Anti-PLA2G2D constructs and uses thereof

JP2024528987A5Pending Publication Date: 2025-08-13APEX IMMUNE THERAPEUTICS INC
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Patent Information

Application Number
JP2024506669
Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
Priority Date
2021-08-04
Filing Date
2022-08-03
Publication Date
2025-08-13

AI Technical Summary

Technical Problem

Undesirable suppression of the immune response in patients with tumors or compromised immune systems hinders effective immunotherapy, as tumor-derived and host immune mechanisms dampen therapeutic efficacy.

Method used

Development of anti-PLA2G2D constructs, such as antibodies with specific heavy and light chain variable regions, to target and modulate the immune response by blocking the suppressive effects of PLA2G2D, enhancing immune activation.

Benefits of technology

Enhances immune cell activation and cytokine production, increasing the effectiveness of immunotherapy against cancers and infections by counteracting the immunosuppressive mechanisms associated with PLA2G2D.

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Abstract

The present application provides anti-PLA2G2D constructs (e.g., anti-PLA2G2D antibodies) that bind to PLA2G2D, nucleic acid molecules encoding the amino acid sequences of anti-PLA2G2D, vectors comprising the nucleic acid molecules, host cells comprising the vectors, methods for preparing anti-PLA2G2D constructs, pharmaceutical compositions comprising anti-PLA2G2D constructs, and methods for using anti-PLA2G2D constructs or compositions. In another aspect, the present application provides anti-PLA2G2D constructs that compete with any of the above anti-PLA2G2D constructs for the binding epitope of PLA2G2D.
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Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 229,437, filed August 4, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] Technical Field The present disclosure relates to anti-PLA2G2D constructs (such as anti-PLA2G2D antibodies) and uses thereof. [Background technology]

[0003] 2. Background of the Invention The mechanism by which immune system responds to infection or disease depends on the complex interplay between the elements of innate immunity and adaptive immunity.Unwanted suppression of immune response remains a major obstacle to promising treatments such as immunotherapy to fight against the patient's own immune system or disease or infection.For example, the fundamental problem in the effort to treat patients with immunotherapy is that tumor-bearing state is associated with immunosuppressive mechanisms originating from both tumor and host's hindered immune system, thereby preventing treatment from achieving ideal efficacy.

[0004] Group IID secretory phospholipase A2 is an enzyme encoded by the PLA2G2D gene in humans. PLA2G2D (sPLA2-IID) is abundantly expressed in the spleen and lymph nodes and attenuates Th1 and Th17 immune responses by mobilizing anti-inflammatory ω3 PUFA metabolites.

[0005] The disclosures of all publications, patents, patent applications and published patent applications mentioned herein are incorporated by reference in their entirety for all purposes. Summary of the Invention [Means for solving the problem]

[0006] BRIEF SUMMARY OF THE PRESENTINVENTION In one aspect, the present application relates to a heavy chain variable region (V H ) and the light chain variable region (V L ) is provided.

[0007] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 131, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 133, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 134, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0008] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 140, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 142, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0009] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 151, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0010] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 145, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 146, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0011] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 157, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 145, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0012] In some embodiments, V H V comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 160, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 145, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0013] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 162, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0014] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 165, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0015] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 278, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0016] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 170, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 171, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0017] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 174, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 175, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0018] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 188, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 189, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0019] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 178, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 181, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0020] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 178, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0021] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 192, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0022] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 192, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 200, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0023] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 203, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0024] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 185, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0025] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 206, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 207, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 208, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0026] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 195, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 196, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 197, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0027] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 211, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0028] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 214, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 215, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 216, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 217, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 218, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 219, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0029] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 222, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 223, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 224, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0030] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 227, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 228, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0031] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 227, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 231, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 232, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 233, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 234, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0032] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 237, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 238, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 189, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0033] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 241, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 242, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0034] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 261, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 262, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 263, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 264, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0035] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 267, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 268, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 269, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 270, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0036] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 45, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 46, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 47, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0037] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0038] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 28, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0039] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 77, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 78, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 28, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 79, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0040] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 82, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 83, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 84, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 86, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0041] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 124, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 125, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 126, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 128, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0042] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 89, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 90, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 91, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 92, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 93, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 94, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0043] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 97, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 99, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 105, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 93, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 106, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0044] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 245, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 246, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 247, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 248, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 249, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 250, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0045] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 253, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 254, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 255, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 256, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 257, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 258, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0046] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 9, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 11, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 14, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0047] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 67, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 68, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 69, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 273, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0048] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 6, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0049] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 51, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 53, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 54, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 55, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 56, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0050] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 116, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 117, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 118, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 119, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 120, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 121, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0051] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 59, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 60, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 61, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 62, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 63, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 64, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0052] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 108, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 109, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 110, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 111, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 112, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 113, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0053] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 40, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 41, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 42, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0054] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 67, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 274, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 69, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 275, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 273, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0055] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 97, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 99, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 100, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 101, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 102, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDRs.

[0056] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 279, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 280, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 133, 140, 145, 151, 162, 165, 170, 174, 178, 185, 188, 192, 196, 203, 206, 216, 223, 228, 232, 238, 242, 262, or 268; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:281, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:282, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:283.

[0057] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 284 or 285, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 286 or 287, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 288, 47, or 19; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:289, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:290.

[0058] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 291, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 292, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 293; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 295, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 295, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 250, 258, 94, or 106.

[0059] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 294, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 246 or 254, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 247 or 255; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 295, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 295, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 250, 258, 94, or 106.

[0060] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 9, 32, or 67, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, 33, 68, or 274, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 11, 34, or 69; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 297, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 298.

[0061] In some embodiments, V Hcomprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, 51, or 116, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, 52, or 117, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, 53, or 118; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 299, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 300, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 6, 56, or 121.

[0062] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 59 or 108, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 60 or 109, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 61 or 110; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:301, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:302, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:303.

[0063] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 67, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 68, 274, or 304, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 69; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 305, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 273.

[0064] In some embodiments, V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 306 or 97, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 307 or 98, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, 99, or 53; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 308 or 54, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 41, 101, or 55, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 309 or 102.

[0065] In some embodiments, the present application provides an anti-PLA2G2D construct comprising an antibody portion that specifically binds to PLA2G2D, 1) V having the sequence shown in SEQ ID NO:7 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:8. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 2) V having the sequence shown in SEQ ID NO: 15 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:16. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 3) V having the sequence shown in SEQ ID NO: 23 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:24. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 4) V having the sequence shown in SEQ ID NO: 30 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:31 LLC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 6) V having the sequence shown in SEQ ID NO: 43 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:44 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 7) V having the sequence shown in SEQ ID NO: 49 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:50. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 8) V having the sequence shown in SEQ ID NO:57 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:58. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 9) V having the sequence shown in SEQ ID NO: 65 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:66 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 10) V having the sequence shown in SEQ ID NO: 70 HHC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:71 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 11) V having the sequence shown in SEQ ID NO: 75 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 76 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 12) V having the sequence shown in SEQ ID NO: 80 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:81. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 13) V having the sequence shown in SEQ ID NO: 87 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:88. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 14) V having the sequence shown in SEQ ID NO: 95 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:96 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 15) V having the sequence shown in SEQ ID NO: 103 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 104. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 16) V having the sequence shown in SEQ ID NO: 103 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 107. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 17) V having the sequence shown in SEQ ID NO: 114 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 115. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 18) V having the sequence shown in SEQ ID NO: 122 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 123. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 19) V having the sequence set forth in SEQ ID NO: 129 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 130. LLC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 20) V having the sequence shown in SEQ ID NO: 137 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 138. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 21) V having the sequence set forth in SEQ ID NO: 143 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 144. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 22) V having the sequence set forth in SEQ ID NO: 148 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 149 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 23) V having the sequence set forth in SEQ ID NO: 153 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 154. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 24) V having the sequence set forth in SEQ ID NO: 158 HHC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 159 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 25) V having the sequence set forth in SEQ ID NO: 155 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 156 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 26) V having the sequence set forth in SEQ ID NO: 163 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 164. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 27) V having the sequence set forth in SEQ ID NO: 168 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 169 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 28) V having the sequence set forth in SEQ ID NO: 172 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 173 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 29) V having the sequence set forth in SEQ ID NO: 166 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 167 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 30) V having the sequence set forth in SEQ ID NO: 176 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 177 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 31) V having the sequence set forth in SEQ ID NO: 183 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 184. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 32) V having the sequence set forth in SEQ ID NO: 186 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 187. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 33) V having the sequence set forth in SEQ ID NO: 190 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:191. LLC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 34) V having the sequence set forth in SEQ ID NO: 179 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 180. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 35) V having the sequence set forth in SEQ ID NO: 193 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 194. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 36) V having the sequence set forth in SEQ ID NO: 198 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:199 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 37) V having the sequence set forth in SEQ ID NO: 201 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 202 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 38) V having the sequence set forth in SEQ ID NO: 204 HHC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 205. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 39) V having the sequence set forth in SEQ ID NO: 209 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 210. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 40) V having the sequence set forth in SEQ ID NO: 212 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 213. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 41) V having the sequence set forth in SEQ ID NO: 220 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 221. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 42) V having the sequence set forth in SEQ ID NO: 225 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 226 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 43) V having the sequence set forth in SEQ ID NO: 229 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 230. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 44) V having the sequence set forth in SEQ ID NO: 235 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 236 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 45) V having the sequence set forth in SEQ ID NO: 239 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 240 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 46) V having the sequence set forth in SEQ ID NO: 243 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 244. L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 47) V having the sequence set forth in SEQ ID NO: 251 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 252 LLC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 48) V having the sequence set forth in SEQ ID NO: 259 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 260 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 49) V having the sequence set forth in SEQ ID NO: 265 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 266 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively; 50) V having the sequence set forth in SEQ ID NO: 271 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 272 L LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3, respectively, within the chain region; or 51) V having the sequence set forth in SEQ ID NO: 276 H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 277 L Anti-PLA2G2D constructs are provided that include LC-CDR1, LC-CDR2 and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3, respectively, within the chain regions.

[0066] In some embodiments according to any of the above anti-PLA2G2D constructs, V H7, 15, 23, 30, 35, 43, 49, 57, 65, 70, 75, 80, 87, 95, 103, 114, 122, 129, 137, 143, 148, 153, 158, 155, 163, 168, 172, 166, 176, 183, 186, 190, 179, 193, 198, 201, 204, 209, 212, 220, 225, 229, 235, 239, 243, 251, 259, 265, 271, and 276, or a variant thereof having at least about 80% sequence identity; and / or L but including any one of the amino acid sequences of SEQ ID NOs: 8, 16, 24, 31, 36, 44, 50, 58, 66, 71, 76, 81, 88, 96, 104, 107, 115, 123, 130, 138, 144, 149, 154, 159, 156, 164, 169, 173, 167, 177, 184, 187, 191, 180, 194, 199, 202, 205, 210, 213, 221, 226, 230, 236, 240, 244, 252, 260, 266, 272, and 277, or variants having at least about 80% sequence identity.

[0067] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 7, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO:8, or an amino acid sequence having at least about 80% sequence identity.

[0068] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 15, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 16, or an amino acid sequence having at least about 80% sequence identity.

[0069] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 23, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO:24, or an amino acid sequence having at least about 80% sequence identity.

[0070] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 30, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 31, or an amino acid sequence having at least about 80% sequence identity.

[0071] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 35, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 36, or an amino acid sequence having at least about 80% sequence identity.

[0072] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 43, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes a variant comprising the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence having at least about 80% sequence identity.

[0073] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 49, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; Lbut includes variants comprising the amino acid sequence of SEQ ID NO:50, or an amino acid sequence having at least about 80% sequence identity.

[0074] In some embodiments according to any of the above anti-PLA2G2D constructs, V H V comprises the amino acid sequence of SEQ ID NO: 57, or a variant thereof having an amino acid sequence with at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO:58, or an amino acid sequence having at least about 80% sequence identity.

[0075] In some embodiments according to any of the above anti-PLA2G2D constructs, V H V comprises the amino acid sequence of SEQ ID NO: 65, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO:66, or an amino acid sequence having at least about 80% sequence identity.

[0076] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 70, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO:71, or an amino acid sequence having at least about 80% sequence identity.

[0077] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 75, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 76, or an amino acid sequence having at least about 80% sequence identity.

[0078] In some embodiments according to any of the above anti-PLA2G2D constructs, V Hcomprises the amino acid sequence of SEQ ID NO: 80, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO:81, or an amino acid sequence having at least about 80% sequence identity.

[0079] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 87, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO:88, or an amino acid sequence having at least about 80% sequence identity.

[0080] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 95, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO:96, or an amino acid sequence having at least about 80% sequence identity.

[0081] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 103, or a variant thereof having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 104, or an amino acid sequence having at least about 80% sequence identity.

[0082] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 103, or a variant thereof having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 107, or an amino acid sequence having at least about 80% sequence identity.

[0083] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 114, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 115, or an amino acid sequence having at least about 80% sequence identity.

[0084] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 122, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 123, or an amino acid sequence having at least about 80% sequence identity.

[0085] In some embodiments according to any of the above anti-PLA2G2D constructs, V H V comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 130, or an amino acid sequence having at least about 80% sequence identity.

[0086] In some embodiments according to any of the above anti-PLA2G2D constructs, V H V comprises the amino acid sequence of SEQ ID NO: 137, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes a variant comprising the amino acid sequence of SEQ ID NO: 138, or an amino acid sequence having at least about 80% sequence identity.

[0087] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 143, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; Lbut includes a variant comprising the amino acid sequence of SEQ ID NO: 144, or an amino acid sequence having at least about 80% sequence identity.

[0088] In some embodiments according to any of the above anti-PLA2G2D constructs, V H V comprises the amino acid sequence of SEQ ID NO: 148, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 149, or an amino acid sequence having at least about 80% sequence identity.

[0089] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 153, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes a variant comprising the amino acid sequence of SEQ ID NO: 154, or an amino acid sequence having at least about 80% sequence identity.

[0090] In some embodiments according to any of the above anti-PLA2G2D constructs, V H V comprises the amino acid sequence of SEQ ID NO: 158, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 159, or an amino acid sequence having at least about 80% sequence identity.

[0091] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 155, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 156, or an amino acid sequence having at least about 80% sequence identity.

