTTCAACCAGGGGGTTCAT TGAGACTGTCATGTGCTGCCAGTGGCTTCACATTTTCCTCATACGCGATGGGT TGGTTTCGCCAGGCGCCAGGAAAGGAGAGAGAGTGGGTGGCGGCGATTTCAG

[0247] GAGGTGGCACTACTTATTATGCGGATTCAGTAAAAGGTCGCTTCACCATCTCT CGTGACAACGCCAAGAATACACTTTATTTGCAGATGAATAGTTTGAAGCCCG AAGATACGGCCGTGTATTACTGTGCAACAGGTAGACAACTGAAAGTGTACAA CTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA (SEQ ID NO:34)

[0248] Nucleic acid sequence encoding anti-PLA2G7 clone #2 (IG4)

[0249] CAGGTACAATTGCAGGAGAGCGGTGGTGGGCTCGTTCAACCAGGGGGTTCAT

[0250] TGAGACTGTCATGTGCTGCCAGTGGCTTCACATTTTCCTCATACGCGATGGGT

[0251] TGGTTTCGCCAGGCGCCAGGAAAGGAGAGAGAGTGGGTGGCGGCGATTTCAG

[0252] GAGGTGGCACTACTTATTATGCGGATTCAGTAAAAGGTCGCTTCACCATCTCT

[0253] CGTGACAACGCCAAGAATACACTTTATTTGCAGATGAATAGTTTGAAGCCCG

[0254] AAGATACGGCCGTGTATTACTGTGTGACAGGATACCTGTGGTGGGATCATAG TTGGGATGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCCTCA (SEQ ID NO:35)

[0255] Nucleic acid sequence encoding anti-PLA2G7 clone #3 (IH8) VH domain

[0256] CAAGTTCAATTAGTGGAGAGCGGCGGCGGATTGGTTAAACCGGGGGGCAGTC TGCGTTTAAGCTGCGCAGCTTCCGGGTTTACTTTTTCGGATTACTATATGAGCT GGATTCGTCAGGCTCCCGGTAAAGGGTTGGAATGGGTTAGCTACATCTCAAG

[0257] TTCCGGCTCTACAATCTACTATGCAGATTCCGTGAAAGGGCGCTTCACCATCT

[0258] CTCGTGACAATGCAAAGAACAGTTTATACTTACAAATGAACTCGCTGCGTGC GGAAGATACGGCCATGTATTACTGTGCGAGAGATAGGAAATTTCGATTTGGG GGCTACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCT

[0259] CCTCA (SEQ ID NO:36) Atorney Docket No. 45049-0092W01 / 06870

[0260] Nucleic acid sequence encoding anti-PLA2G7 clone #3 (IH8) VL domain

[0261] GATATTCAAATGACCCAGTCTCCTTCTTCCTTGAGCGCGTCTGTGGGAGACCG TGTAACTATCACGTGTCGTGCATCCCAAAGCATTTCGAGTTACTTGAACTGGT ATCAACAAAAGCCTGGTAAAGCGCCCAAACTGTTGATCTATGCTGCCAGTAG TCTTCAATCTGGTGTGCCCTCGCGCTTCTCAGGTTCGGGGTCAGGAACGGACT TTACCCTGACCATTAGCTCTCTGCAACCGGAAGATGCTGCAACGTATTACTGC ATGCAAGGTACACACTGGCCTTGGACGTTCGGCCAAGGGACCAAGGTGGAAA TCAAA (SEQ ID NO:37)

[0262] Example 5: Exemplary Bispecific PLA2G7 -Binding Molecules

[0263] This Example provides structures of exemplary bispecific antibodies designed to bind a PLA2G7 polypeptide. The various components of each bispecific antibody (e.g., domains and linkers) are provided and delineated.

