Anti-SIRP alpha antibodies and methods of use thereof

Abstract

The present disclosure provides antibodies and antibody fragments that bind to human SIRPA. In some embodiments, the antibodies are SIRPA agonists. The antibodies and antibody fragments disclosed herein can be used to treat and / or diagnose diseases, disorders, and conditions associated with decreased SIRPA activity.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 227,649, filed July 30, 2021, the contents of which are incorporated herein by reference for all purposes.

[0002] Sequence Listing This application has been submitted electronically in XML format along with a Sequence Listing, which is incorporated herein by reference in its entirety. The Sequence Listing is provided as a file entitled "01209-0013-00PCT_ST26.xml," created on July 21, 2022, and is 524,000 bytes in size.

[0003] The present disclosure relates to anti-SIRPα antibodies and uses (eg, therapeutic uses) of such antibodies. [Background technology]

[0004] An appropriate immune response triggered by a challenge requires specific signals for immune activation and restoration of homeostasis to provide a survival advantage to the host. Professional phagocytes, such as macrophages, play a crucial role in fulfilling this broad mandate by interpreting local environmental cues and orchestrating proinflammatory responses or resolving inflammation. However, despite numerous homeostatic control mechanisms, excessive, misdirected, or chronic immune activation often forms the basis of inflammatory diseases with autoimmune etiology. There is a need for the development of anti-inflammatory therapies that can alleviate these chronic inflammatory conditions with the goal of restoring normal tissue homeostasis.

[0005] Phagocyte activity is regulated by the expression of inhibitory receptors, one of which is signal-regulatory protein α (SIRPA). This receptor belongs to the SIRP family of transmembrane receptors and is primarily expressed in myeloid cell lineages (including MΦ, DC, and granulocytes). It is characterized by an extracellular domain containing two membrane-proximal IgC domains and a distal IgV domain. Unique to this family, SIRPA contains an intracellular cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM). Upon receptor crosslinking, the tyrosine-phosphorylated ITIM site recruits and activates Src homology region 2 domain-containing phosphatase 1 / 2 (SHP-1 / 2), negatively regulating cellular functions such as phagocytosis or inflammatory cytokine release. CD47 functions as the primary ligand for SIRPA and is broadly expressed on most cell types, including endothelial / epithelial cells, leukocytes, and erythrocytes, suggesting that CD47 mediates a "don't-eat-me" signal to protect healthy cells from phagocyte-dependent clearance. Supporting this view, several studies have shown that adoptive transfer of erythrocytes or leukocytes from CD47 knockout mice to wild-type recipients results in rapid clearance of CD47-deficient cells. Conversely, positional genetic analysis of multiple strains of immunodeficient mice receiving human hematopoietic cells identified the SIRPA allele in NOD mice as a causative factor for successful engraftment in xenotransplantation models. Subsequent studies demonstrated that allelic variants of SIRPA expressed in NOD mice retain the ability to bind to human CD47 expressed on human hematopoietic stem cells, thereby suppressing macrophage-dependent graft rejection.

[0006] Regulation of SIRPA and CD47 expression establishes a homeostatic control mechanism that regulates phagocyte activity. For example, apoptotic cells downregulate CD47 expression to promote phagocytosis by resident macrophages, while viable cells remain intact. Similarly, inflammatory stimuli such as LPS reduce SIRPA expression in MΦs and DCs, enhancing their activation during inflammation. However, dysregulation of SIRPA or CD47 expression contributes to inflammatory disorders. For example, hemophagocytic lymphohistiocytosis (HLH) is a syndrome involving excessive immune activation characterized by unregulated phagocytosis of hematopoietic stem cells (HSCs) by bone marrow macrophages. Accordingly, over 80% of HLH patients exhibit cytopenias. Cell analysis revealed that CD47 is significantly downregulated in the CD34+CD38- HSC fraction of HLH patients during disease relapse, rendering these cells susceptible to macrophage-mediated clearance. In another example, transcriptomic and proteomic profiles of pathological multiple sclerosis (MS) brain lesions obtained from deceased patients revealed decreased expression of CD47 at the mRNA and protein levels. Studies investigating the role of CD47 in the pathology of a mouse model of MS observed that administration of an anti-CD47 blocking antibody at the peak of paralysis exacerbated neuroinflammation and disease severity, suggesting that CD47 acts to regulate inflammation via SIRPA.

[0007] Apart from data from human patients establishing a correlation between CD47 expression levels and inflammation, animal models of autoimmunity suggest that drug interventions stimulating the SIRPA pathway can ameliorate disease. For example, in trinitrobenzene sulfonic acid (TNBS)-induced colitis, a mouse model of intestinal inflammation driven by proinflammatory SIRPA+CD103- dendritic cells, administration of recombinant CD47-Fc fusion protein before TNBS injection protected against colonic inflammation (as determined by body weight, intestinal tissue damage, and serum cytokine levels). Similar observations have been reported in collagen antibody-induced arthritis, a mouse model of rheumatoid arthritis, in which prophylactic treatment with CD47-Fc reduced disease incidence and total disease score. Thus, the SIRPA-CD47 axis may serve as a basis for the development of novel therapeutic strategies to alleviate inflammatory disorders.