[0092] In some embodiments according to any of the above anti-PLA2G2D constructs, V Hcomprises the amino acid sequence of SEQ ID NO: 163, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes a variant comprising the amino acid sequence of SEQ ID NO: 164, or an amino acid sequence having at least about 80% sequence identity.

[0093] In some embodiments according to any of the above anti-PLA2G2D constructs, V H V comprises the amino acid sequence of SEQ ID NO: 168, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 169, or an amino acid sequence having at least about 80% sequence identity.

[0094] In some embodiments according to any of the above anti-PLA2G2D constructs, V H V comprises the amino acid sequence of SEQ ID NO: 172, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 173, or an amino acid sequence having at least about 80% sequence identity.

[0095] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 166, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 167, or an amino acid sequence having at least about 80% sequence identity.

[0096] In some embodiments according to any of the above anti-PLA2G2D constructs, V H V comprises the amino acid sequence of SEQ ID NO: 176, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 177, or an amino acid sequence having at least about 80% sequence identity.

[0097] In some embodiments according to any of the above anti-PLA2G2D constructs, V H V comprises the amino acid sequence of SEQ ID NO: 183, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 184, or an amino acid sequence having at least about 80% sequence identity.

[0098] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 186, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 187, or an amino acid sequence having at least about 80% sequence identity.

[0099] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 190, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 191, or an amino acid sequence having at least about 80% sequence identity.

[0100] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 179, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 180, or an amino acid sequence having at least about 80% sequence identity.

[0101] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 193, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; Lbut includes a variant comprising the amino acid sequence of SEQ ID NO: 194, or an amino acid sequence having at least about 80% sequence identity.

[0102] In some embodiments according to any of the above anti-PLA2G2D constructs, V H V comprises the amino acid sequence of SEQ ID NO: 198, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 199, or an amino acid sequence having at least about 80% sequence identity.

[0103] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 201, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 202, or an amino acid sequence having at least about 80% sequence identity.

[0104] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 204, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes a variant comprising the amino acid sequence of SEQ ID NO: 205, or an amino acid sequence having at least about 80% sequence identity.

[0105] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 209, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 210, or an amino acid sequence having at least about 80% sequence identity.

[0106] In some embodiments according to any of the above anti-PLA2G2D constructs, V Hcomprises the amino acid sequence of SEQ ID NO: 212, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 213, or an amino acid sequence having at least about 80% sequence identity.

[0107] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 220, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 221, or an amino acid sequence having at least about 80% sequence identity.

[0108] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 225, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes a variant comprising the amino acid sequence of SEQ ID NO: 226, or an amino acid sequence having at least about 80% sequence identity.

[0109] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 229, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 230, or an amino acid sequence having at least about 80% sequence identity.

[0110] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 235, or a variant thereof having at least about 80% sequence identity; L but includes a variant comprising the amino acid sequence of SEQ ID NO: 236, or an amino acid sequence having at least about 80% sequence identity.

[0111] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 239, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 240, or an amino acid sequence having at least about 80% sequence identity.

[0112] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 243, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes a variant comprising the amino acid sequence of SEQ ID NO: 244, or an amino acid sequence having at least about 80% sequence identity.

[0113] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 251, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes a variant comprising the amino acid sequence of SEQ ID NO: 252, or an amino acid sequence having at least about 80% sequence identity.

[0114] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 259, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 260, or an amino acid sequence having at least about 80% sequence identity.

[0115] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 265, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; Lbut includes a variant comprising the amino acid sequence of SEQ ID NO: 266, or an amino acid sequence having at least about 80% sequence identity.

[0116] In some embodiments according to any of the above anti-PLA2G2D constructs, V H V comprises the amino acid sequence of SEQ ID NO: 271, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 272, or an amino acid sequence having at least about 80% sequence identity.

[0117] In some embodiments according to any of the above anti-PLA2G2D constructs, V H comprises the amino acid sequence of SEQ ID NO: 276, or a variant thereof having an amino acid sequence having at least about 80% sequence identity; L but includes variants comprising the amino acid sequence of SEQ ID NO: 277, or an amino acid sequence having at least about 80% sequence identity.

[0118] In some embodiments according to any of the above anti-PLA2G2D constructs, the antibody portion is an antibody or an antigen-binding fragment thereof selected from the group consisting of a full-length antibody, a bispecific antibody, a single chain Fv (scFv) fragment, a Fab fragment, a Fab' fragment, a F(ab')2, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, an Fv-Fc fusion, an scFv-Fc fusion, an scFv-Fv fusion, a diabody, a tribody, and a tetrabody. In some embodiments, the antibody portion is a full-length antibody.

[0119] In some embodiments of any of the above anti-PLA2G2D constructs, the antibody portion has an Fc fragment selected from the group consisting of Fc fragments from IgG, IgA, IgD, IgE, IgM, and combinations and hybrids thereof.In some embodiments, the Fc fragment is selected from the group consisting of Fc fragments from IgG1, IgG2, IgG3, IgG4, and combinations and hybrids thereof.In some embodiments, the Fc fragment has reduced effector function compared to the corresponding wild-type Fc fragment.In some embodiments, the Fc fragment has enhanced effector function compared to the corresponding wild-type Fc fragment.

[0120] In some embodiments according to any of the above anti-PLA2G2D constructs, the construct is a full-length antibody, a fusion protein, or an immunoconjugate.

[0121] In some embodiments according to any of the above anti-PLA2G2D constructs, the PLA2G2D is human PLA2G2D.

[0122] In another aspect, the application provides an anti-PLA2G2D construct that competes with any of the above anti-PLA2G2D constructs for the binding epitope of PLA2G2D.

[0123] In another aspect, the application provides a pharmaceutical composition comprising any of the anti-PLA2G2D constructs described above and a pharma- ceutically acceptable carrier.

[0124] In another aspect, the application provides an isolated nucleic acid encoding any of the above anti-PLA2G2D constructs.

[0125] In another aspect, the application provides a vector comprising any of the above isolated nucleic acids.

[0126] In another aspect, the application provides an isolated host cell comprising any of the above-described isolated nucleic acids or vectors.

[0127] In another aspect, the present application provides a method for producing an anti-PLA2G2D construct, the method comprising: a) culturing any of the above-mentioned isolated host cells under conditions effective to express the anti-PLA2G2D construct, and b) obtaining the expressed anti-PLA2G2D construct from the host cell.

[0128] In another aspect, the present application provides a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of any of the above anti-PLA2G2D constructs or pharmaceutical compositions. In some embodiments, the disease or condition is cancer, and optionally the cancer is a solid tumor. In some embodiments, the cancer is an advanced or malignant tumor. In some embodiments, the cancer has an increased level of PLA2G2D. In some embodiments, the cancer is selected from the group consisting of lung cancer, breast cancer, liver cancer, gastric cancer, cervical cancer, endometrial cancer, thyroid cancer, colorectal cancer, head and neck cancer, pancreatic cancer, kidney cancer, prostate cancer, urothelial cancer, testicular cancer, ovarian cancer, and melanoma. In some embodiments, the disease or condition is a viral infection. In some embodiments, the expression level of PLA2G2D at the infected site is higher than at the non-infected site.

[0129] In some embodiments according to any of the above methods of treatment, the method further comprises administering a second agent. In some embodiments, the second agent is selected from the group consisting of a chemotherapeutic agent, an immunomodulatory agent, an anti-angiogenic agent, a growth inhibitory agent, and an anti-neoplastic agent. In some embodiments, the second agent is an immunomodulatory agent. In some embodiments, the immunomodulatory agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor specifically targets PD-L1, PD-L2, CTLA4, PD-L2, PD-1, CD47, TIGIT, GITR, TIM3, LAG3, CD27, 4-1BB, or B7H4. In some embodiments, the second agent comprises cells comprising a chimeric antigen receptor that specifically binds to a tumor antigen. In some embodiments, the anti-PLA2G2D construct and the second agent are administered simultaneously or concurrently. In some embodiments, the anti-PLA2G2D construct and the second agent are administered sequentially. In some embodiments, the anti-PLA2G2D construct and / or the second agent are administered parenterally.

[0130] In some embodiments according to any of the above methods of treatment, the anti-PLA2G2D construct is administered directly to the cancer tissue or site of infection.

[0131] In some embodiments according to any of the above methods of treatment, the anti-PLA2G2D construct is administered at a dose of about 0.001 μg / kg to about 100 mg / kg.

[0132] In some embodiments of any of the above treatment methods, the individual has an increased number of immune cells in the cancer tissue or infection site after administration of the anti-PLA2G2D construct. In some embodiments, the immune cells are T cells. In some embodiments, the T cells are activated T cells. In some embodiments, the number of immune cells in the cancer tissue or infection site increases by at least about 5% after administration of the anti-PLA2G2D construct.

[0133] In some embodiments of any of the above treatment methods, immune cells in cancer tissue or infection site produce increased levels of cytokines after administration of anti-PLA2G2D construct. In some embodiments, the cytokines are IFNγ and / or IL-2. In some embodiments, the levels of cytokines are increased by at least about 5% after administration of anti-PLA2G2D construct. [Brief description of the drawings]

[0134] [Figure 1] FIG. 1 shows overlaid histograms of anti-PLA2G2D or isotype control antibody binding to human and mouse PLA2G2D-TM stably expressed on the surface of HEK-293T cells, or to parental untransfected HEK-293T cells, as detected by flow cytometry.

[0135] [Diagram 2] FIG. 2 shows that the mean fluorescence intensity (MFI) of PLA2G2D-Fc binding to activated T cells in PBMC cultures can be blocked by the presence of anti-PLA2G2D antibodies.

[0136] [Diagram 3] FIG. 3 shows that PLA2G2D-Fc-mediated inhibition of IL-2 secretion in T cell-activated PBMC cultures can be reversed by the addition of anti-PLA2G2D antibodies. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0137] Detailed Description of the Invention The present application provides novel anti-PLA2G2D constructs (e.g., anti-PLA2G2D monoclonal or multispecific antibodies) that specifically bind to PLA2G2D, methods for preparing the anti-PLA2G2D constructs, and methods for using the constructs (e.g., methods for treating a disease or condition).

[0138] I. Definition It is understood that embodiments of the present application described herein with the term "comprising" include "consisting of" and / or "consisting essentially of."

[0139] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this application belongs. Furthermore, any methods or materials similar or equivalent to those described herein can be used in the practice of this application. For the purposes of this application, the following terms are defined.

[0140] The term "antibody" is used in its broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies and antigen-binding fragments thereof, so long as they exhibit the desired antigen-binding activity. The term "antibody portion" refers to a full-length antibody or an antigen-binding fragment thereof.

[0141] A full-length antibody contains two heavy chains and two light chains. The variable regions of the light and heavy chains are responsible for antigen binding. The variable domains of the heavy and light chains are each called "V H " and "V L". The variable regions of both chains generally contain three highly variable loops called complementarity determining regions (CDRs) (light chain (LC) CDRs including LC-CDR1, LC-CDR2 and LC-CDR3, and heavy chain (HC) CDRs including HC-CDR1, HC-CDR2 and HC-CDR3). The CDR boundaries of the antibodies and antigen-binding fragments disclosed herein may be defined or identified by the conventions of Kabat, Chothia, or Al-Lazikani (Al-Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991). The three CDRs of the heavy or light chain are interposed between adjacent stretches known as framework regions (FRs), which are more highly conserved than the CDRs and form a scaffold to support the hypervariable loops. The constant regions of the heavy and light chains are not involved in antigen binding, but exhibit various effector functions. Antibodies are assigned to classes based on the amino acid sequence of the constant region of their heavy chains. The five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, characterized by the presence of α, δ, ε, γ, and μ heavy chains, respectively. Some of the major antibody classes are divided into subclasses, such as IgG1 (γ1 heavy chain), IgG2 (γ2 heavy chain), IgG3 (γ3 heavy chain), IgG4 (γ4 heavy chain), lgA1 (α1 heavy chain), or lgA2 (α2 heavy chain).

[0142] The term "antigen-binding fragment" as used herein refers to antibody fragments including, for example, diabodies, Fab, Fab', F(ab')2, Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabodies (ds diabodies), single-chain Fvs (scFv), scFv dimers (bivalent diabodies), multispecific antibodies formed from a portion of an antibody containing one or more CDRs, camelid single domain antibodies, nanobodies, domain antibodies, bivalent domain antibodies, or any other antibody fragment that binds to an antigen but does not contain a complete antibody structure. An antigen-binding fragment can bind to the same antigen that the parent antibody or parent antibody fragment (e.g., parent scFv) binds. In some embodiments, an antigen-binding fragment can contain one or more CDRs from a particular human antibody grafted onto framework regions from one or more different human antibodies.

[0143] "Fv" is the smallest antibody fragment that contains a complete antigen recognition and binding site. This fragment consists of a dimer of one heavy chain variable region domain and one light chain variable region domain in tight non-covalent association. The folding of these two domains results in six hypervariable loops (three loops each from the heavy and light chains) that contribute amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three CDRs specific for an antigen) has the ability to recognize and bind antigen, but often with lower affinity than the entire binding site.

[0144] A "single-chain Fv" (also abbreviated as "sFv" or "scFv") is a VF linked to a single polypeptide chain. H and V L In some embodiments, the scFv polypeptide is an antibody fragment that contains an antibody domain, which enables the scFv to form the desired structure for antigen binding. H Domain and V LIt further comprises a polypeptide linker between the domains. For a review of scFvs, see Plueckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds. Springer-Verlag, New York, pp. 269-315 (1994).