[0264] Exemplary bispecific antibody:

[0265] Heavy Chain Variable Domain A + Linker + Heavy Chain Variable Domain B

[0266] Exemplary bispecific antibody:

[0267] Heavy Chain Variable Domain B + Linker + Heavy Chain Variable Domain A

[0268] Exemplary bispecific antibody:

[0269] Complete IgG + Linker + Heavy’ Chain Variable Domain

[0270] Exemplary bispecific antibody:

[0271] Heavy Chain Variable Domain + Linker + Complete IgG

[0272] Exemplary bispecific antibody:

[0273] IgG Heavy Chain + Linker + Heavy Chain Variable Domain

[0274] Exemplary bispecific antibody:

[0275] Heavy Chain Variable Domain + Linker + IgG Heavy Chain Atorney Docket No. 45049-0092W01 / 06870

[0276] Clone #1 and Clone #3 Bispecific Antibody (also referred to as 1H8 lgG-lA9)

[0277] QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSS

[0278] GSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAMYYCARDRKFRFGGYY

[0279] YGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT

[0280] VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK

[0281] VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD

[0282] VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK

[0283] EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF

[0284] YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNFIYTOKSLSLSPGKGGGGSGGGGSGGGGSOVOLOESGGGLVOPGGS LRLSCAASGFTFSSYAMGWFRQAPGKEREWVAAISGGGTTYYADSVKGRFTISR DNAKNTLYLQMNSLKPEDTAVYYCATGRQLKVYNWFDPWGQGTLVTVSS (SEQ 1D NO:38)

[0285] VH1

[0286] QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSS GSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAMYYCARDRKFRFGGYY YGMDVWGQGTTVTVSS (SEQ ID NO:24)

[0287] VH2

[0288] QVQLQESGGGLVQPGGSLRLSCAASGFTFSSYAMGWFRQAPGKEREWVAAISG GGTTYYADSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCATGRQLKVYNW FDPWGQGTLVTVSS (SEQ ID NO: 8)

[0289] Linker

[0290] GGGGSGGGGSGGGGS (SEQ ID NO:40)

[0291] Clone #2 and Clone #3 Bispecific Antibody (also referred to as 1H8 IgG-lG4)

[0292] QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSS

[0293] GSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAMYYCARDRKFRFGGYY

[0294] YGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT

[0295] VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK Atorney Docket No. 45049-0092W01 / 06870

[0296] VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTOKSLSLSPGKGGGGSGGGGSGGGGSOVOLOESGGGLVOPGGS LRLSCAASGFTFSSYAMGWFRQAPGKEREWVAAISGGGTTYYADSVKGRFTISR DNAKNTLYLQMNSLKPEDTAVYYCVTGYLWWDHSWDAFDIWGQGTMVTVSS (SEQ ID NO: 39)

[0297] Mil

[0298] QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSS GSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAMYYCARDRKFRFGGYY YGMDVWGQGTTVTVSS (SEQ ID NO:24)

[0299] VH2

[0300] QVQLQESGGGLVQPGGSLRLSCAASGFTFSSYAMGWFRQAPGKEREWVAAISG GGTTYYADSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCVTGYLWWDHS WDAFDIWGQGTMVTVSS (SEQ ID NO: 16)

[0301] Linker

[0302] GGGGSGGGGSGGGGS (SEQ ID NO:40)

[0303] OTHER EMBODIMENTS

[0304] It is to be understood that while the invention has been described in conjunction wi th the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are w ithin the scope of the following claims.

Claims

Attorney Docket No. 45049-0092W01 / 06870WHAT is CLAIMED is:

1. A single-domain antibody comprising:(i) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:3 (or SEQ ID NO:3 with one, two, or three amino acid additions, deletions, or substitutions); or(ii) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:9 (or SEQ ID NO:9 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 10 (or SEQ ID NO: 10 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one, two, or three amino acid additions, deletions, or substitutions).

2. The single-domain antibody of claim 1, wherein said single-domain antibody comprises the ability to bind to a polypeptide sequence set forth in SEQ ID NO: 33.