[0008] Microglial SIRPA is downregulated in Alzheimer's disease pathology and has been shown to play a critical role in regulating synaptic remodeling in the central nervous system (Ding et al., 2021, Nature Communications, 12:2030; Lehrman et al., 2018, Neuron, 100:120-134). Such studies demonstrated that CD47-SIRPA signaling prevents excessive microglial phagocytosis. In particular, the "don't eat me" signal associated with the SIRPA-CD47 axis is required to prevent excessive pruning and abnormal microglial phagocytosis during postnatal development, suggesting that CD47 protects specific synaptic populations from targeting by microglial cells. Furthermore, loss of microglial SIRPA leads to increased synapse loss mediated, at least in part, by microglial phagocytosis, enhancing cognitive impairment (see, e.g., Ding et al., 2021, Nature Communications, 12:2030).

[0009] Anti-SIRPA antibodies have been previously described, for example, in International Patent Application Publication Nos. WO2018 / 057669, WO2018 / 026600, WO2017 / 178653, WO2017 / 068164, WO2016 / 063233, WO2016 / 205042, WO2015 / 138600, WO2013 / 0956352, WO2009 / 091547, WO2009 / 131453, and WO2009 / 046541.

[0010] Therefore, there is a need for therapeutic anti-SIRPA therapies to treat diseases, disorders, and conditions associated with reduced SIRPA activity.

[0011] All references cited herein, including patent applications and publications, are hereby incorporated by reference in their entirety. Summary of the Invention

[0012] The present disclosure relates to an antibody that specifically binds to SIRPA. In some embodiments, the antibody is a SIRPA agonist. The present disclosure includes multiple embodiments, including but not limited to the following embodiments:

[0013] Embodiment 1 is an isolated antibody that specifically binds to human SIRPA, the antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises: a. HVR-H1 comprising an amino acid sequence selected from any one of SEQ ID NOs: 102 to 122, 318 to 328, and 346 to 349; b. HVR-H2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 123 to 146 and 329 to 345, and c. HVR-H3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 147 to 201, 350 to 360, and 371 to 386.

[0014] Embodiment 2 is the antibody of embodiment 1, wherein the light chain variable region (VL) comprises: a. HVR-L1 comprising an amino acid sequence selected from any one of SEQ ID NOs: 7 to 28; b. HVR-L2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 29 to 40, and c. HVR-L3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 41 to 101.

[0015] Embodiment 3 is the antibody of embodiment 1 or 2, wherein the antibody comprises a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to an amino acid sequence selected from any one of SEQ ID NOs: 202-256, 361-370, and 387-412.

[0016] Embodiment 4 is the antibody of any one of embodiments 1 to 3, wherein the antibody comprises a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to an amino acid sequence selected from any one of SEQ ID NOs: 257-317, 261, 264, 269, 275, 312, and 413.

[0017] Embodiment 5 is the antibody of any one of embodiments 1 to 4, wherein the VH comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, insertions, and / or deletions compared to an amino acid sequence selected from any one of SEQ ID NOs: 202 to 256, 361 to 370, and 387 to 412.

[0018] Embodiment 6 is the antibody of any one of embodiments 1 to 5, wherein the VL comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, insertions, and / or deletions compared to an amino acid sequence selected from any one of SEQ ID NOs: 257-317, 261, 264, 269, 275, 312, and 413.

[0019] Embodiment 7 is the antibody of any one of Embodiments 1 to 6, wherein the antibody comprises a VH comprising an amino acid sequence selected from any one of SEQ ID NOs: 202 to 256, 361 to 370, and 387 to 412.

[0020] Embodiment 8 is the antibody of any one of Embodiments 1 to 7, wherein the antibody comprises a VL comprising an amino acid sequence selected from any one of SEQ ID NOs: 257-317, 261, 264, 269, 275, 312, and 413.

[0021] In Embodiment 9, the antibody is SA-1, SA-2, SA-3, SA-4, SA-5, SA-6, SA-7, SA-8, SA-9, SA-10, SA-11, SA-12, SA-13, SA-14, SA-15, SA-16, SA- 17, SA-18, SA-19, SA-20, SA-21, SA-22, SA-23, SA-24, SA-25, SA-26, SA-27, SA-28, SA-29, SA-30, SA-31, SA-32, SA-33, SA -34, SA-35, SA-36, SA-36, SA-37, SA-38, SA-39, SA-40, SA-41, SA-42, SA-43, SA-44, SA-45, SA-46, SA-47, SA-48, SA-49, S A-50, SA-51, SA-52, SA-53, SA-54, SA-55, SA-56, SA-57, SA-58, SA-59, SA-60, SA-61, SA-62, SA-5-57, SA-5-58, SA-5-59, S A-5-61, SA-8-62, SA-8-64, SA-8-66, SA-8-67, SA-13-68, SA-13-69, SA-13-71, SA-19-72, SA-19-73, SA-19-74, SA-19-75 , SA-19-76, SA-19-77, SA-19-78, SA-19-79, SA-19-80, SA-19-81, SA-19-82, SA-19-83, SA-19-84, SA-56-85, SA-56-86, SA and a VL comprising HVR-L1, HVR-L2, and HVR-L3 of any one of antibodies SA-56-87, SA-56-88, SA-56-89, SA-56-90, SA-56-91, SA-56-92, SA-56-93, SA-56-94, SA-56-95, or SA-56-96 (shown in Tables 3 and 7).