[0145] As used herein, the term "CDR" or "complementarity determining region" is intended to mean the discontinuous antigen-binding sites found within the variable regions of both heavy and light chain polypeptides. These specific regions were identified by Kabat et al., J.Biol.Chem.252:6609-6616(1977);Kabat et al.,USDept.of Health and Human Services, "Sequences of proteins of immunological interest"(1991);Chothia et al.,J.Mol.Biol.196:901-917(1987);Al-Lazikani B.et al.,J.Mol.Biol.,273:927-948(1997);MacCallum et al.,J.Mol.Biol.262:732-745(1996);Abhinandan and Martin,Mol.Immunol.,45:3832-3839(2008);Lefranc MPet al., Dev. Comp. Immunol., 27:55-77 (2003); and Honegger and Plueckthun, J. Mol. Biol., 309:657-670 (2001), where the definitions include overlapping or subsets of amino acid residues when compared with each other. Nevertheless, application of either definition to refer to the CDR of an antibody or grafted antibody or variants thereof is intended to be within the scope of the term as defined and used herein. The amino acid residues encompassing the CDRs defined by each of the above cited references are shown in Table 1 below for comparison. CDR prediction algorithms and interfaces are known in the art (e.g., Abhinandan and Martin, Mol. Immunol., 45:3832-3839(2008); Ehrenmann F. et al., Nucleic Acids Res., 38:D301-D307(2010); and Adolf-Bryfogle J. et al., Nucleic Acids Res., 43:D432-D438(2015)).The contents of the references cited in this paragraph are incorporated herein by reference in their entirety for use in this application and for possible inclusion in one or more claims herein. In some embodiments, the CDR sequences provided herein are based on the IMGT definition. For example, CDR sequences can be determined by the VBASE2 tool (http: / / www.vbase2.org / vbase2.php, see also VBASE2, an integrated V gene database: Retter I, Althaus HH, Muench R, Mueller W. Nucleic Acids Res. 2005 Jan 1;33 (database issue):D671-4, incorporated herein by reference in its entirety). Table 1: CDR definition [Table 1]

[0146] The phrases "Kabat variable domain residue numbering" or "Kabat amino acid position numbering" and variations thereof refer to the numbering system used for the heavy or light chain variable domains of the antibody compilation of Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening or insertion of the FR or hypervariable region (HVR) of the variable domain. For example, a heavy chain variable domain may contain a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and an inserted residue after heavy chain FR residue 82 (e.g., residues 82a, 82b and 82c, etc., according to Kabat). The Kabat numbering of residues may be determined for a given antibody by alignment of the antibody's sequence with the "standard" Kabat numbering sequence at the regions of homology.

[0147] Unless otherwise indicated herein, the numbering of residues in an immunoglobulin heavy chain is that of the EU index in Kabat et al., supra. "EU index in Kabat" refers to the residue numbering of the human IgG1 EU antibody.

[0148] "Framework" or "FR" residues are those variable domain residues other than the CDR residues as herein defined.

[0149] "Humanized" forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region (HVR) of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having the desired antibody specificity, affinity, and capacity. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies can contain residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. In general, humanized antibodies will contain substantially all of at least one, and typically two, variable domains, with all or substantially all of the hypervariable loops corresponding to those of a non-human immunoglobulin and all or substantially all of the FRs being those of human immunoglobulin sequences. Humanized antibodies also optionally contain at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992).

[0150] A "human antibody" is an antibody having an amino acid sequence that corresponds to that of an antibody produced by a human and / or has been produced using any of the techniques for producing human antibodies disclosed herein. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Also available for the preparation of human monoclonal antibodies are the methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p.77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5:368-74 (2001). Human antibodies can be prepared by administering antigen to transgenic animals, such as immunized xenomouse, that have been engineered to produce such antibodies in response to antigen challenge but whose endogenous loci have been disabled (see, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584 for XENOMOUSE™). See also Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006) for human antibodies generated via human B cell hybridoma technology.

[0151] "Percent (%) amino acid sequence identity" or "homology" with respect to the polypeptide and antibody sequences identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the polypeptide being compared, after the sequences are aligned, taking into account any conservative substitutions as part of the sequence identity. Alignment to determine percent amino acid sequence identity can be achieved in a variety of ways that are within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), or MUSCLE software. Those skilled in the art can determine the appropriate parameters for measuring alignment, including any algorithms required to achieve maximum alignment over the entire length of the sequences being compared. However, for the purposes of this specification, % amino acid sequence identity values ​​are generated using the sequence comparison computer program MUSCLE (Edgar, RC, Nucleic Acids Research 32(5):1792-1797, 2004; Edgar, RC, BMC Bioinformatics 5(1):113, 2004).

[0152] "Homologous" refers to sequence similarity or sequence identity between two polypeptides or two nucleic acid molecules. If both positions of two compared sequences are occupied by the same base or amino acid monomer subunit, for example, if each position of two protein molecules is occupied by lysine, or each position of two DNA molecules is occupied by adenine, then the molecules are homologous at that position. The percentage of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences multiplied by 100 divided by the number of positions compared. For example, if 6 out of 10 positions in two sequences are matching or homologous, then the two sequences are 60% homologous. As an example, the protein sequences SGTSTD and TGTSDA share 50% homology. Generally, comparisons are made when the two sequences are aligned to obtain maximum homology.

[0153] The term "constant domain" refers to the portion of an immunoglobulin molecule that has a more conserved amino acid sequence compared to the other portion of the immunoglobulin, the variable domain, which contains the antigen binding site. The constant domain is the C H 1. C H 2 and C H 3 domains (collectively C H ) and light chain CHL (or C L ) domain.

[0154] The "light chains" of antibodies (immunoglobulins) from any mammalian species can be assigned to one of two clearly distinct types, called kappa ("κ") and lambda ("λ"), based on the amino acid sequences of their constant domains.

[0155] The "CH1 domain" (also called "C1" for "H1" domain) typically spans from about amino acid 118 to about amino acid 215 (EU numbering system).

[0156] The "hinge region" is generally defined as the region in IgG corresponding to Glu216-Pro230 of human IgG1 (Burton, Molec. Immunol. 22:161-206 (1985)). Hinge regions of other IgG isotypes can be aligned with the IgG1 sequence by placing the first and last cysteine ​​residues that form the inter-heavy chain S-S bonds in the same positions.

[0157] The "CH2 domain" (also called the "C2" domain) of the human IgG Fc region typically extends from about amino acid 231 to about amino acid 340. The CH2 domain is unique in that it is not closely paired with another domain. Rather, two N-linked branched carbohydrate chains are sandwiched between the two CH2 domains in intact native IgG molecules. It has been speculated that the carbohydrates may provide a surrogate for domain-domain pairing and help stabilize the CH2 domain. Burton, Molec Immunol. 22:161-206 (1985).

[0158] The "CH3 domain" (also called the "C2" domain) comprises the stretch of residues C-terminal to the CH2 domain in the Fc region (i.e., from about amino acid residue 341 to the C-terminus of the antibody sequence, typically amino acid residue 446 or 447 for IgG).

[0159] The term "Fc region" or "fragment crystallizable region" herein is used to define the C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and variant Fc regions. Although the boundaries of an immunoglobulin heavy chain Fc region may vary, the human IgG heavy chain Fc region is usually defined to extend from the amino acid residue at position Cys226 or the amino acid residue at Pro230 to its carboxyl terminus. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding the heavy chain of the antibody. Thus, a composition of intact antibodies may include an antibody population in which all K447 residues have been removed, an antibody population in which the K447 residue has not been removed, and an antibody population having a mixture of antibodies with and without the K447 residue. Suitable native sequence Fc regions for use in the antibodies described herein include human IgG1, IgG2 (IgG2A, IgG2B), IgG3, and IgG4.

[0160] "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. A preferred FcR is a native sequence human FcR. Additionally, a preferred FcR is one that binds IgG antibodies (gamma receptors) and includes receptors of the FcγRI, FcγRII, FcRN, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors, with FcγRII receptors including FcγRIIA ("activating receptor") and FcγRIIB ("inhibitory receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain. (See M. Daeron, Annu. Rev. Immunol. 15:203-234 (1997). FcRNs are important for the recycling of antibodies to the blood allowing for increased serum half-life of the antibody. FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those identified in the future, are encompassed by the term "FcR" herein.

[0161] The term "epitope" as used herein refers to the particular group of atoms or amino acids on an antigen to which an antibody or antibody portion binds. Two antibodies or antibody portions may bind to the same epitope in an antigen if they exhibit competitive binding to the antigen.

[0162] As used herein, a first antibody or fragment thereof "competes" with a second antibody or fragment thereof for binding to a target antigen if the first antibody or fragment thereof inhibits target antigen binding of the second antibody or fragment thereof by at least about 50% (e.g., at least about any one of 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99%) in the presence of an equimolar concentration of the first antibody or fragment thereof, or vice versa. A high throughput process for "binning" antibodies based on cross-competition is described in PCT Publication No. WO 03 / 48731.

[0163] As used herein, the terms "specifically bind," "specifically recognize," and "specific for" refer to a measurable and reproducible interaction, such as binding, between a target and an antibody or antibody portion that determines the presence of the target in the presence of a heterogeneous population of molecules, including biological molecules. For example, an antibody or antibody portion that specifically recognizes a target (which may be an epitope) is an antibody or antibody portion that binds to this target with higher affinity, avidity, more readily, and / or with longer duration than its binding to other targets. In some embodiments, the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the target, as measured, for example, by radioimmunoassay (RIA). In some embodiments, an antibody that specifically binds to a target has a binding affinity of ≦10%. -5 M, ≦10 -6 M, ≦10 -7 M, ≦10 -8 M, ≦10 -9 M, ≦10 -10 M, ≦10 -11 M, or ≤ 10 -12 Dissociation constant of M (K D). In some embodiments, the antibody specifically binds to an epitope on a protein that is conserved among proteins from different species. In some embodiments, specific binding may include, but does not require, exclusive binding. The binding specificity of an antibody or antigen-binding domain can be determined experimentally by methods known in the art. Such methods include, but are not limited to, Western blot, ELISA-, BLI, RIA-, ECL-, IRMA-, EIA-, BIACORE™-test and peptide scan.

[0164] An "isolated" or "purified" antibody (or construct) is one that has been identified, separated and / or recovered from a component of its production environment (e.g., natural or recombinant). Preferably, an isolated polypeptide is free of association with all other components from its production environment.

[0165] An "isolated" nucleic acid molecule encoding a construct, antibody, or antigen-binding fragment thereof described herein is a nucleic acid molecule that is identified and separated from at least one contaminating nucleic acid molecule with which it is normally associated in the environment in which it is produced. Preferably, an isolated nucleic acid is not associated with all components associated with the production environment. An isolated nucleic acid molecule encoding a polypeptide and antibody described herein is in a form other than the form or situation in which it is found in nature. Thus, an isolated nucleic acid molecule is distinct from a nucleic acid encoding a polypeptide and antibody described herein that naturally occurs in a cell. An isolated nucleic acid includes a nucleic acid molecule contained in a cell that normally contains the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location different from its natural chromosomal location.

[0166] The term "control sequence" refers to a DNA sequence required for the expression of an operably linked coding sequence in a particular host organism. Control sequences suitable for prokaryotes include, for example, a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.

[0167] A nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to promote translation. Generally, "operably linked" means that the DNA sequences being linked are contiguous, and in the case of a secretory leader, contiguous and in reading frame. Enhancers, however, need not be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.

[0168] The term "vector" as used herein refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes vectors as self-replicating nucleic acid structures as well as vectors integrated into the genome of a host cell into which it is introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as "expression vectors."

[0169] The terms "transfected" or "transformed" or "transduced" as used herein refer to the process by which exogenous nucleic acid is transferred or introduced into a host cell. A "transfected" or "transformed" or "transduced" cell is one that has been transfected, transformed or transduced with exogenous nucleic acid. The cell includes the primary subject cell and its progeny.

[0170] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and its progeny, regardless of the number of passages. The progeny may not be completely identical in nucleic acid content to the parent cell and may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.

[0171] The term "immunoconjugate" includes reference to the covalent attachment of a therapeutic agent or detectable label to an antibody, such as an antibody portion described herein. The linkage can be direct or indirect, such as through a linker (such as a peptide linker).

[0172] As used herein, "treatment" or "treating" is an approach to obtain beneficial or desired results, including clinical results. For purposes of this application, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms attributable to a disease, reducing the extent of the disease, stabilizing the disease (e.g., preventing or slowing the progression of the disease), preventing or slowing the spread of the disease (e.g., metastasis), preventing or slowing the recurrence of the disease, slowing or slowing the progression of the disease, improving the disease state, providing remission (partial or total) of the disease, reducing the dose of one or more other medications required to treat the disease, slowing the progression of the disease, improving or improving quality of life, increasing weight gain, and / or prolonging survival. Reduction in the pathological consequences of cancer (e.g., tumor volume, etc.) is also encompassed by "treatment". The methods of this application contemplate any one or more of these aspects of treatment.

[0173] In the context of cancer, the term "treating" includes any or all of inhibiting the growth of cancer cells, inhibiting the replication of cancer cells, reducing the overall tumor burden, and ameliorating one or more symptoms associated with the disease.

[0174] The term "inhibition" or "inhibiting" refers to the reduction or cessation of any phenotypic characteristic, or the reduction or cessation of the incidence, degree, or likelihood of that characteristic. "Reducing" or "inhibiting" is the reduction, reduction, or cessation of an activity, function, and / or amount compared to a reference. In certain embodiments, "reducing" or "inhibiting" refers to the ability to cause an overall reduction of 20% or more. In another embodiment, "reducing" or "inhibiting" refers to the ability to cause an overall reduction of 50% or more. In yet another embodiment, "reducing" or "inhibiting" refers to the ability to cause an overall reduction of 75%, 85%, 90%, 95%, or more.

[0175] As used herein, "reference" refers to any sample, standard, or level used for comparison purposes. Reference can be obtained from healthy and / or non-disease samples. In some examples, reference can be obtained from untreated samples. In some examples, reference is obtained from non-disease or non-treated samples of individuals. In some examples, reference is obtained from one or more healthy individuals who are not individuals or patients.

[0176] As used herein, "delaying the onset of disease" means to defer, hinder, slow down, prevent, stabilize, inhibit and / or postpone the onset of a disease (such as cancer). This delay can be of various lengths of time, depending on the disease being treated and / or the medical history of the individual. As will be apparent to one of skill in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, late-stage cancer, such as the onset of metastases, can be delayed.

[0177] "Preventing" as used herein includes providing prophylaxis against the occurrence or recurrence of a disease in an individual who may have a predisposition to the disease, but has not yet been diagnosed with the disease.

[0178] As used herein, "inhibiting" a function or activity is to decrease a function or activity when compared to conditions that are otherwise the same except for the condition or parameter of interest, or when compared to another condition, For example, an antibody that inhibits tumor growth reduces the rate of tumor growth compared to the rate of tumor growth in the absence of the antibody.

[0179] The terms "subject," "individual," and "patient" are used interchangeably herein to refer to a mammal, including, but not limited to, a human, bovine, equine, feline, canine, rodent, or primate. In some embodiments, an individual is a human.