3. The single-domain antibody of any one of claims 1-2, wherein said antibody comprises said heavy chain variable domain of said (i).

4. The single-domain antibody of claim 3, wherein said heavy chain variable domain comprises an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 8.

5. The single-domain antibody of any one of claims 1-2, wherein said antibody comprises said heavy chain variable domain of said (ii).

6. The single-domain antibody of claim 5, wherein said heavy chain variable domain comprises an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 16.

7. A nucleic acid comprising a nucleic acid sequence encoding a single-domain antibody of any one of claims 1-6.Atorney Docket No. 45049-0092W01 / 068708. The nucleic acid of claim 7, wherein said nucleic acid sequence encodes said (i) of claim 1.

9. The nucleic acid of claim 7, wherein said nucleic acid sequence encodes said (ii) of claim 1.

10. The nucleic acid of any one of claims 7-9, wherein said nucleic acid is in the form of a viral vector.

11. A host cell comprising a nucleic acid of any one of claims 7-10.

12. An antigen binding fragment comprising:(i) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one. two, or three amino acid additions, deletions, or substitutions); and(ii) a light chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:25 (or SEQ ID NO:25 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:26 (or SEQ ID NO:26 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:27 (or SEQ ID NO:27 with one. two, or three amino acid additions, deletions, or substitutions).

13. The antigen binding fragment of claim 12, wherein said antigen binding fragment comprises the ability to bind to a polypeptide sequence set forth in SEQ ID NO: 33.

14. The antigen binding fragment of any one of claims 12-13, wherein said heavy chain variable domain comprises an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 24.Atorney Docket No. 45049-0092W01 / 0687015. The antigen binding fragment of any one of claims 12-14, wherein said light chain variable domain comprises an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:32.

16. A nucleic acid comprising a nucleic acid sequence encoding an antigen binding fragment of any one of claims 12-15.

17. The nucleic acid of claiml6, wherein said nucleic acid is in the form of a viral vector.

18. A host cell comprising a nucleic acid of any one of claims 16-17.

19. A bispecific antibody comprising:(i) an antigen binding fragment comprising a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 with one, tw o, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, two. or three amino acid additions, deletions, or substitutions) and a light chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:25 (or SEQ ID NO:25 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:26 (or SEQ ID NO:26 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:27 (or SEQ ID NO:27 with one, two. or three amino acid additions, deletions, or substitutions); and(ii) a heavy chain variable domain comprising:(a) the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:3 (or SEQ ID NO:3 wdth one, two, or three amino acid additions, deletions, or substitutions); or(b) the amino acid sequences set forth in SEQ ID NO: 9 (or SEQ ID NO: 9 with one, two, or three amino acid additions, deletions, or substitutions), SEQ IDAttorney Docket No. 45049-0092W01 / 06870NO: 10 (or SEQ ID NO: 10 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one, two, or three amino acid additions, deletions, or substitutions).

20. The bispecific antibody of claim 19, wherein said bispecific antibody comprises the ability to bind to a polypeptide sequence set forth in SEQ ID NO:33.

21. The bispecific antibody of any one of claims 19-20, wherein said heavy chain variable domain of said (i) comprises an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:24.

22. The bispecific antibody of any one of claims 19-20, wherein said light chain variable domain of said (i) comprises an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO:32.

23. The bispecific antibody of any one of claims 19-20, wherein said heavy chain variable domain of said (ii)(a) comprises an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 8.

24. The bispecific antibody of any one of claims 19-20, wherein said heavy chain variable domain of said (ii)(b) comprises an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 16.

25. The bispecific antibody of any one of claims 19-24, wherein said heavy chain variable domain of said (i) and said (ii) are attached by a polypeptide linker.