[0022] In Embodiment 10, the antibody is SA-1, SA-2, SA-3, SA-4, SA-5, SA-6, SA-7, SA-8, SA-9, SA-10, SA-11, SA-12, SA-13, SA-14, SA-15, SA-16, S A-17, SA-18, SA-19, SA-20, SA-21, SA-22, SA-23, SA-24, SA-25, SA-26, SA-27, SA-28, SA-29, SA-30, SA-31, SA-32, SA-33 , SA-34, SA-35, SA-36, SA-36, SA-37, SA-38, SA-39, SA-40, SA-41, SA-42, SA-43, SA-44, SA-45, SA-46, SA-47, SA-48, SA- 49, SA-50, SA-51, SA-52, SA-53, SA-54, SA-55, SA-56, SA-57, SA-58, SA-59, SA-60, SA-61, SA-62, SA-5-57, SA-5-58, SA- 5-59, SA-5-61, SA-8-62, SA-8-64, SA-8-66, SA-8-67, SA-13-68, SA-13-69, SA-13-71, SA-19-72, SA-19-73, SA-19-74, S A-19-75, SA-19-76, SA-19-77, SA-19-78, SA-19-79, SA-19-80, SA-19-81, SA-19-82, SA-19-83, SA-19-84, SA-56-85, SA 10. The isolated antibody of embodiment 9, comprising a VH and / or VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to that of any one of antibodies SA-56-86, SA-56-87, SA-56-88, SA-56-89, SA-56-90, SA-56-91, SA-56-92, SA-56-93, SA-56-94, SA-56-95, or SA-56-96 (shown in Tables 3 and 7).

[0023] In Embodiment 11, the antibody is SA-1, SA-2, SA-3, SA-4, SA-5, SA-6, SA-7, SA-8, SA-9, SA-10, SA-11, SA-12, SA-13, SA-14, SA-15, SA -16, SA-17, SA-18, SA-19, SA-20, SA-21, SA-22, SA-23, SA-24, SA-25, SA-26, SA-27, SA-28, SA-29, SA-30, SA-31, S A-32, SA-33, SA-34, SA-35, SA-36, SA-36, SA-37, SA-38, SA-39, SA-40, SA-41, SA-42, SA-43, SA-44, SA-45, SA-46, SA-47, SA-48, SA-49, SA-50, SA-51, SA-52, SA-53, SA-54, SA-55, SA-56, SA-57, SA-58, SA-59, SA-60, SA-61, SA-62, SA-5-57, SA-5-58, SA-5-59, SA-5-61, SA-8-62, SA-8-64, SA-8-66, SA-8-67, SA-13-68, SA-13-69, SA-13-71, SA-1 9-72, SA-19-73, SA-19-74, SA-19-75, SA-19-76, SA-19-77, SA-19-78, SA-19-79, SA-19-80, SA-19-81, SA-19-82, 11. The isolated antibody of embodiment 9 or embodiment 10, comprising the VH and / or VL of any one of antibodies SA-19-83, SA-19-84, SA-56-85, SA-56-86, SA-56-87, SA-56-88, SA-56-89, SA-56-90, SA-56-91, SA-56-92, SA-56-93, SA-56-94, SA-56-95, or SA-56-96 (shown in Tables 3 and 7).