[0180] An "effective amount" of an agent refers to an amount effective at the dosage and duration required to achieve the desired therapeutic or prophylactic result. The specific dosage may vary depending on one or more of the specific agent selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried.

[0181] The "therapeutically effective amount" of a substance / molecule, agonist or antagonist of the present application may vary according to factors such as the disease state, age, sex and weight of the individual, and the ability of the substance / molecule, agonist or antagonist to induce a desired response in the individual. A therapeutically effective amount is also an amount in which any toxic or detrimental effects of the substance / molecule, agonist or antagonist are outweighed by therapeutically beneficial effects. A therapeutically effective amount may be delivered in one or more administrations.

[0182] A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, but not necessarily, the prophylactically effective amount is less than the therapeutically effective amount, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease.

[0183] The terms "pharmaceutical formulation" and "pharmaceutical composition" refer to a preparation that is in a form that allows the biological activity of the active ingredient(s) to be effective and does not contain additional components that are unacceptably toxic to the individual to whom the formulation is administered. Such formulations may be sterile.

[0184] "Pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material, formulation aid or carrier conventional in the art for use with therapeutic agents that together comprise a "pharmaceutical composition" for administration to an individual. A pharmaceutically acceptable carrier is non-toxic to a recipient at the dosage and concentration used and is compatible with other ingredients of the formulation. A pharmaceutically acceptable carrier is suitable for the formulation used.

[0185] A "sterile" preparation is sterile or essentially free of living microorganisms and their spores.

[0186] Administration "in combination with" one or more further therapeutic agents includes simultaneous (concurrent) and consecutive or sequential administration in any order.

[0187] The term "concurrently" is used herein to refer to the administration of two or more therapeutic agents where at least a portion of the administration overlaps in time or where the administration of one therapeutic agent falls within a short period of time compared to the administration of the other therapeutic agent. For example, the two or more therapeutic agents are administered within a time interval of about 60 minutes or less, such as about any of 30, 15, 10, 5, or 1 minutes or less.

[0188] The term "sequentially" is used herein to refer to the administration of two or more therapeutic agents, where administration of one or more agents continues after administration of one or more other agents is discontinued. For example, the administration of the two or more therapeutic agents is administered at a time interval of more than about 15 minutes, e.g., about 20, 30, 40, 50, or 60 minutes, one day, two days, three days, one week, two weeks, or one month or more.

[0189] As used herein, "in combination with" refers to the administration of one treatment modality in addition to another treatment modality. Thus, "in combination with" refers to the administration of one treatment modality before, during or after the administration of another treatment modality to an individual.

[0190] The term "package insert" is used to refer to instructions customarily included in commercial packaging of a therapeutic product that contain information regarding the indications, directions for use, dosage, administration, concomitant therapy, contraindications and / or warnings regarding the use of such therapeutic product.

[0191] An "article of manufacture" is any article of manufacture (e.g., package or container) or kit that contains at least one reagent, such as a pharmaceutical agent for treating a disease or disorder (e.g., cancer), or a probe for specifically detecting a biomarker described herein. In certain embodiments, the article of manufacture or kit is promoted, distributed, or sold as a unit for performing the methods described herein.

[0192] Reference herein to "about" a value or parameter includes (and accounts for) the variation that is directed to the value or parameter itself. For example, a statement of "about X" includes the statement "X."

[0193] As used herein, reference to a value or parameter "is not" generally means and describes a value or parameter "other than." For example, the method is not used to treat cancer of type X means that the method is used to treat cancers other than type X.

[0194] Here, "about X to Y" is synonymous with "about X to about Y."

[0195] As used in this specification and the appended claims, the singular forms "a," "or," and "the" include plural referents unless the context clearly dictates otherwise.

[0196] II. Anti-PLA2G2D construct In one aspect, the application provides an anti-PLA2G2D construct comprising an anti-PLA2G2D antibody portion that specifically binds to PLA2G2D as described herein.

[0197] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V Hcomprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 131, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 133, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 134, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0198] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 131, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 133; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 134, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136.

[0199] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 137. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 138. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0200] In some embodiments, VH includes an amino acid sequence of SEQ ID NO: 137, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 138, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0201] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 140, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 142, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0202] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 140; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 142.

[0203] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 143. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 144. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0204] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 143, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 144, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0205] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 151, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0206] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 151; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136.

[0207] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 153. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 154. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0208] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 153, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; Lincludes variants comprising an amino acid sequence of SEQ ID NO: 154, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0209] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 145, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 146, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0210] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 145; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 146, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147.

[0211] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:148. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 149 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0212] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 148, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 149, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0213] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 157, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 145, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0214] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 157, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 145; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147.

[0215] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 158. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 159 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0216] In some embodiments, V H comprises an amino acid sequence of SEQ ID NO: 158, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 159, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0217] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 160, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 145, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0218] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 160, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 145; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147.

[0219] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 155. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 156 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0220] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 155, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 156, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0221] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 162, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0222] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 162; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147.

[0223] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 163. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 164. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0224] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 163, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 164, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0225] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 165, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0226] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 165; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136.

[0227] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 168. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 169 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0228] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 168, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; Lincludes variants comprising an amino acid sequence of SEQ ID NO: 169, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0229] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 278, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0230] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 278, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:20, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22.

[0231] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 166.H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 167 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0232] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 166, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 167, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0233] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 170, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 171, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0234] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 170; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 171, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136.

[0235] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 172. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 173 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0236] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 172, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 173, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0237] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V Hcomprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 174, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 175, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0238] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 174; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 175.

[0239] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 176. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 177 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0240] In some embodiments, VH includes an amino acid sequence of SEQ ID NO: 176, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 177, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0241] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 188, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 189, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0242] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 188; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 189.

[0243] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 190. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:191. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0244] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 190, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 191, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0245] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 178, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 181, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0246] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 178; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 181, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182.

[0247] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 183. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 184. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0248] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 183, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; Lincludes variants comprising an amino acid sequence of SEQ ID NO: 184, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0249] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 178, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0250] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 178; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147.

[0251] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 179. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 180. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0252] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 179, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 180, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0253] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 192, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0254] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 192; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136.

[0255] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 193. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 194. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0256] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 193, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 194, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0257] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 192, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 200, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0258] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 192; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 200, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136.

[0259] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:201. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 202 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0260] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 201, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 202, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0261] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 203, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0262] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 203; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136.

[0263] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:204. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 205. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0264] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 204, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 205, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0265] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 185, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0266] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 185; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136.

[0267] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 186. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 187. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0268] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 186, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; Lincludes variants comprising an amino acid sequence of SEQ ID NO: 187, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0269] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 206, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 207, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 208, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0270] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 206; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 207, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 208.

[0271] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:209. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 210. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0272] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 209, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 210, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0273] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 195, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 196, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 197, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0274] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 195, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 196; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 197, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136.

[0275] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:198. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:199 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0276] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 198, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 199, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0277] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 211, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0278] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 211; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147.

[0279] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:212. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 213. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0280] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 212, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 213, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0281] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 214, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 215, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 216, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 217, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 218, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 219, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0282] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 214, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 215, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 216; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:217, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:218, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:219.

[0283] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:220. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 221. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0284] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 220, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 221, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0285] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 222, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 223, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 224, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0286] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 222, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 223; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 224.

[0287] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:225. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 226 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0288] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 225, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; Lincludes variants comprising an amino acid sequence of SEQ ID NO: 226, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0289] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 227, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 228, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0290] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 227, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 228; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182.

[0291] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:229. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 230. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0292] In some embodiments, V H comprises an amino acid sequence of SEQ ID NO: 229, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 230, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0293] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 227, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 231, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 232, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 233, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 234, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0294] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 227, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 231, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 232; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 233, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 234, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182.

[0295] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:235. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 236 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0296] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 235, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 236, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0297] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 237, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 238, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 189, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0298] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 237, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 238; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 189.

[0299] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:239. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 240 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0300] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 239, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 240, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0301] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 241, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 242, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0302] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 241, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 242; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136.

[0303] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:243. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 244. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0304] In some embodiments, V H comprises an amino acid sequence of SEQ ID NO: 243, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO:244, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0305] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 261, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 262, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 263, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 264, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0306] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 261, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 262; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 263, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 264.

[0307] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:265. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 266 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0308] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 265, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; Lincludes variants comprising an amino acid sequence of SEQ ID NO: 266, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0309] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 267, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 268, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 269, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 270, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0310] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 267, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 268; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 269, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 270, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182.

[0311] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:271. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 272 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0312] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 271, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 272, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0313] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 45, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 46, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 47, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0314] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 45, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 46, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 47; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:48, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22.

[0315] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:49. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:50. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0316] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 49, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO:50, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0317] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V Hcomprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0318] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:20, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22.

[0319] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:23. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:24. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0320] In some embodiments, V Hincludes an amino acid sequence of SEQ ID NO: 23, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO:24, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0321] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 28, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0322] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:28, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:29.

[0323] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:30. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:31 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0324] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 30, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 31, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0325] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 77, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 78, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 28, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 79, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0326] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 77, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 78, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:28, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:79.

[0327] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:80. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:81. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0328] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 80, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; Lincludes variants comprising an amino acid sequence of SEQ ID NO:81, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0329] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 82, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 83, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 84, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 86, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0330] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 82, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 83, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 84; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:85, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:86.

[0331] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:87.H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:88. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0332] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 87, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 88, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0333] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 124, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 125, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 126, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 128, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0334] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 124, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 125, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 126; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 128.

[0335] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 129. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 130. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0336] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 129, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 130, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0337] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V Hcomprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 89, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 90, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 91, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 92, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 93, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 94, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0338] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 89, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 90, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 91; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:92, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:93, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:94.

[0339] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:95. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:96 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0340] In some embodiments, V Hincludes an amino acid sequence of SEQ ID NO: 95, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 96, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0341] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 97, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 99, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 105, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 93, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 106, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0342] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 97, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 99; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 105, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 93, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 106.

[0343] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 103. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 107. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0344] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 103, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 107, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0345] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 245, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 246, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 247, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 248, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 249, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 250, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0346] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 245, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 246, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 247; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 248, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 249, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 250.

[0347] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:251. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 252 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0348] In some embodiments, V H comprises an amino acid sequence of SEQ ID NO: 251, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; Lincludes variants comprising an amino acid sequence of SEQ ID NO: 252, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0349] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 253, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 254, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 255, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 256, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 257, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 258, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0350] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 253, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 254, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 255; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:256, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:257, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:258.

[0351] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:259. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 260 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0352] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 259, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 260, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0353] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 9, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 11, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 14, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0354] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 9, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 11; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:13, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:14.

[0355] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:15. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:16. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0356] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 15, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 16, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0357] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V Hcomprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 67, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 68, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 69, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 273, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0358] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 67, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 68, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 69; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 273.

[0359] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:75. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 76 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0360] In some embodiments, V Hincludes an amino acid sequence of SEQ ID NO: 75, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 76, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0361] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 6, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0362] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO:1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO:2, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO:3; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:4, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:5, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:6.

[0363] In some embodiments, the antibody portion has the sequence shown in SEQ ID NO:7. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:8. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0364] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 7, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO:8, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0365] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 51, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 53, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 54, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 55, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 56, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0366] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 51, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 53; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:54, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:55, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:56.

[0367] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:57. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:58. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0368] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 57, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; Lincludes variants comprising an amino acid sequence of SEQ ID NO:58, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0369] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 116, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 117, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 118, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 119, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 120, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 121, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0370] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 116, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 117, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 118; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:119, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:120, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:121.

[0371] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 122. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 123. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0372] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 122, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 123, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0373] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO:59, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO:60, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO:61, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 62, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 63, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 64, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0374] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 59, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 60, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 61; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:62, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:63, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:64.

[0375] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:65. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:66 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0376] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 65, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO:66, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0377] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V Hcomprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 108, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 109, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 110, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 111, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 112, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 113, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0378] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 108, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 109, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 110; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:111, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:112, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:113.

[0379] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:114. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 115. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0380] In some embodiments, VH includes an amino acid sequence of SEQ ID NO: 114, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 115, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0381] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 40, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 41, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 42, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0382] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:40, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:41, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:42.

[0383] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:43. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO:44 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0384] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 43, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO:44, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0385] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 67, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 274, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 69, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; Lcomprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 275, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 273, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0386] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 67, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 274, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 69; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 275, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 273.

[0387] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:276. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 277 L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0388] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 276, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; Lincludes variants comprising an amino acid sequence of SEQ ID NO: 277, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0389] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 97, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 99, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDRs; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 100, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 101, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 102, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0390] In some embodiments, the anti-PLA2G2D antibody portion comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), a humanized antibody derived from an anti-PLA2G2D antibody comprising V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 97, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 99; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:100, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:101, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:102.

[0391] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 103.H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, respectively, and V having the sequence shown in SEQ ID NO: 104. L The amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions are included as LC-CDR1, LC-CDR2 and LC-CDR3, respectively.

[0392] In some embodiments, V H includes an amino acid sequence of SEQ ID NO: 103, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of SEQ ID NO: 104, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0393] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 279, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 280, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 133, 140, 145, 151, 162, 165, 170, 174, 178, 185, 188, 192, 196, 203, 206, 216, 223, 228, 232, 238, 242, 262, or 268; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:281, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:282, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:283.

[0394] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V Hcomprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 284 or 285, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 286 or 287, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 288, 47, or 19; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:289, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:290.

[0395] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 291, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 292, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 293; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 295, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 295, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 250, 258, 94, or 106.

[0396] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 294, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 246 or 254, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 247 or 255; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 295, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 295, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 250, 258, 94, or 106.

[0397] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V Hcomprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 9, 32, or 67, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, 33, 68, or 274, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 11, 34, or 69; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 297, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 298.

[0398] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, 51, or 116, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, 52, or 117, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, 53, or 118; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 299, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 300, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 6, 56, or 121.

[0399] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 59 or 108, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 60 or 109, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 61 or 110; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:301, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:302, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:303.

[0400] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V Hcomprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 67, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 68, 274, or 304, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 69; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 305, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 273.

[0401] In some embodiments, the anti-PLA2G2D construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 306 or 97, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 307 or 98, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, 99, or 53; L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 308 or 54, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 41, 101, or 55, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 309 or 102.

[0402] In some embodiments, V H and / or V L In some embodiments, the signaling peptide further comprises a signaling peptide. H and / or V L In some embodiments, the signaling peptide has an amino acid sequence set forth in any of SEQ ID NOs: 310-340.