26. The bispecific antibody of claim 25, wherein said polypeptide linker is a (G4S)? polypeptide linker.

27. The bispecific antibody of claim 26, wherein said (i) is attached to the C-terminus of said (ii).Atorney Docket No. 45049-0092W01 / 0687028. A bispecific antibody comprising:(i) a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO: 17 (or SEQ ID NO: 17 vvi th one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 18 (or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 19 (or SEQ ID NO: 19 with one, two, or three amino acid additions, deletions, or substitutions); and(ii) a heavy chain variable domain comprising:(a) the amino acid sequences set forth in SEQ ID NO: 1 (or SEQ ID NO: 1 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:2 (or SEQ ID NO:2 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:3 (or SEQ ID NO:3 with one, two, or three amino acid additions, deletions, or substitutions); or(b) the amino acid sequences set forth in SEQ ID NO: 9 (or SEQ ID NON with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO: 10 (or SEQ ID NO: 10 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO: 11 (or SEQ ID NO: 11 with one, two, or three amino acid additions, deletions, or substitutions).

29. The bispecific antibody of claim 28, wherein said bispecific antibody comprises the ability to bind to a polypeptide sequence set forth in SEQ ID NO:33.

30. The bispecific antibody of any one of claims 28-29, wherein said heavy chain variable domain of said (i) comprises an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 24.

31. The bispecific antibody of any one of claims 28-30, wherein said heavy chain variable domain of said (ii)(a) comprises an amino acid sequence having at least 90 percent identity to the amino acid sequence set forth in SEQ ID NO: 8.

32. The bispecific antibody of any one of claims 28-30, wherein said heavy chain variable domain of said (ii)(b) comprises an amino acid sequence having at least 90 percent identity to the ammo acid sequence set forth in SEQ ID NO: 16.Atorney Docket No. 45049-0092W01 / 0687033. The bispecific antibody of any one of claims 28-32, wherein said (i) and said (ii) are attached by a polypeptide linker.

34. The bispecific antibody of claim 33, wherein said polypeptide linker is a (G4S)? polypeptide linker.

35. A nucleic acid comprising a nucleic acid sequence encoding a bispecific antibody of any one of claims 19-34.

36. The nucleic acid of claim 35, wherein said nucleic acid is in the form of a viral vector.

37. A host cell comprising a nucleic acid of any one of claims 35-36.

38. A composition comprising a single-domain antibody of any one of claims 1-6.

39. A composition comprising an antigen binding fragment of any one of claims 12-15.

40. A composition comprising a bispecific antibody of any one of claims 19-34.

41. A method of treating a mammal having a condition or disease associated with an increased level of PLA2G7 polypeptide activity, wherein said method comprises administering, to said mammal, a composition of any one of claims 38-40.

42. The method of claim 41, wherein said mammal is a human.

43. The method of any one of claims 41-42, wherein said condition or disease associated with an increased level of PLA2G7 polypeptide activity7is a cancer.Atorney Docket No. 45049-0092W01 / 0687044. The method of claim 43. wherein said cancer is selected from the group consisting of a colorectal cancer, colon cancer, gastric cancer, gastrointestinal cancer, and pancreatic cancer.

45. The method of any one of claims 41-42, wherein said condition or disease associated with an increased level of PLA2G7 polypeptide activity is a cardiovascular disease.

46. The method of claim 45, wherein said cardiovascular disease is selected from the group consisting of atherosclerosis, coronary artery disease, and ischemic stroke.

47. The method of any one of claims 41-46, wherein said increased level of PLA2G7 polypeptide activity is reduced following said administration.

48. A method for binding a binding molecule to a PLA2G7 polypeptide, wherein said method comprises contacting said PLA2G7 polypeptide with a single-domain antibody of any one of claims 1-8, an antigen binding fragment of any one of claims 12-15, or a bispecific antibody of any one of claims 19-34.

49. The method of claim 48, wherein said contacting is performed in vitro.

50. The method of claim 48, wherein said contacting is performed in vivo.

51. The method of claim 50, wherein said contacting is performed within a mammal by administering said single-domain antibody, said antigen binding fragment, or said bispecific antibody to said mammal.

52. The method of claim 51, wherein said mammal is a human.

Images