[0024] Embodiment 12 is an isolated antibody that specifically binds to human SIRPA, comprising: a. a VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 102, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 123, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 41, b. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 124, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 148; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 8, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42. c. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 104, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 125, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 149; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 43. d. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 105, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 125, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 150; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 44. e. a VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 106, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 125, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 151; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 45; f. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 126, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 152; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 46. g. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 127, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 47. h. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 124, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 154; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48. i. a VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 106, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 155; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 49, j. a VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 126, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 156; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 34, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 50; k. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 102, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 123, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 157; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 51. l. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 108, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 129, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 158; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 52. m. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 106, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 125, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 53. n. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 130, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 160; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 15, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54. o. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 110, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 131, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 161; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 55. p. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 111, an HVR-H2 having the amino acid sequence of SEQ ID NO: 132, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 162; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 7, an HVR-L2 having the amino acid sequence of SEQ ID NO: 31, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 56, q. a VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 110, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 133, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 163; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 16, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 57; r. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 112, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 164; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 58. s. a VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 124, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59; t. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 124, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 154; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60. u. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 113, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 135, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 166; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 8, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 61. v. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 109, an HVR-H2 having the amino acid sequence of SEQ ID NO: 130, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 167; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 11, an HVR-L2 having the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 62. w. a VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 136, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 168; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 17, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 37, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 63; x. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 137, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 169; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 64. y. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 110, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 138, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 170; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 65. z. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 111, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 132, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 18, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66. aa. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 139, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 172; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 67, bb. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 116, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 173; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 68. cc. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 173; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 69, dd. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 137, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 174; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 70. ee. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 110, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 138, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 170; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 71. ff. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 175; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72; gg. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 110, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 133, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 176; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 73; hh. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 118, an HVR-H2 having the amino acid sequence of SEQ ID NO: 141, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 177; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 13, an HVR-L2 having the amino acid sequence of SEQ ID NO: 35, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 74. ii. a VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 119, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 129, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 178; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 75; jj. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 113, an HVR-H2 having the amino acid sequence of SEQ ID NO: 135, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 179; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 22, an HVR-L2 having the amino acid sequence of SEQ ID NO: 31, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 76. kk. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 116, an HVR-H2 having the amino acid sequence of SEQ ID NO: 139, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 180; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 23, an HVR-L2 having the amino acid sequence of SEQ ID NO: 38, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 77. ll. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 116, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 139, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 180; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 16, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78. mm. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 120, an HVR-H2 having the amino acid sequence of SEQ ID NO: 129, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 181; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 24, an HVR-L2 having the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 79, nn. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 119, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 142, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 182; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 80; oo. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 121, an HVR-H2 having the amino acid sequence of SEQ ID NO: 143, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 183; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 16, an HVR-L2 having the amino acid sequence of SEQ ID NO: 36, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 81. pp. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 143, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 25, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 82, qq. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 122, an HVR-H2 having the amino acid sequence of SEQ ID NO: 139, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 184; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 12, an HVR-L2 having the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 83, rr. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 144, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 185; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, ss. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 186; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 85, tt. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 104, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 125, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 187; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 86; a VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 119, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 129, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 188; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 87; vv. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 124, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 189; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 88, ww. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 109, an HVR-H2 having the amino acid sequence of SEQ ID NO: 130, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 190; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 12, an HVR-L2 having the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 89, xx. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 144, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 191; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90. yy. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 110, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 138, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 192; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 91. zz. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 118, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 141, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 193; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 40, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 92. aaa. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 145, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 194; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 93, bbb. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 139, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 195; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 94. ccc. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 112, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 196; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 27, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 95, ddd. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 130, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 197; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, eee. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 122, an HVR-H2 having the amino acid sequence of SEQ ID NO: 139, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 198; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 7, an HVR-L2 having the amino acid sequence of SEQ ID NO: 31, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 97. fff. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 139, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 199; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 98, ggg. VH comprising HVR-H1 having the amino acid sequence of SEQ ID NO: 121, HVR-H2 having the amino acid sequence of SEQ ID NO: 143, and HVR-H3 having the amino acid sequence of SEQ ID NO: 200; and VL comprising HVR-L1 having the amino acid sequence of SEQ ID NO: 11, HVR-L2 having the amino acid sequence of SEQ ID NO: 33, and HVR-L3 having the amino acid sequence of SEQ ID NO: 99, hhh. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 109, an HVR-H2 having the amino acid sequence of SEQ ID NO: 144, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 201; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 7, an HVR-L2 having the amino acid sequence of SEQ ID NO: 29, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 100. iii. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 119, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 129, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 178; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 75. jjj. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 109, an HVR-H2 having the amino acid sequence of SEQ ID NO: 144, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 201; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 28, an HVR-L2 having the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 101. kkk. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 318, an HVR-H2 having the amino acid sequence of SEQ ID NO: 329, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 350; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 9, an HVR-L2 having the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 45, III. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 318, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 330, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 351; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 45. mmm. a VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 319, an HVR-H2 having the amino acid sequence of SEQ ID NO: 331, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 352; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 9, an HVR-L2 having the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 45, nnn. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 318, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 125, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 353; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 45, ooo. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 320, an HVR-H2 having the amino acid sequence of SEQ ID NO: 332, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 371; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 11, an HVR-L2 having the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 48. ppp. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 320, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 332, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 154; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, qqq. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 103, an HVR-H2 having the amino acid sequence of SEQ ID NO: 333, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 154; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 11, an HVR-L2 having the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 45, rrr. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 320, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 334, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 154; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, sss. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 321, an HVR-H2 having the amino acid sequence of SEQ ID NO: 125, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 372; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 14, an HVR-L2 having the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 53. ttt. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 321, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 335, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 373; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 53; a VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 322, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 125, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 53; vvv. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 323, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 336, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 354; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59. www. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 323, an HVR-H2 having the amino acid sequence of SEQ ID NO: 336, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 355; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 11, an HVR-L2 having the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 59, xxx. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 346, an HVR-H2 having the amino acid sequence of SEQ ID NO: 336, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 356; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 11, an HVR-L2 having the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 59. yyy. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 337, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 357; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59. zzz. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 103, an HVR-H2 having the amino acid sequence of SEQ ID NO: 337, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 374; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 33, an HVR-L2 having the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 59, aaaa. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 347, an HVR-H2 having the amino acid sequence of SEQ ID NO: 338, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 165; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 11, an HVR-L2 having the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 59, bbbb. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 337, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 375; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59. cccc. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 339, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 376; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59. dddd. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 103, an HVR-H2 having the amino acid sequence of SEQ ID NO: 336, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 377; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 11, an HVR-L2 having the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 59. eeee. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 348, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 337, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 378; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59. ffff. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 323, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 336, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 379; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59, gggg. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 349, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 340, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 380; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59. hhhh. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 337, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 381; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59. iiii. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 324, an HVR-H2 having the amino acid sequence of SEQ ID NO: 341, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 197; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 12, an HVR-L2 having the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 96. jjjj. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 325, an HVR-H2 having the amino acid sequence of SEQ ID NO: 342, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 197; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 12, an HVR-L2 having the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 96. kkkk. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 325, an HVR-H2 having the amino acid sequence of SEQ ID NO: 341, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 382; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 12, an HVR-L2 having the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 96, III. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 325, an HVR-H2 having the amino acid sequence of SEQ ID NO: 343, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 383; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 12, an HVR-L2 having the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 96. mmmm. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 325, an HVR-H2 having the amino acid sequence of SEQ ID NO: 341, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 197; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 12, an HVR-L2 having the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 96. nnnn. A VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 326, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 341, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 197; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96. oooo. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 327, an HVR-H2 having the amino acid sequence of SEQ ID NO: 341, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 384; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 12, an HVR-L2 having the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 96. pppp. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 325, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 341, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 385; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96. qqqq. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 325, an HVR-H2 having the amino acid sequence of SEQ ID NO: 341, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 386; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 12, an HVR-L2 having the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 96, rrrr. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 325, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 341, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 358; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, a VH comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 327, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 344, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 359; and a VL comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, or tttt. A VH comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 328, an HVR-H2 having the amino acid sequence of SEQ ID NO: 345, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 360; and a VL comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 12, an HVR-L2 having the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 96.