[0403] In some embodiments, the constructs include full length antibodies, bispecific antibodies, single chain Fv (scFv) fragments, Fab fragments, Fab' fragments, F(ab'), Fv fragments, disulfide stabilized Fv fragments (dsFv), (dsFv), V HH, Fv-Fc fusion, scFv-Fc fusion, scFv-Fv fusion, diabody, tribody, and tetrabody, or an antigen-binding fragment thereof.

[0404] In some embodiments, the anti-PLA2G2D antibody portion is a full-length antibody.

[0405] In some embodiments, the anti-PLA2G2D antibody portion is an scFv.

[0406] In some embodiments, the anti-PLA2G2D antibody portion comprises an Fc fragment of an immunoglobulin selected from the group consisting of IgG, IgA, IgD, IgE, IgM, and combinations and hybrids thereof. In some embodiments, the anti-PLA2G2D antibody portion or full-length antibody comprises an Fc fragment of an immunoglobulin selected from the group consisting of IgG1, IgG2, IgG3, IgG4, and combinations and hybrids thereof. In some embodiments, the Fc fragment has reduced effector function compared to the corresponding wild-type Fc fragment. In some embodiments, the Fc fragment has enhanced effector function compared to the corresponding wild-type Fc fragment. In some embodiments, the Fc fragment is modified to have increased serum half-life compared to the corresponding wild-type Fc fragment. In some embodiments, the Fc fragment is modified to have decreased serum half-life compared to the corresponding wild-type Fc fragment.

[0407] In some embodiments, the antibody portion comprises a humanized antibody of any of the antibody portions described herein.

[0408] In some embodiments, the anti-PLA2G2D construct comprises or is an anti-PLA2G2D fusion protein.

[0409] In some embodiments, the anti-PLA2G2D construct comprises or is a multispecific anti-PLA2G2D construct (such as a bispecific antibody).

[0410] In some embodiments, the anti-PLA2G2D construct comprises or is an anti-PLA2G2D immunoconjugate.

[0411] In some embodiments, the PLA2G2D is human PLA2G2D.

[0412] PLA2G2D PLA2G2D (phospholipase A2 group IID, sPLA2-IID) is a secreted member of the phospholipase A2 family. Phospholipase A2 family members hydrolyze the sn-2 fatty acid ester bond of glycerophospholipids to produce lysophospholipids and free fatty acids. To date, ten sPLA2 isoforms (IB, IIA, IIC, IID, IIE, IIF, III, V, X and XII) have been identified in mammals. These isoforms, except for group III isoforms, have a highly conserved catalytic site, a Ca 2+ binding loop, and a common molecular weight of 14-19 kDa. Of these sPLA2 isoforms, sPLA2-IIA, sPLA2-IIC, sPLA2-IID, sPLA2-IIE, sPLA2-IIF and sPLA2-V have the same chromosomal locus (1p34-p36), often referred to as group II subfamily sPLA2. A biological feature of the group II subfamily sPLA2 is that almost all isoforms, except for sPLA2-IIC (a pseudogene in humans), are associated with inflammatory and immune processes.

[0413] Human PLA2G2D is a basic protein (pI approx. 8.7) with 14 cysteines at precisely conserved positions. PLA2G2D binds to heparin in vitro or to heparin sulfate on the cell surface when overexpressed in cultured cells, presumably due to its cationic nature.

[0414] In some embodiments, PLA2G2D comprises the amino acid sequence set forth in SEQ ID NO: 349 or 350. In some embodiments, PLA2G2D comprises the amino acid sequence set forth in SEQ ID NO: 353 or 354.

[0415] a) Antibody affinity The binding specificity of an antibody moiety can be determined experimentally by methods known in the art, including, but not limited to, Western blot, ELISA-, RIA-, ECL-, IRMA-, EIA-, BLI, BIACORE™-test, flow cytometry and peptide scanning.

[0416] In some embodiments, the K of binding between the antibody moiety and PLA2G2D is D is about 10 -7 M~about 10 -12 M, about 10 -7 M~about 10 -8 M, about 10 -8 M~about 10 -9 M, about 10 -9 M~about 10 -10 M, about 10 -10 M~about 10 -11 M, about 10 -11 M~about 10 -12 M, about 10 -7 M~about 10 -12 M, about 10 -8 M~about 10 -12 M, about 10 -9 M~about 10 -12 M, about 10 -10 M~about 10 -12 M, about 10 -7 M~about 10 -11 M, about 10 -8 M~about 10 -11 M, about 10 -9 M~about 10 -11 M, about 10 -7 M~about 10 -10 M, about 10 -8 M~about 10 -10 M, or about 10 -7 M~about 10 -9In some embodiments, the K of binding between the antibody moiety and PLA2G2D is D is about 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, or 10 -12 M. In some embodiments, the PLA2G2D is human PLA2G2D.

[0417] In some embodiments, the K of binding between the antibody moiety and PLA2G2D is on is about 10 3 M -1 s -1 ~about 10 8 M -1 s -1 , about 10 3 M -1 s -1 ~about 10 4 M -1 s -1 , about 10 4 M -1 s -1 ~about 10 5 M -1 s -1 , about 10 5 M -1 s -1 ~about 10 6 M -1 s -1 , about 10 6 M -1 s -1 ~about 10 7 M -1 s -1 , or about 10 7 M -1 s -1 ~about 10 8 M -1 s -1 In some embodiments, the K of binding between the antibody moiety and PLA2G2D is on is about 10 3 M -1 s -1 ~about 10 5 M -1 s -1 , about 10 4 M -1s -1 ~about 10 6 M -1 s -1 , about 10 5 M -1 s -1 ~about 10 7 M -1 s -1 , about 10 6 M -1 s -1 ~about 10 8 M -1 s -1 , about 10 4 M -1 s -1 ~about 10 7 M -1 s -1 , or about 10 5 M -1 s -1 ~about 10 8 M -1 s -1 In some embodiments, the K of binding between the antibody moiety and PLA2G2D is on is about 10 3 M -1 s -1 , 10 4 M -1 s -1 , 10 5 M -1 s -1 , 10 6 M -1 s -1 , 10 7 M -1 s -1 or 10 8 M -1 s -1 In some embodiments, the PLA2G2D is human PLA2G2D.

[0418] In some embodiments, the K of binding between the antibody moiety and PLA2G2D is off takes about 1s -1 ~about 10 -6 s -1 , about 1s -1 ~about 10 -2 s -1 , about 10 -2 s -1 ~about 10-3 s -1 , about 10 -3 s -1 ~about 10 -4 s -1 , about 10 -4 s -1 ~about 10 -5 s -1 , about 10 -5 s -1 ~about 10 -6 s -1 , about 1s -1 ~about 10 -5 s -1 , about 10 -2 s -1 ~about 10 -6 s -1 , about 10 -3 s -1 ~about 10 -6 s -1 , about 10 -4 s -1 ~about 10 -6 s -1 , about 10 -2 s -1 ~about 10 -5 s -1 , or about 10 -3 s -1 ~about 10 -5 s -1 In some embodiments, the K of binding between the antibody moiety and PLA2G2D is off is at least about 1s -1 , 10 -2 s -1 , 10 -3 s -1 , 10 -4 s -1 , 10 -5 s -1 or 10 -6 s -1 In some embodiments, the PLA2G2D is human PLA2G2D.

[0419] In some embodiments, the binding affinity of an anti-PLA2G2D antibody portion or anti-PLA2G2D construct is higher (e.g., K D value is smaller).

[0420] b) Chimeric or humanized antibodies In some embodiments, the anti-PLA2G2D antibody portion is a chimeric antibody. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). In some embodiments, the chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse) and a human constant region. In some embodiments, the chimeric antibody is a "class-switched" antibody whose class or subclass is changed from that of the parent antibody. The chimeric antibody includes its antigen-binding fragment.

[0421] In some embodiments, the anti-PLA2G2D antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which the HVR, e.g., CDR (or a portion thereof) is derived from a non-human antibody and the FR (or a portion thereof) is derived from a human antibody sequence. The humanized antibody also optionally comprises at least a portion of a human constant region. In some embodiments, some FR residues in the humanized antibody are replaced with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve the specificity or affinity of the antibody.

[0422] Humanized antibodies and methods for making them are reviewed, e.g., in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and further described, e.g., in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing SDR (a-CDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing "resurfacing"); Dall'Acqua et al., Methods 36:43-60 (2005) (describing "FR shuffling"); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing a "guided selection" approach to FR shuffling).

[0423] Human framework regions that can be used for humanization include, but are not limited to, framework regions selected using the "best-fit" method (see, e.g., Sims et al. J. Immunol. 151:2296 (1993)); framework regions derived from consensus sequences of human antibodies of particular subgroups of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening of FR libraries (see, e.g., Baca et al. al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996).

[0424] It is understood that humanization of mouse-derived antibody is a common and routinely used technique.Therefore, it is understood that any and all humanized formats of anti-PLA2G2D antibody disclosed in sequence listing can be used in preclinical or clinical situations.When any humanized format of the referenced anti-PLA2G2D antibody or its antigen-binding region is used in such preclinical or clinical situations, it is expected that the humanized format has the same or similar biological activity and profile as the original non-humanized format.

[0425] c) Human antibodies In some embodiments, the anti-PLA2G2D antibody portion is a human antibody (known as a human domain antibody or human DAb). Human antibodies can be produced using various techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr.Opin.Pharmacol.5:368-74(2001), Lonberg, Curr.Opin.Immunol.20:450-459(2008), and Chen, Mol.Immunol.47(4):912-21(2010). Transgenic mice or rats capable of producing fully human single domain antibodies (or DAbs) are known in the art. See, e.g., US20090307787A1, U.S. Patent No. 8,754,287, US20150289489A1, US20100122358A1, and WO2004049794.

[0426] Human antibodies (e.g., human DAbs) can be prepared by administering immunogens to transgenic animals that have been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigen challenge. Such animals typically contain all or part of a human immunoglobulin locus that replaces the endogenous immunoglobulin locus, is extrachromosomal, or is randomly integrated into the animal's chromosomes. In such transgenic mice, the endogenous immunoglobulin locus is generally inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 (describing XENOMOUSE™ technology); U.S. Pat. No. 5,770,429 (describing HuMab®); U.S. Pat. No. 7,041,870 (describing KM MOUSE®), and U.S. Patent Application No. 2007 / 0061900 (describing VelociMouse®). The human variable regions from intact antibodies produced by such animals can be further modified, for example, by combining with different human constant regions.

[0427] Human antibodies (e.g., human DAbs) can also be produced by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for producing human monoclonal antibodies have been described (see, for example, Kozbor J.Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp.51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J.Immunol., 147:86 (1991)). Human antibodies generated via human B-cell hybridoma technology are also described in Li et al., Proc.Natl.Acad.Sci.USA, 103:3557-3562 (2006). Further methods include those described, for example, in U.S. Patent No. 7,189,826 (describing the production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).

[0428] Human antibodies (e.g., human DAbs) can also be made by isolating Fv clone variable domain sequences selected from a human-derived phage display library. Such variable domain sequences can then be combined with the desired human constant domains. Techniques for selecting human antibodies from an antibody library are described below.

[0429] d) Library-derived antibodies The anti-PLA2G2D antibody portion described herein can be isolated by screening combinatorial libraries for antibodies with one or more desired activities.For example, various methods are known in the art for making phage display libraries and screening such libraries for antibodies with desired binding properties. Such methods are reviewed, for example, in Hoogenboom et al., Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001), and further described, for example, in McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352:624-628 (1991); Marks et al., J. Mol. Biol. 222:581-597 (1992); Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2):299-310 (2004); Lee et al. al., J. Mol. Biol. 340(5):1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34):12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132 (2004). Methods for constructing single domain antibody libraries have been described (see, e.g., U.S. Pat. No. 7,371,849).

[0430] In certain phage display methods, V H and V LGene repertoires can be cloned separately by polymerase chain reaction (PCR) and randomly recombined in phage libraries, which can then be screened for antigen-binding phages as described in Winter et al., Ann. Rev. Immunol., 12:433-455 (1994). Phages typically display antibody fragments as either scFv fragments or Fab fragments. Libraries from immunized sources provide high affinity antibodies to immunogens without the need to construct hybridomas. Alternatively, naive repertoires can be cloned (e.g., from humans) without any immunization to provide a single source of antibodies against a wide range of non-self antigens and self antigens as well, as described in Griffiths et al., EMBO J, 12:725-734 (1993). Finally, naive libraries can also be generated synthetically by cloning unrearranged V gene segments from stem cells and using PCR primers containing random sequences to encode highly variable CDR3 regions and achieve rearrangement in vitro, as described by Hoogenboom and Winter, J. Mol. Biol., 227:381-388 (1992). Patent publications describing human antibody phage libraries include, for example, U.S. Pat. No. 5,750,373, and U.S. Patent Application Publication Nos. 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936, and 2009 / 0002360.

[0431] Antibodies or antibody fragments isolated from a human antibody library are considered herein to be human antibodies or human antibody fragments.

[0432] e) Substitutions, insertions, deletions and mutations In some embodiments, antibody variants with one or more amino acid substitutions are provided. Sites of interest for substitution mutagenesis include HVRs (or CDRs) and FRs. Conservative substitutions are shown in Table 2 under the heading of "preferred substitutions". More substantial changes are provided in Table 2 under the heading of "exemplary substitutions" and are further described below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest and the products screened for the desired activity, for example, retained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC. Table 2. Amino acid substitutions [Table 2]

[0433] Amino acids can be grouped according to general side chain properties: (1) hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that affect chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe.

[0434] Non-conservative substitutions involve exchanging a member of one of these classes for another class.

[0435] One type of substitution variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variant(s) selected for further study have an alteration (e.g., improvement) in a particular biological property (e.g., increased affinity, reduced immunogenicity) compared to the parent antibody and / or substantially retain a particular biological property of the parent antibody. An exemplary substitution variant is an affinity matured antibody, which can be conveniently generated using, for example, phage display-based affinity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated and the variant antibodies are displayed on phage and screened for a particular biological activity (e.g., binding affinity).

[0436] For example, alterations (e.g., substitutions) may be made to HVRs to improve antibody affinity. Such alterations may be made at HVR "hot spots," i.e., codons that undergo high frequency mutation during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)) and / or residues encoded by the SDRs (a-CDRs), to improve the affinity of the resulting mutant V H or V Lare tested for binding affinity. Affinity maturation by constructing and reselecting a secondary library is described, for example, by Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some embodiments of affinity maturation, diversity is introduced into the variable genes selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity or molecular behavior. Another method of introducing diversity involves an HVR-directed approach, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding can be specifically identified using, for example, alanine or histidine scanning mutagenesis or modeling. In particular, the HC-CDR3 and LC-CDR3 are often targeted.

[0437] In some embodiments, substitutions, insertions or deletions may occur within one or more HVRs, so long as such changes do not substantially reduce the ability of the antibody to bind to the antigen. For example, conservative changes (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in HVRs. Such changes may be outside of HVR "hot spots" or CDRs.

[0438] A useful method for identifying antibody residues or regions that can be targeted for mutagenesis is called "alanine scanning mutagenesis" described in Cunningham and Wells (1989) Science, 244:1081-1085. In this method, residues or groups of target residues (e.g., charged residues such as Arg, Asp, His, Lys and Glu) are identified and replaced with neutral or negatively charged amino acids (e.g., alanine or polyalanine) to determine whether the interaction of the antibody with the antigen is affected. Further substitutions can be introduced at amino acid positions that show functional sensitivity to the initial substitution. Alternatively, or in addition, a crystal structure of an antigen-antibody complex to identify contact points between the antibody and the antigen. Such contact and adjacent residues can be targeted or eliminated as candidates for substitution. Mutants can be screened to determine whether they contain the desired properties of the antibody.

[0439] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. An example of a terminal insertion is an antibody with an N-terminal methionyl residue. Other insertional variants of antibody molecules include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g., for ADEPT) or a polypeptide which increases the serum half-life of the antibody.

[0440] f) Glycosylation variants In some embodiments, the anti-PLA2G2D antibody portion is altered to increase or decrease the extent to which the construct is glycosylated. Addition or deletion of glycosylation sites to an antibody can be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites are created or removed.

[0441] If the antibody moiety comprises an Fc region, the carbohydrate attached thereto can be altered. Native antibodies produced by mammalian cells typically have a C-terminal end with an Fc region.H The oligosaccharides of the antibody moiety include branched, biantennary oligosaccharides that are generally linked by N-linkage to Asn297 of the 2 domain. See, for example, Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharides may contain various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose and sialic acid, as well as fucose linked to GlcNAc in the "stem" of the biantennary oligosaccharide structure. In some embodiments, modification of the oligosaccharides of the antibody moiety may be performed to generate antibody variants with specific improved properties.

[0442] In some embodiments, the anti-PLA2G2D antibody portion has a carbohydrate structure that lacks fucose attached (directly or indirectly) to the Fc region. For example, the amount of fucose in such an antibody can be 1%-80%, 1%-65%, 5%-65% or 20%-40%. The amount of fucose is determined by calculating the average amount of fucose in the glycan at Asn297 relative to the sum of all glycan structures (e.g., complex, hybrid and high mannose structures) attached to Asn297 as measured by MALDI-TOF mass spectrometry, e.g., as described in WO 2008 / 077546. Asn297 refers to an asparagine residue located at about position 297 of the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located about ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to slight sequence variations in the antibody. Such fucosylation variants may have improved ADCC function. For example, US Patent Application Publication Nos. US2003 / 0157108 (Presta, L.); US2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd.). Examples of publications related to "defucosylated" or "fucose-deficient" antibody variants include: US2003 / 0157108; WO2000 / 61739; WO2001 / 29246; US2003 / 0115614; US2002 / 0164328; US2004 / 0093621; US2004 / 01 32140;US2004 / 0110704;US2004 / 0110282;US2004 / 0109865;WO2003 / 085119;WO2003 / 084570;WO2005 / 035586;WO2005 / 035778;WO2005 / 053742;WO2002 / 031140;Okazaki et al.J.Mol.Biol.336:1239-1249(2004);Yamane-Ohnuki et al.Biotech.Bioeng.87:614(2004).Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells, which are deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); U.S. Patent Application No. US2003 / 0157108A1, Presta, L; and WO2004 / 056312A1, Adams et al., especially Example 11), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO2003 / 085107).

[0443] In some embodiments, the anti-PLA2G2D antibody portion has bisected oligosaccharides, for example, biantennary oligosaccharides attached to the Fc region of the antibody are bisected by GlcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, for example, in WO2003 / 011878 (Jean-Mairet et al.); U.S. Patent No. 6,602,684 (Umana et al.); and US2005 / 0123546 (Umana et al.). Antibody variants having at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, in WO1997 / 30087 (Patel et al.); WO1998 / 58964 (Raju, S.); and WO1999 / 22764 (Raju, S.).

[0444] g) Fc region mutants In some embodiments, the anti-PLA2G2D antibody portion comprises an Fc fragment.

[0445] The term "Fc region", "Fc domain", "Fc fragment" or "Fc" refers to the C-terminal non-antigen binding region of an immunoglobulin heavy chain that contains at least a portion of the constant region. This term includes native and variant Fc regions. In some embodiments, a human IgG heavy chain Fc region extends from Cys226 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may be present or absent without affecting the structure or stability of the Fc region. Unless otherwise specified herein, the numbering of amino acid residues in an IgG or Fc region follows the EU numbering system for antibodies, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0446] In some embodiments, the Fc fragment is derived from an immunoglobulin selected from the group consisting of IgG, IgA, IgD, IgE, IgM, and combinations and hybrids thereof. In some embodiments, the Fc fragment is derived from an immunoglobulin selected from the group consisting of IgG1, IgG2, IgG3, IgG4, and combinations and hybrids thereof.

[0447] In some embodiments, the Fc fragment has reduced effector function compared to a corresponding wild-type Fc fragment (e.g., at least about 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% reduced effector function as measured by the level of antibody-dependent cellular cytotoxicity (ADCC).

[0448] In some embodiments, the Fc fragment is an IgG1 Fc fragment. In some embodiments, the IgG1 Fc fragment comprises a L234A mutation and / or a L235A mutation. In some embodiments, the Fc fragment is an IgG2 or IgG4 Fc fragment. In some embodiments, the Fc fragment is an IgG4 Fc fragment comprising a S228P, F234A and / or a L235A mutation. In some embodiments, the Fc fragment comprises a N297A mutation. In some embodiments, the Fc fragment comprises a N297G mutation.

[0449] In some embodiments, one or more amino acid modifications can be introduced into the Fc region of an antibody moiety, thereby generating an Fc region variant. The Fc region variant can comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) that contains an amino acid modification (e.g., a substitution) at one or more amino acid positions.

[0450] In some embodiments, the Fc fragment has some, but not all, effector functions, making it a desirable candidate for applications where the half-life of the antibody portion in vivo is important, but where certain effector functions (such as complement and ADCC) are unnecessary or harmful. In vitro and / or in vivo cytotoxicity assays can be performed to confirm the reduction / depletion of CDC and / or ADCC activity. For example, Fc receptor (FcR) binding assays can be performed to ensure that the antibody lacks FcγR binding (and thus likely lacks ADCC activity) but retains FcRn binding ability. NK cells, the primary cells for mediating ADCC, express only FcγRIII, while monocytes express FcγRI, FcγRII and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 2 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest are described in U.S. Pat. No. 5,500,362 (see, e.g., Hellstrom, I. et al. Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); 5,821,337 (see, Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assay methods may be used (see, for example, the ACTI™ Non-Radioactive Cytotoxicity Assay for Flow Cytometry (CellTechnology, Inc. Mountain View, CA; and CytoTox 96® Non-Radioactive Cytotoxicity Assay (Promega, Madison, WI)). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells.Alternatively, or in addition, the ADCC activity of the molecule of interest can be evaluated in vivo, for example, in an animal model as disclosed in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). A C1q binding assay can also be performed to confirm that the antibody cannot bind to C1q and therefore lacks CDC activity. See, for example, the C1q and C3c binding ELISAs in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDC assay can be performed (see, e.g., Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ Glennie, Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance / half-life determinations can also be performed using methods known in the art (see, e.g., Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006)).

[0451] Antibodies with reduced effector function include those with substitutions at one or more of Fc region residues 238, 265, 269, 270, 297, 327, and 329 (U.S. Patent No. 6,737,056). Such Fc variants include Fc variants with substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc variant in which residues 265 and 297 are substituted with alanine (U.S. Patent No. 7,332,581). In some embodiments, the Fc fragment comprises a N297A mutation. In some embodiments, the Fc fragment comprises a N297G mutation.

[0452] Certain antibody variants with improved or diminished binding to FcRs have been described. (See, e.g., U.S. Pat. No. 6,737,056; WO 2004 / 056312; and Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001).)

[0453] In some embodiments, the Fc fragment is an IgG1 Fc fragment. In some embodiments, the IgG1 Fc fragment comprises a L234A mutation and / or a L235A mutation. In some embodiments, the IgG1 Fc fragment comprises a L235A mutation and / or a G237A mutation. In some embodiments, the Fc fragment is an IgG2 or IgG4 Fc fragment. In some embodiments, the Fc fragment is an IgG4 Fc fragment comprising S228P, F234A and / or L235A mutations.

[0454] In some embodiments, the antibody portion comprises an Fc region with one or more amino acid substitutions that improve ADCC, e.g., substitutions at positions 298, 333 and / or 334 of the Fc region (EU numbering of residues).

[0455] In some embodiments, modifications are made to the Fc region that result in altered (i.e., either improved or decreased) C1q binding and / or complement dependent cytotoxicity (CDC), e.g., as described in U.S. Pat. No. 6,194,551, WO 99 / 51642, and Idusogie et al. J. Immunol. 164:4178-4184 (2000).

[0456] In some embodiments, the antibody partial variants comprise variant Fc regions that contain one or more amino acid substitutions that alter half-life and / or change binding to the neonatal Fc receptor (FcRn). Antibodies with increased half-life and improved binding to the neonatal Fc receptor (FcRn), which is responsible for maternal IgG transfer to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)), are described in US2005 / 0014934A1 (Hinton et al.). These antibodies comprise Fc regions with one or more substitutions that alter binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more Fc region residues (e.g., substitution at Fc region residue 434) (U.S. Patent No. 7,371,826).

[0457] See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821; and WO 94 / 29351 for other examples of Fc region variants.

[0458] h) Cysteine ​​Engineered Antibody Variants In some embodiments, it may be desirable to generate cysteine ​​engineered antibody moieties, e.g., "thioMAbs," in which one or more residues of an antibody are replaced with cysteine ​​residues. In certain embodiments, the replaced residues are located at accessible sites of the antibody. By replacing those residues with cysteine, reactive thiol groups are thereby placed at accessible sites of the antibody, which can be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to generate immunoconjugates, as further described herein. In some embodiments, any one or more of the following residues can be replaced with cysteine: A118 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region. Cysteine ​​engineered antibody moieties can be generated, for example, as described in U.S. Pat. No. 7,521,541.

[0459] i) Antibody derivatives In some embodiments, the antibody moieties described herein may be further modified to include additional non-proteinaceous moieties that are known and readily available in the art. Moieties suitable for derivatization of antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (either homopolymers or random copolymers), and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymer, propylene oxide / ethylene oxide copolymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight and may be branched or unbranched. The number of polymers attached to the antibody can vary, and when more than one polymer is attached, they can be the same or different molecules. In general, the number and / or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular property or function of the antibody to be improved, whether the antibody derivative will be used for diagnosis under defined conditions, etc.

[0460] In some embodiments, the antibody portion may be further modified to include one or more biologically active proteins, polypeptides, or fragments thereof. "Biological activity" or "biologically active", as used interchangeably herein, means to exhibit biological activity in the body to perform a specific function. For example, it may mean combination with a specific biomolecule, such as a protein, DNA, and then promoting or inhibiting the activity of such a biomolecule. In some embodiments, the biologically active protein or fragment thereof includes proteins and polypeptides administered to a patient as active drug substances for the prevention or treatment of a disease or condition, as well as proteins and polypeptides used for diagnostic purposes, such as enzymes used in diagnostic tests or in vitro assays, and proteins and polypeptides administered to a patient to prevent a disease (such as a vaccine).

[0461] Anti-PLA2G2D fusion protein In some embodiments, the anti-PLA2G2D construct comprises an anti-PLA2G2D antibody portion (eg, an anti-PLA2G2D scFv) and a second portion.

[0462] In some embodiments, the second moiety comprises a half-life extending moiety. In some embodiments, the half-life extending moiety is an albumin binding moiety (e.g., an albumin binding antibody moiety). In some embodiments, the anti-PLA2G2D antibody moiety and the half-life extending moiety are linked via a linker (such as any of the linkers described in the "Linkers" section).

[0463] Anti-PLA2G2D immunoconjugates In some embodiments, the anti-PLA2G2D constructs described herein further comprise a second moiety. In some embodiments, the second moiety comprises a therapeutic agent. In some embodiments, the second moiety comprises a label. In some embodiments, the anti-PLA2G2D antibody moiety and the second moiety are linked via a linker (such as any of the linkers described in the "Linkers" section).

[0464] In some embodiments, the second agent is a cytotoxic agent. In some embodiments, the cytotoxic agent is a chemotherapeutic agent. In some embodiments, the cytotoxic agent is a growth inhibitory agent. In some embodiments, the cytotoxic agent is a toxin (e.g., a protein toxin, an enzymatically active toxin of bacterial, fungal, plant or animal origin, or a fragment thereof). In some embodiments, the cytotoxic agent is a radioactive isotype (i.e., a radioconjugate).

[0465] Immunoconjugates allow for targeted delivery of, and in some embodiments, intracellular accumulation of, drug moieties to tissues (such as tumors) where systemic administration of unconjugated drugs can result in unacceptable levels of toxicity to normal cells (Polakis P. (2005) Current Opinion in Pharmacology 5:382-387).

[0466] Antibody-drug conjugates (ADCs) are targeted chemotherapy molecules that combine the properties of both antibodies and cytotoxic drugs by targeting potent cytotoxic drugs to antigen-expressing tumor cells (Teicher, BA (2009) Current Cancer Drug Targets 9:982-1004), thereby enhancing the therapeutic index by maximizing efficacy and minimizing off-target toxicity (Carter, PJ and Senter PD (2008) The Cancer Jour:14(3):154-169; Chari, RV (2008) ACC. Chen. Res. 41.98-107.