[0025] Embodiment 13 is the antibody of embodiment 12, wherein the antibody comprises: a. The HVR of embodiment 12.a (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 202); b. The HVR of embodiment 12.b (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 203); c. The HVR of embodiment 12.c (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 204); d. The HVR of embodiment 12.d (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 205); e. The HVR of embodiment 12.e (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 206); f. The HVR of embodiment 12.f (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 207); g. The HVR of embodiment 12.g (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 208); h. The HVR of embodiment 12.h (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 209); i. The HVR of embodiment 12.i (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 210); j. The HVR of embodiment 12.j (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 211); k. The HVR of embodiment 12.k (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 212); l. The HVR of embodiment 12.l (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 213); m. The HVR of embodiment 12.m (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 214); n. The HVR of embodiment 12.n (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 215); o. The HVR of embodiment 12.o (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 216); p. The HVR of embodiment 12.p (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 217); q. The HVR of embodiment 12.q (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 218); r. The HVR of embodiment 12.r (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 219); s. The HVR of embodiment 12.s (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 220); t. The HVR of embodiment 12.t (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 209); u. The HVR of embodiment 12.u (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 221); v. The HVR of embodiment 12.v (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 222); w. The HVR of embodiment 12.w (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 223); x. The HVR of embodiment 12.x (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 224); y. The HVR of embodiment 12.y (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 225); z. The HVR of embodiment 12.z (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 226); aa. The HVR of embodiment 12.aa. (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 227); bb. The HVR of embodiment 12.bb (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 228); cc. The HVR of embodiment 12.cc (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 228); dd. The HVR of embodiment 12.dd (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 229); ee. The HVR of embodiment 12.ee (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 225); ff. The HVR of embodiment 12.ff (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 230); gg. The HVR of embodiment 12.gg (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 231); hh. The HVR of embodiment 12. hh (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 232); ii. The HVR of embodiment 12.ii, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 233; jj. The HVR of embodiment 12.jj (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 234); kk. The HVR of embodiment 12.kk (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 235); ll. The HVR of embodiment 12.ll (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 235); mm. Embodiment 12. The HVR of mm (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 236), nn. The HVR of embodiment 12.nn (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 237); oo. The HVR of embodiment 12.oo (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 238); the HVR of embodiment 12.pp (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 238); qq. The HVR of embodiment 12.qq (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 239); rr. The HVR of embodiment 12.rr (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 240); ss. the HVR of embodiment 12.ss (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 241); tt. The HVR of embodiment 12.tt (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 242); uu. The HVR of embodiment 12.uu (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 243); vv. Embodiment 12. The HVR of vv (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 244), ww. Embodiment 12. The HVR of ww (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 245), xx. The HVR of embodiment 12.xx (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 246); yy. The HVR of embodiment 12.yy (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 247), zz. The HVR of embodiment 12.zz (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 248); aaa. Embodiment 12. The HVR of aaa (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 249), bbb. Embodiment 12. The HVR of bbb (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 250), ccc. The HVR of embodiment 12.ccc (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 251); ddd. The HVR of embodiment 12. ddd (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 252); eee. The HVR of embodiment 12. eee (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 253); fff. The HVR of embodiment 12.fff (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 254), ggg. Embodiment 12. The HVR of ggg (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 255), hhh. Embodiment 12. The HVR of hhh (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 256), iii. The HVR of embodiment 12.iii, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 233; jjj. The HVR of embodiment 12.jjj (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 256); kkk. Embodiment 12. The HVR of kkk (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 361); III. The HVR of embodiment 12.III (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 362); mmm. Embodiment 12. The HVR of mmm (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 363), nnn. The HVR of embodiment 12.nnn (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 364), ooo. The HVR of embodiment 12.ooo (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 365); ppp. The HVR of embodiment 12.ppp (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 366); qqq. Embodiment 12. The HVR of qqq (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 367), rrr. The HVR of embodiment 12. rrr (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 368); sss. The HVR of embodiment 12.sss (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 369), ttt. Embodiment 12. The HVR of ttt (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 370), uuu. The HVR of embodiment 12.uuu (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 387); vvv. Embodiment 12. The HVR of vvv (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 388), www. Embodiment 12. The HVR of www (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 389); xxx. The HVR of embodiment 12.xxx (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 390); yyy. The HVR of embodiment 12.yyy (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 391), zzz. Embodiment 12. The HVR of zzz (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 392), aaaa. Embodiment 12. The HVR of aaaa (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 393), bbbb. Embodiment 12. The HVR of bbbb (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 394); cccc. The HVR of embodiment 12.cccc (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 395), dddd. The HVR of embodiment 12.dddd (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 396); eeee. The HVR of embodiment 12. eeee (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 398); ffff. The HVR of embodiment 12.ffff (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 399); gggg. Embodiment 12. The HVR of gggg (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 400), hhhh. The HVR of embodiment 9hhhh (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 401); iiii. The HVR of embodiment 12.iiii (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 402); jjjj. The HVR of embodiment 12.jjjj (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 403); kkkk. Embodiment 12. An HVR of kkkk (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 404), III1. The HVR of embodiment 12.III1 (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 405); mmmm. Embodiment 12. The HVR of mmmm (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 406), nnnn. The HVR of embodiment 12.nnnn (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 407), oooo. The HVR of embodiment 12.oooo (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 408), pppp. Embodiment 12. The HVR of pppp (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 409), qqqq. Embodiment 12. The HVR of qqqq (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 410), rrrr. Embodiment 12. The HVR of rrrr (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 411), ssss. The HVR of embodiment 12.ssss (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 397), or tttt. The HVR of embodiment 12.tttt (further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 412).

[0026] Embodiment 14 is the antibody of embodiment 12 or 13, wherein the antibody comprises: a. The HVR of embodiment 12.a (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 257); b. The HVR of embodiment 12.b (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 258); c. The HVR of embodiment 12.c (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 259); d. The HVR of embodiment 12.d (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 260); e. The HVR of embodiment 12.e (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 261); f. The HVR of embodiment 12.f (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 262); g. The HVR of embodiment 12.g (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 263); h. The HVR of embodiment 12.h (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 264); i. The HVR of embodiment 12.i (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 265); j. The HVR of embodiment 12.j (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 266); k. The HVR of embodiment 12.k (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 267); l. The HVR of embodiment 12.l (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 268); m. The HVR of embodiment 12.m (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 269); n. The HVR of embodiment 12.n (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 270); o. The HVR of embodiment 12.o (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 271); p. The HVR of embodiment 12.p (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 272); q. The HVR of embodiment 12.q (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 273); r. The HVR of embodiment 12.r (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 274); s. The HVR of embodiment 12.s (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275); t. The HVR of embodiment 12.t (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 276); u. The HVR of embodiment 12.u (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 277); v. The HVR of embodiment 12.v (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 278); w. The HVR of embodiment 12.w (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 279); x. The HVR of embodiment 12.x (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 280); y. The HVR of embodiment 12.y (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 281); z. The HVR of embodiment 12.z (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 282); aa. The HVR of embodiment 12.ss (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 283); bb. The HVR of embodiment 12.bb (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 284); cc. The HVR of embodiment 12.cc (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 285); dd. The HVR of embodiment 12.dd (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 286); ee. The HVR of embodiment 12.ee (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 287); ff. The HVR of embodiment 12.ff (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 288); gg. The HVR of embodiment 12.gg (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 289); hh. The HVR of embodiment 12.hh (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 290); ii. The HVR of embodiment 12.ii, further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 291; jj. The HVR of embodiment 12.jj (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 292); kk. The HVR of embodiment 12.kk (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 293), ll. The HVR of embodiment 12.ll (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 294); mm. Embodiment 12. The HVR of mm (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 295), nn. The HVR of embodiment 12.nn (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 296); oo. The HVR of embodiment 12.oo (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 297); the HVR of embodiment 12.pp (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 298); qq. The HVR of embodiment 12.qq (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 299); rr. The HVR of embodiment 12.rr (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 300); ss. the HVR of embodiment 12.ss (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 301); tt. The HVR of embodiment 12.tt (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 302); uu. The HVR of embodiment 12.uu (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 303); vv. The HVR of embodiment 12. vv (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 304), ww. Embodiment 12. The HVR of ww (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 305), xx. The HVR of embodiment 12.xx (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 306); yy. The HVR of embodiment 12.yy (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 307), zz. The HVR of embodiment 12.zz (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 308); aaa. Embodiment 12. The HVR of aaa (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 309), bbb. Embodiment 12. The HVR of bbb (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 310), ccc. The HVR of embodiment 12.ccc (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 311); ddd. The HVR of embodiment 12. ddd (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312); eee. The HVR of embodiment 12. eee (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 313); fff. The HVR of embodiment 12.fff (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 314), ggg. Embodiment 12. The HVR of ggg (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 315), hhh. Embodiment 12. The HVR of hhh (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 316), iii. The HVR of embodiment 12.iii, further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 291; jjj. The HVR of embodiment 12.jjj (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 317); kkk. Embodiment 12. The HVR of kkk (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 261), lll. The HVR of embodiment 12.lll (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 261); mmm. Embodiment 12. The HVR of mmm (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 261), nnn. The HVR of embodiment 12.nnn (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 261), ooo. The HVR of embodiment 12.ooo (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 264), ppp. The HVR of embodiment 12.ppp (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 264), qqq. Embodiment 12. The HVR of qqq (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 264), rrr. The HVR of embodiment 12.rrr (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 264); sss. The HVR of embodiment 12.sss (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 269), ttt. Embodiment 12. The HVR of ttt (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 269), uuu. The HVR of embodiment 12.uuu (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 269), vvv. Embodiment 12. The HVR of vvv (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275), www. Embodiment 12. The HVR of www (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275), xxx. The HVR of embodiment 12.xxx (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275); yyy. The HVR of embodiment 12.yyy (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275), zzz. Embodiment 12. The HVR of zzz (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275), aaaa. Embodiment 12. The HVR of aaaa (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275), bbbb. Embodiment 12. The HVR of bbbb (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275), cccc. The HVR of embodiment 12.cccc (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275), dddd. The HVR of embodiment 12.dddd (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275), eeee. The HVR of embodiment 12. eeee (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 264); ffff. The HVR of embodiment 12.ffff (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275); gggg. Embodiment 12. The HVR of gggg (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275), hhhh. Embodiment 12. An HVR of hhhh (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275); iiii. The HVR of embodiment 12.iiii (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 416); jjjj. The HVR of embodiment 12.jjjj (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312); kkkk. Embodiment 12. An HVR of kkkk (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312), III1. The HVR of embodiment 12.III1 (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312), mmmm. Embodiment 12. The HVR of mmmm (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312), nnnn. The HVR of embodiment 12.nnnn (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312), oooo. The HVR of embodiment 12.oooo (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312), pppp. Embodiment 12. The HVR of pppp (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312), qqqq. Embodiment 12. The HVR of qqqq (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312), rrrr. The HVR of embodiment 12.rrrr (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312), ssss. The HVR of embodiment 12.ssss (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312), or tttt. The HVR of embodiment 12.tttt (further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312).