[0467] In the context of cancer treatment, the ADC compounds of the present application include those that have anti-cancer activity. In some embodiments, the ADC compounds include an antibody conjugated, i.e., covalently linked, to a drug moiety. In some embodiments, the antibody is covalently linked to the drug moiety via a linker. In some embodiments, the second agent is connected to the anti-PLA2G2D antibody moiety via a linker (such as a linker described herein). In some embodiments, the linker is cleavable. In some embodiments, the linker is non-cleavable.

[0468] The antibody-drug conjugates (ADCs) of the present application selectively deliver an effective dose of drug to tumor tissue, thereby allowing greater selectivity, i.e., lower effective doses, to be achieved while increasing the therapeutic index ("therapeutic window"). The drug moiety of the antibody-drug conjugates (ADCs) may include any compound, moiety, or group that has a cytotoxic or cytostatic effect. The drug moieties may impart their cytotoxic and cytostatic effects by mechanisms including, but not limited to, tubulin binding, DNA binding or intercalation, and inhibition of RNA polymerase, protein synthesis, and / or topoisomerase. Exemplary drug moieties include, but are not limited to, maytansinoids, dolastatins, auristatins, calicheamicins, pyrrolobenzodiazepines (PBDs), nemobicin and its derivatives, PNU-159682, anthracyclines, duocarmycins, vinca alkaloids, taxanes, trichothecenes, CC1065, camptothecins, elinafides, and their stereoisomers, isosteres, analogs, and derivatives that have cytotoxic activity.

[0469] Production of the immunoconjugates described herein can be found, for example, in US Pat. No. 9,562,099 and US Pat. No. 7,541,034, which are incorporated herein by reference in their entireties.

[0470] Linker In some embodiments, the anti-PLA2G2D constructs described herein include one or more linkers between two moieties (e.g., the anti-PLA2G2D antibody moiety and the half-life extending moiety, the anti-PLA2G2D antibody moiety and the second binding moiety in the above constructs). The length, degree of flexibility and / or other properties of the linker(s) used in the anti-PLA2G2D constructs may have some effect on the properties including, but not limited to, affinity, specificity or avidity for one or more particular antigens or epitopes. For example, a longer linker may be selected to ensure that two adjacent domains do not sterically interfere with each other. In some embodiments, the linker (such as a peptide linker) includes flexible residues (such as glycine and serine) so that the adjacent domains can move freely relative to each other. For example, a glycine-serine doublet may be a suitable peptide linker. In some embodiments, the linker is a non-peptide linker. In some embodiments, the linker is a peptide linker. In some embodiments, the linker is a non-cleavable linker. In some embodiments, the linker is a cleavable linker.

[0471] Other linker considerations include their effect on the physical or pharmacokinetic properties of the resulting compound, such as solubility, lipophilicity, hydrophilicity, hydrophobicity, stability (more or less stable and programmed degradation), rigidity, flexibility, immunogenicity, modulation of antibody binding, ability to be incorporated into micelles or liposomes, etc.

[0472] a) Peptide Linker The peptide linker may have a naturally occurring or non-naturally occurring sequence. For example, a sequence derived from the hinge region of a heavy chain-only antibody may be used as a linker. See, for example, WO1996 / 34103.

[0473] The peptide linker can be any suitable length. In some embodiments, the peptide linker is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 75, 100 or more amino acids in length. In some embodiments, the peptide linker is no more than about 100, 75, 50, 40, 35, 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5 or less amino acids in length. In some embodiments, the length of the peptide linker is from about 1 amino acid to about 10 amino acids, from about 1 amino acid to about 20 amino acids, from about 1 amino acid to about 30 amino acids, from about 5 amino acids to about 15 amino acids, from about 10 amino acids to about 25 amino acids, from about 5 amino acids to about 30 amino acids, from about 10 amino acids to about 30 amino acids in length, from about 30 amino acids to about 50 amino acids, from about 50 amino acids to about 100 amino acids, or from about 1 amino acid to about 100 amino acids.

[0474] The essential technical feature of such peptide linkers is that said peptide linkers do not contain any polymerization activity. The features of peptide linkers, including the absence of promotion of secondary structures, are known in the art and are described, for example, in Dall'Acqua et al. (Biochem. (1998) 37, 9266-9273), Cheadle et al. (Mol Immunol (1992) 29, 21-30) and Raag and Whitlow (FASEB (1995) 9(1), 73-80). A particularly preferred amino acid in the context of "peptide linkers" is Gly. Furthermore, peptide linkers that do not promote any secondary structures are preferred. The linkage of domains to each other can be provided, for example, by genetic engineering. Methods for preparing fused, operably linked bispecific single-chain constructs and expressing them in mammalian cells or bacteria are well known in the art (e.g., WO 99 / 54440; Ausubel, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, NY 1989 and 1994 or Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2001).

[0475] The peptide linker may be a stable linker that is not cleaved by proteases, particularly matrix metalloproteinases (MMPs).

[0476] The linker may be a flexible linker. Exemplary flexible linkers include glycine polymers (G) n (SEQ ID NO: 341), glycine-serine polymers (e.g., (GS) n (SEQ ID NO: 342), (GSGGS) n (SEQ ID NO:343), (GGGGS) n (SEQ ID NO: 344), and (GGGS) n(SEQ ID NO: 345), where n is an integer of at least 1), glycine-alanine polymers, alanine-serine polymers, and other flexible linkers known in the art. Glycine and glycine-serine polymers are relatively unstructured and can therefore function as neutral tethers between components. Glycine has access to much more phi-psi space than alanine and is much less restricted than residues with longer side chains (see Scheraga, Rev. Computational Chem. 11 173-142 (1992)). Those skilled in the art will recognize that the design of antibody fusion proteins can include linkers that are entirely or partially flexible, such that the linker can include a flexible linker portion as well as one or more portions that provide a less flexible structure to provide the desired antibody fusion protein structure.

[0477] Additionally, exemplary linkers also include (GGGGS) n (SEQ ID NO: 344), where n is an integer from 1 to 8, such as (GGGGS)3 (SEQ ID NO: 346; hereinafter referred to as "(G4S)3" or "GS3"), or (GGGGS)6 (SEQ ID NO: 347; hereinafter referred to as "(G4S)6" or "GS6"). In some embodiments, the peptide linker is (GSTSGSGKPGSGEGS) n (SEQ ID NO: 348), where n is an integer from 1 to 3.

[0478] b) Non-peptide Linkers The coupling of the two moieties can be achieved by any chemical reaction that binds the two molecules, so long as both components retain their respective activity, for example, binding to PLA2G2D in an anti-PLA2G2D multispecific antibody and to a second agent, respectively. This binding can include many chemical mechanisms, such as covalent binding, affinity binding, intercalation, coordinate binding, and complexation. In some embodiments, the binding is covalent. Covalent binding can be achieved either by direct condensation of existing side chains or by incorporation of an external crosslinking molecule. Many bivalent or polyvalent linking agents can be useful in coupling protein molecules in this context. For example, representative coupling agents can include organic compounds such as thioesters, carbodiimides, succinimide esters, diisocyanates, glutaraldehyde, diazobenzene, and hexamethylenediamine. This list is not intended to be exhaustive of the various classes of coupling agents known in the art, but rather, is illustrative of the more common coupling agents (see Killen and Lindstrom, Jour. Immun. 133:1335-2549 (1984); Jansen et al., Immunological Reviews 62:185-216 (1982); and Vitetta et al., Science 238:1098 (1987)).

[0479] Linkers that may be applied in the present application have been described in the literature (see, for example, Ramakrishnan, S. et al., Cancer Res. 44:201-208 (1984) which describes the use of MBS (M-maleimidobenzoyl-N-hydroxysuccinimide ester)). In some embodiments, non-peptide linkers used herein include: (i) EDC (1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride; (ii) SMPT (4-succinimidyloxycarbonyl-alpha-methyl-alpha-(2-pyridyl-dithio)-toluene (Pierce Chem. Co., Cat. (21558G); (iii) SPDP (succinimidyl-6[3-(2-pyridyldithio)propionamido]hexanoate (Pierce Chem. Co., Cat. #21651G); (iv) sulfo-LC-SPDP (sulfosuccinimidyl-6[3-(2-pyridyldithio)-propianamido]hexanoate (Pierce Chem. Co., Cat. #2165-G); and (v) sulfo-NHS (N-hydroxysulfo-succinimide: Pierce Chem. Co., Cat. #2165-G) conjugated to EDC. Chem. Co., Cat. #24510). In some embodiments, the linker is a PEG-containing linker.

[0480] The above linkers contain components with different attributes and therefore may result in bispecific antibodies with different physiochemical properties. For example, sulfo-NHS esters of alkyl carboxylates are more stable than sulfo-NHS esters of aromatic carboxylates. NHS ester-containing linkers are less soluble than sulfo-NHS esters. The linker SMPT also contains a sterically hindered disulfide bond, which can form a highly stable antibody fusion protein. Disulfide bonds are generally less stable than other bonds because disulfide bonds are cleaved in vitro, resulting in less available antibody fusion protein. In particular, sulfo-NHS can increase the stability of carbodiimide coupling. Carbodiimide coupling (such as EDC) when used in combination with sulfo-NHS forms esters that are more resistant to hydrolysis than the carbodiimide coupling reaction alone.

[0481] III. Preparation method In some emb...

Claims

1. Heavy chain variable region (V Ｈ ) and the light chain variable region (V Ｌ ) an anti-PLA2G2D construct comprising an antibody portion comprising: 1) the V H comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO:237, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO:132, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO:238; and the V L comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO:152, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO:135, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO:189; 2) the V H comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 145; and the V L comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 146, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147; 3) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 131, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 133; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 134, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136; 4) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 140; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 142; 5) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 151; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136; 6) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 157, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 145; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147; 7) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 160, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 145; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147; 8) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 162; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147; 9) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 165; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136; 10) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 278, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22; 11) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 170; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 171, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136; 12) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 174; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 175; 13) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 188; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 189; 14) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 178; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 181, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182; 15) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 178; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147; 16) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 192; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136; 17) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 192; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 200, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136; 18) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 203; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136; 19) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 185; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136; 20) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 206; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 207, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 208; 21) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 195, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 196; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 197, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136; 22) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 211; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147; 23) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO:214, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO:215, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO:216; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:217, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:218, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:219; 24) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 222, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 223; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 224; 25) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 227, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 228; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182; 26) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO:227, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO:231, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO:232; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 233, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 234, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182; 27) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO:241, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO:132, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO:242; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136; 28) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 261, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 262; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:263, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:135, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:264; 29) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 267, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 268; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 269, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 270, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182; 30) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 45, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 46, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 47; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:48, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22; 31) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22; 32) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO:25, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO:26, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO:27; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:28, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:29; 33) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 77, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 78, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:28, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:79; 34) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 82, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 83, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 84; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 85, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 86; 35) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 124, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 125, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 126; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 128; 36) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 89, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 90, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 91; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:92, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:93, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:94; 37) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO:97, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO:98, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO:99; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 105, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 93, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 106; 38) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO:245, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO:246, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO:247; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 248, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 249, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 250; 39) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO:253, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO:254, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO:255; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:256, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:257, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:258; 40) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 9, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 11; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 14; 41) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 67, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 68, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 69; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 273; 42) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:4, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:5, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:6; 43) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 51, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 53; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 54, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 55, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 56; 44) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 116, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 117, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 118; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 119, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 120, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 121; 45) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO:59, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO:60, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO:61; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 62, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 63, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 64; 46) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 108, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 109, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 110; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 111, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 112, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 113; 47) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 40, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 41, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 42; 48) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO:67, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO:274, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO:69; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 275, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 273; 49) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO:97, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO:98, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO:99; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 100, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 101, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 102; 50) The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO:279, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO:280, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO:133, 140, 145, 151, 162, 165, 170, 174, 178, 185, 188, 192, 196, 203, 206, 216, 223, 228, 232, 238, 242, 262, or 268; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:281, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:282, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:283; 51) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 284 or 285, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 286 or 287, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 288, 47, or 19, Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:289, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:290; 52) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 291, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 292, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 293; Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 295, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 295, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 250, 258, 94, or 106; 53) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 294, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 246 or 254, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 247 or 255, Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 295, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 295, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 250, 258, 94, or 106; 54) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 9, 32, or 67, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, 33, 68, or 274, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 11, 34, or 69, Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 297, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 298; 55) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, 51, or 116, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, 52, or 117, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, 53, or 118, Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:299, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:300, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:6, 56, or 121; 56) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 59 or 108, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 60 or 109, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 61 or 110, Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 301, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 302, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 303; 57) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 67, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 68, 274, or 304, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 69, Ｌ comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 305, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 273; or 58) The above V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 306 or 97, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 307 or 98, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, 99, or 53, Ｌ an anti-PLA2G2D construct comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 308 or 54, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 41, 101, or 55, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 309 or 102.