[0027] Embodiment 15 is the antibody of any one of embodiments 12-14, wherein the antibody comprises: a. The HVR of embodiment 12.a (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 202); b. The HVR of embodiment 12.b (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 203); c. The HVR of embodiment 12.c (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 204); d. The HVR of embodiment 12.d (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 205); e. The HVR of embodiment 12.e (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 206); f. The HVR of embodiment 12.f (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 207); g. The HVR of embodiment 12.g (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 208); h. The HVR of embodiment 12.h (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 209); i. The HVR of embodiment 12.i (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 210); j. The HVR of embodiment 12.j (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 211); k. The HVR of embodiment 12.k (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 212); l. The HVR of embodiment 12.l (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 213); m. The HVR of embodiment 12.m (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 214); n. The HVR of embodiment 12.n (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 215); o. The HVR of embodiment 12.o (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 216); p. The HVR of embodiment 12.p (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 217); q. The HVR of embodiment 12.q (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 218); r. The HVR of embodiment 12.r (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 219); s. The HVR of embodiment 12.s (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 220); t. The HVR of embodiment 12.t (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 209); u. The HVR of embodiment 12.u (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 221); v. The HVR of embodiment 12.v (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 222); w. The HVR of embodiment 12.w (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 223); x. The HVR of embodiment 12.x (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 224); y. The HVR of embodiment 12.y (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 225); z. The HVR of embodiment 12.z (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 226); aa. The HVR of embodiment 12.aa. (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 227); bb. The HVR of embodiment 12.bb (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 228); cc. The HVR of embodiment 12.cc (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 228); dd. The HVR of embodiment 12.dd (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 229); ee. The HVR of embodiment 12.ee (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 225); ff. The HVR of embodiment 12.ff (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 230); gg. The HVR of embodiment 12.gg (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 231); hh. The HVR of embodiment 12. hh (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 232); ii. The HVR of embodiment 12.ii (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 233); jj. The HVR of embodiment 12.jj (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 234); kk. The HVR of embodiment 12.kk (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 235), ll. The HVR of embodiment 12.ll (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 235); mm. Embodiment 12. The HVR of mm (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 236), nn. The HVR of embodiment 12.nn (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 237); oo. The HVR of embodiment 12.oo (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 238); pp. 12. The HVR of embodiment 12.pp (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 238); qq. The HVR of embodiment 12.qq (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 239); rr. The HVR of embodiment 12.rr (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 240); ss. the HVR of embodiment 12.ss (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 241); tt. The HVR of embodiment 12.tt (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 242); uu. The HVR of embodiment 12.uu (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 243); vv. Embodiment 12. The HVR of vv (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 244), ww. Embodiment 12. The HVR of ww (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 245), xx. The HVR of embodiment 12.xx (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 246); yy. The HVR of embodiment 12.yy (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 247), zz. The HVR of embodiment 12.zz (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 248); aaa. Embodiment 12. The HVR of aaa (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 249), bbb. Embodiment 12. The HVR of bbb (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 250), ccc. The HVR of embodiment 12.ccc (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 251), ddd. The HVR of embodiment 12. ddd (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 252); eee. The HVR of embodiment 12. eee (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 253), fff. The HVR of embodiment 12.fff (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 254), ggg. Embodiment 12. A HVR of ggg (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 255), hhh. Embodiment 12. The HVR of hhh (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 256), iii. The HVR of embodiment 12.iii (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 233); jjj. The HVR of embodiment 12.jjj (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 256); kkk. Embodiment 12. The HVR of kkk (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 361), lll. The HVR of embodiment 12.lll (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 362), mmm. Embodiment 12. The HVR of mmm (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 363), nnn. The HVR of embodiment 12.nnn (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 364), ooo. The HVR of embodiment 12. ooo (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 365); ppp. The HVR of embodiment 12. ppp (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 366), qqq. Embodiment 12. The HVR of qqq (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 367), rrr. The HVR of embodiment 12. rrr (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 368); sss. The HVR of embodiment 12.sss (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 369), ttt. Embodiment 12. The HVR of ttt (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 370), uuu. The HVR of embodiment 12.uuu (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 387), vvv. Embodiment 12. The HVR of vvv (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 388), www. Embodiment 12. The HVR of www (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 389), xxx. The HVR of embodiment 12.xxx (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 390); yyy. Embodiment 12. The HVR of yyy (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 391), zzz. Embodiment 12. The HVR of zzz (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 392), aaaa. Embodiment 12. The HVR of aaaa (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 393), bbbb. Embodiment 12. The HVR of bbbb (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 394), cccc. Embodiment 12. The HVR of cccc (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 395), dddd. The HVR of embodiment 12.dddd (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 396), eeee. The HVR of embodiment 12. eeee (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 398); ffff. The HVR of embodiment 12.ffff (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 399), gggg. Embodiment 12. The HVR of gggg (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 400), hhhh. The HVR of embodiment 9hhhh (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 401), iiii. The HVR of embodiment 12.iiii (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 402); jjjj. Embodiment 12. The HVR of jjjj (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 403), kkkk. Embodiment 12. An HVR of kkkk (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 404), IIIl. The HVR of embodiment 12.IIIl (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 405), mmmm. Embodiment 12. The HVR of mmmm (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 406), nnnn. The HVR of embodiment 12.nnnn (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 407), oooo. The HVR of embodiment 12.oooo (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 408), pppp. Embodiment 12. The HVR of pppp (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 409), qqqq. Embodiment 12. The HVR of qqqq (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 410), rrrr. Embodiment 12. The HVR of rrrr (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 411), ssss. The HVR of embodiment 12.ssss (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 397), or tttt. The HVR of embodiment 12.tttt (further comprising a VH comprising the amino acid sequence of SEQ ID NO: 412).