2. 1. An anti-PLA2G2D construct comprising an antibody portion that specifically binds to PLA2G2D, 1) HC-CDR1, HC-CDR2, and HC-CDR3 comprising the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within a V H chain region having the sequence set forth in SEQ ID NO:239, and LC-CDR1, LC-CDR2, and LC-CDR3 comprising the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within a V L chain region having the sequence set forth in SEQ ID NO:240; 2) HC-CDR1, HC-CDR2 and HC-CDR3 comprising the amino acid sequences of CDR1, CDR2 and CDR3, respectively, within a V H chain region having the sequence set forth in SEQ ID NO: 148, and LC-CDR1, LC-CDR2 and LC-CDR3 comprising the amino acid sequences of CDR1, CDR2 and CDR3, respectively, within a V L chain region having the sequence set forth in SEQ ID NO: 149; 3) V having the sequence shown in SEQ ID NO: 7 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence shown in SEQ ID NO:

8. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 4) V having the sequence shown in SEQ ID NO: 15 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence shown in SEQ ID NO:

16. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 5) V having the sequence shown in SEQ ID NO: 23 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

24. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 6) V having the sequence shown in SEQ ID NO: 30 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

31. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 7) V having the sequence shown in SEQ ID NO: 43 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

44. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 8) V having the sequence set forth in SEQ ID NO: 49 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence shown in SEQ ID NO:

50. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 9) V having the sequence set forth in SEQ ID NO: 57 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

58. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 10) V having the sequence set forth in SEQ ID NO: 65 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3, respectively, within the chain region, and V having the sequence shown in SEQ ID NO:

66. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 11) V having the sequence set forth in SEQ ID NO: 70 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

71. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 12) V having the sequence set forth in SEQ ID NO: 75 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

76. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 13) V having the sequence set forth in SEQ ID NO: 80 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

81. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 14) V having the sequence set forth in SEQ ID NO: 87 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

88. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 15) V having the sequence set forth in SEQ ID NO: 95 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

96. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 16) V having the sequence set forth in SEQ ID NO: 103 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

104. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 17) V having the sequence set forth in SEQ ID NO: 103 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

107. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 18) V having the sequence set forth in SEQ ID NO: 114 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

115. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 19) V having the sequence set forth in SEQ ID NO: 122 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

123. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 20) V having the sequence set forth in SEQ ID NO: 129 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

130. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 21) V having the sequence set forth in SEQ ID NO: 137 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

138. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 22) V having the sequence set forth in SEQ ID NO: 143 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

144. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 23) V having the sequence set forth in SEQ ID NO: 153 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

154. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 24) V having the sequence set forth in SEQ ID NO: 158 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

159. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 25) V having the sequence set forth in SEQ ID NO: 155 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

156. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 26) V having the sequence set forth in SEQ ID NO: 163 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

164. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 27) V having the sequence set forth in SEQ ID NO: 168 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

169. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 28) V having the sequence set forth in SEQ ID NO: 172 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

173. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 29) V having the sequence set forth in SEQ ID NO: 166 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

167. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 30) V having the sequence set forth in SEQ ID NO: 176 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

177. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 31) V having the sequence set forth in SEQ ID NO: 183 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

184. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 32) V having the sequence set forth in SEQ ID NO: 186 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

187. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 33) V having the sequence set forth in SEQ ID NO: 190 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

191. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 34) V having the sequence set forth in SEQ ID NO: 179 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

180. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 35) V having the sequence set forth in SEQ ID NO: 193 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

194. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 36) V having the sequence set forth in SEQ ID NO: 198 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

199. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 37) V having the sequence set forth in SEQ ID NO: 201 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

202. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 38) V having the sequence set forth in SEQ ID NO: 204 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

205. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 39) V having the sequence set forth in SEQ ID NO: 209 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

210. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 40) V having the sequence set forth in SEQ ID NO: 212 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

213. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 41) V having the sequence set forth in SEQ ID NO: 220 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

221. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 42) V having the sequence set forth in SEQ ID NO: 225 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

226. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 43) V having the sequence set forth in SEQ ID NO: 229 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

230. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 44) V having the sequence set forth in SEQ ID NO: 235 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

236. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 45) V having the sequence set forth in SEQ ID NO: 243 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

244. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 46) V having the sequence set forth in SEQ ID NO: 251 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

252. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 47) V having the sequence set forth in SEQ ID NO: 259 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

260. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 48) V having the sequence set forth in SEQ ID NO: 265 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

266. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; 49) V having the sequence set forth in SEQ ID NO: 271 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

272. Ｌ LC-CDR1, LC-CDR2 and LC-CDR3 comprising the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively; or 50) V having the sequence set forth in SEQ ID NO: 276 Ｈ HC-CDR1, HC-CDR2 and HC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively, and V having the sequence set forth in SEQ ID NO:

277. Ｌ An anti-PLA2G2D construct comprising LC-CDR1, LC-CDR2 and LC-CDR3 comprising the amino acid sequences of CDR1, CDR2 and CDR3 within the chain regions, respectively.

3. 3. The anti-PLA2G2D construct of claim 1 or claim 2, 1) the V H comprises the amino acid sequence of SEQ ID NO: 239, or a variant thereof having at least about 80% sequence identity; and the V L comprises the amino acid sequence of SEQ ID NO: 240, or a variant thereof having at least about 80% sequence identity; 2) the V H comprises a variant comprising the amino acid sequence of SEQ ID NO: 148, or an amino acid sequence having at least about 80% sequence identity; and the V L comprises the amino acid sequence of SEQ ID NO: 149, or a variant comprising an amino acid sequence having at least about 80% sequence identity; 3) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 7, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 8, or a variant thereof having at least about 80% sequence identity thereto; 4) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 15, or a variant thereof having an amino acid sequence with at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof having at least about 80% sequence identity thereto; 5) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 23, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 24, or a variant thereof having at least about 80% sequence identity thereto; 6) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 30, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 31, or a variant thereof having at least about 80% sequence identity thereto; 7) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 43, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 44, or a variant thereof having at least about 80% sequence identity thereto; 8) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 49, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 50, or a variant thereof having at least about 80% sequence identity thereto; 9) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 57, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 58, or a variant thereof having at least about 80% sequence identity thereto; 10) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 65, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 66, or a variant thereof having at least about 80% sequence identity thereto; 11) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 70, or a variant thereof having an amino acid sequence with at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 71, or a variant thereof having at least about 80% sequence identity thereto; 12) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 75, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 76, or a variant thereof having at least about 80% sequence identity thereto; 13) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 80, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 81, or a variant thereof having at least about 80% sequence identity thereto; 14) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 87, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 88, or a variant thereof having at least about 80% sequence identity thereto; 15) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 95, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 96, or a variant thereof having at least about 80% sequence identity thereto; 16) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 103, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 104, or a variant thereof having at least about 80% sequence identity thereto; 17) The above V Ｈ comprises the amino acid sequence of SEQ ID NO: 103, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 107, or a variant thereof having at least about 80% sequence identity thereto; 18) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 114, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 115, or a variant thereof having at least about 80% sequence identity thereto; 19) The above V Ｈ comprises the amino acid sequence of SEQ ID NO: 122, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 123, or a variant thereof having at least about 80% sequence identity thereto; 20) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 130, or a variant thereof having at least about 80% sequence identity thereto; 21) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 137, or a variant thereof having an amino acid sequence with at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 138, or a variant thereof having at least about 80% sequence identity thereto; 22) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 143, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 144, or a variant thereof having at least about 80% sequence identity thereto; 23) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 153, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 154, or a variant thereof having at least about 80% sequence identity thereto; 24) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 158, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 159, or a variant thereof having at least about 80% sequence identity thereto; 25) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 155, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 156, or a variant thereof having at least about 80% sequence identity thereto; 26) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 163, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 164, or a variant thereof having at least about 80% sequence identity thereto; 27) The above V Ｈ comprises the amino acid sequence of SEQ ID NO: 168, or a variant thereof having an amino acid sequence with at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 169, or a variant thereof having at least about 80% sequence identity thereto; 28) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 172, or a variant thereof having an amino acid sequence with at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 173, or a variant thereof having at least about 80% sequence identity thereto; 29) The above V Ｈ comprises the amino acid sequence of SEQ ID NO: 166, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 167, or a variant thereof having at least about 80% sequence identity thereto; 30) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 176, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 177, or a variant thereof having at least about 80% sequence identity thereto; 31) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 183, or a variant thereof having an amino acid sequence with at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 184, or a variant thereof having at least about 80% sequence identity thereto; 32) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 186, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 187, or a variant thereof having at least about 80% sequence identity thereto; 33) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 190, or a variant thereof having an amino acid sequence with at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 191, or a variant thereof having at least about 80% sequence identity thereto; 34) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 179, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 180, or a variant thereof having at least about 80% sequence identity thereto; 35) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 193, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 194, or a variant thereof having at least about 80% sequence identity thereto; 36) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 198, or a variant thereof having an amino acid sequence with at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 199, or a variant thereof having at least about 80% sequence identity thereto; 37) The above V Ｈ comprises the amino acid sequence of SEQ ID NO: 201, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 202, or a variant thereof having at least about 80% sequence identity thereto; 38) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 204, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 205, or a variant thereof having at least about 80% sequence identity thereto; 39) The above V Ｈ comprises the amino acid sequence of SEQ ID NO: 209, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 210, or a variant thereof having at least about 80% sequence identity thereto; 40) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 212, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 213, or a variant thereof having at least about 80% sequence identity thereto; 41) The above V Ｈ comprises the amino acid sequence of SEQ ID NO: 220, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 221, or a variant thereof having at least about 80% sequence identity thereto; 42) The above V Ｈ comprises the amino acid sequence of SEQ ID NO: 225, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 226, or a variant thereof having at least about 80% sequence identity thereto; 43) The above V Ｈ comprises the amino acid sequence of SEQ ID NO: 229, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 230, or a variant thereof having at least about 80% sequence identity thereto; 44) The above V Ｈ comprises the amino acid sequence of SEQ ID NO: 235, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 236, or a variant thereof having at least about 80% sequence identity thereto; 45) The above V Ｈ comprises the amino acid sequence of SEQ ID NO: 243, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 244, or a variant thereof having at least about 80% sequence identity thereto; 46) The above V Ｈ comprises the amino acid sequence of SEQ ID NO: 251, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 252, or a variant thereof having at least about 80% sequence identity thereto; 47) The above V Ｈ comprises the amino acid sequence of SEQ ID NO: 259, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 260, or a variant thereof having at least about 80% sequence identity thereto; 48) The above V Ｈ comprises the amino acid sequence of SEQ ID NO: 265, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 266, or a variant thereof having at least about 80% sequence identity thereto; 49) The above V Ｈ comprises the amino acid sequence of SEQ ID NO: 271, or a variant thereof having at least about 80% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 272, or a variant comprising an amino acid sequence having at least about 80% sequence identity; or 50) The V Ｈ comprises the amino acid sequence of SEQ ID NO: 276, or a variant thereof having at least about 80% sequence identity; Ｌ An anti-PLA2G2D construct comprising the amino acid sequence of SEQ ID NO: 277, or a variant thereof having at least about 80% sequence identity.

4. The antibody portion may be a full-length antibody, a diabody, a single chain Fv (scFv) fragment, a Fab fragment, a Fab' fragment, a F(ab')2, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv) ２ 3. The anti-PLA2G2D construct of claim 1 or 2, which is an antibody or antigen-binding fragment thereof selected from the group consisting of an Fv-Fc fusion, an scFv-Fc fusion, an scFv-Fv fusion, a diabody, a tribody, and a tetrabody.

5. The anti-PLA2G2D construct of claim 1 or 2, wherein the antibody portion has an Fc fragment selected from the group consisting of Fc fragments derived from IgG, IgA, IgD, IgE, IgM, and combinations and hybrids thereof.

6. The anti-PLA2G2D construct of claim 5, wherein the Fc fragment is selected from the group consisting of Fc fragments from IgG1, IgG2, IgG3, IgG4, and combinations and hybrids thereof.

7. The anti-PLA2G2D construct of claim 5, wherein the Fc fragment a) has reduced effector function compared to the corresponding wild-type Fc fragment, or b) has enhanced effector function compared to the corresponding wild-type Fc fragment.

8. The anti-PLA2G2D construct of claim 1 or 2, wherein the construct is a full-length antibody, a fusion protein, or an immunoconjugate.

9. The anti-PLA2G2D construct of claim 1 or 2, wherein the PLA2G2D is human PLA2G2D.

10. An anti-PLA2G2D construct that competes with the anti-PLA2G2D construct of claim 1 or 2 for the binding epitope of PLA2G2D.

11. A pharmaceutical composition comprising the anti-PLA2G2D construct of claim 1 or 2 and a pharmaceutically acceptable carrier.

12. 3. An isolated nucleic acid encoding the anti-PLA2G2D construct of claim 1 or 2, or a portion thereof.

13. A vector comprising the isolated nucleic acid of claim 12.

14. 13. An isolated host cell comprising the isolated nucleic acid of claim 12 or a vector comprising the isolated nucleic acid of claim 12.

15. 1. A method of producing an anti-PLA2G2D construct, comprising: a) culturing the isolated host cell of claim 14 under conditions effective to express the anti-PLA2G2D construct; b) obtaining the expressed anti-PLA2G2D construct from the host cell; and A method comprising:

16. A composition comprising an anti-PLA2G2D construct according to claim 1 or 2, or a pharmaceutical composition according to claim 11, for treating a disease or condition in an individual.

17. 17. The composition of claim 16, wherein the disease or condition is cancer.

18. The cancer is (a) is a solid tumor; (b) an advanced or malignant tumor; (c) have an increased expression level of PLA2G2D, and / or (d) selected from the group consisting of lung cancer, breast cancer, liver cancer, gastric cancer, cervical cancer, endometrial cancer, thyroid cancer, colorectal cancer, head and neck cancer, pancreatic cancer, kidney cancer, prostate cancer, urothelial cancer, testicular cancer, ovarian cancer and melanoma; 18. The composition of claim 17.

19. 17. The composition of claim 16, wherein the disease or condition is a viral infection.

20. The composition of claim 19, wherein the expression level of PLA2G2D is higher at the infected site than at a non-infected site.

21. The composition of claim 16, wherein the composition is administered in combination with a second drug.

22. 22. The composition of claim 21, wherein the second agent is selected from the group consisting of a chemotherapeutic agent, an immunomodulatory agent, an anti-angiogenic agent, a growth inhibitory agent, and an anti-neoplastic agent.

23. 23. The composition of claim 22, wherein the immunomodulatory agent is an immune checkpoint inhibitor, and the immune checkpoint inhibitor specifically targets PD-L1, PD-L2, CTLA4, PD-L2, PD-1, CD47, TIGIT, GITR, TIM3, LAG3, CD27, 4-1BB, or B7H4.

24. 22. The composition of claim 21, wherein the second agent comprises a cell comprising a chimeric antigen receptor that specifically binds to a tumor antigen.

25. 22. The composition of claim 21, wherein the composition and the second agent are (a) administered simultaneously or concurrently, or (b) administered sequentially, and / or the composition and / or the second agent are administered parenterally, and / or the composition is administered directly to cancer tissue or a site of infection, and / or the anti-PLA2G2D construct is administered at a dose of about 0.001 μg / kg to about 100 mg / kg.

26. 18. The composition of claim 17, wherein the individual has an increased number of immune cells in the cancer tissue after administration of the composition.

27. 27. The composition of claim 26, wherein the immune cell is a T cell.

28. 28. The composition of claim 27, wherein the T cells are activated T cells.

29. 18. The composition of claim 17, wherein immune cells in the cancer tissue produce increased levels of cytokines after administration of the composition, and the cytokines are IFNγ and / or IL-2.