[0028] Embodiment 16 is the antibody of any one of embodiments 12 to 15, wherein the antibody comprises: a. The HVR of embodiment 12.a (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 257); b. The HVR of embodiment 12.b (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 258); c. The HVR of embodiment 12.c (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 259); d. The HVR of embodiment 12.d (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 260); e. The HVR of embodiment 12.e (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 261); f. The HVR of embodiment 12.f (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 262); g. The HVR of embodiment 12.g (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 263); h. The HVR of embodiment 12.h (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 264); i. The HVR of embodiment 12.i (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 265); j. The HVR of embodiment 12.j (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 266); k. The HVR of embodiment 12.k (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 267); l. The HVR of embodiment 12.l (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 268); m. The HVR of embodiment 12.m (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 269); n. The HVR of embodiment 12.n (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 270); o. The HVR of embodiment 12.o (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 271); p. The HVR of embodiment 12.p (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 272); q. The HVR of embodiment 12.q (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 273); r. The HVR of embodiment 12.r (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 274); s. The HVR of embodiment 12.s (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275); t. The HVR of embodiment 12.t (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 276); u. The HVR of embodiment 12.u (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 277); v. The HVR of embodiment 12.v (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 278); w. The HVR of embodiment 12.w (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 279); x. The HVR of embodiment 12.x (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 280); y. The HVR of embodiment 12.y (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 281); z. The HVR of embodiment 12.z (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 282); aa. The HVR of embodiment 12.ss (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 283), bb. The HVR of embodiment 12.bb (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 284); cc. The HVR of embodiment 12.cc (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 285); dd. The HVR of embodiment 12.dd (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 286); ee. The HVR of embodiment 12.ee (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 287); ff. the HVR of embodiment 12.ff (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 288); gg. The HVR of embodiment 12.gg (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 289); hh. The HVR of embodiment 12. hh (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 290), ii. The HVR of embodiment 12.ii (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 291); jj. The HVR of embodiment 12.jj (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 292); kk. The HVR of embodiment 12.kk (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 293), ll. The HVR of embodiment 12.ll (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 294); mm. Embodiment 12. The HVR of mm (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 295), nn. The HVR of embodiment 12.nn (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 296); oo. The HVR of embodiment 12.oo (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 297); pp. 12. The HVR of embodiment 12.pp (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 298); qq. The HVR of embodiment 12.qq (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 299), rr. The HVR of embodiment 12.rr (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 300); ss. the HVR of embodiment 12.ss (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 301); tt. The HVR of embodiment 12.tt (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 302); uu. The HVR of embodiment 12.uu (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 303); vv. Embodiment 12. The HVR of vv (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 304), ww. Embodiment 12. The HVR of ww (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 305), xx. The HVR of embodiment 12.xx (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 306); yy. The HVR of embodiment 12.yy (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 307), zz. The HVR of embodiment 12.zz (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 308), aaa. Embodiment 12. The HVR of aaa (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 309), bbb. Embodiment 12. The HVR of bbb (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 310), ccc. The HVR of embodiment 12.ccc (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 311), ddd. The HVR of embodiment 12. ddd (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 312); eee. The HVR of embodiment 12. eee (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 313), fff. The HVR of embodiment 12.fff (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 314), ggg. Embodiment 12. The HVR of ggg (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 315), hhh. Embodiment 12. The HVR of hhh (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 316), iii. The HVR of embodiment 12.iii (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 291); jjj. The HVR of embodiment 12.jjj (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 317); kkk. Embodiment 12. The HVR of kkk (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 261), lll. The HVR of embodiment 12.lll (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 261), mmm. Embodiment 12. The HVR of mmm (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 261), nnn. The HVR of embodiment 12.nnn (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 261), ooo. The HVR of embodiment 12. ooo (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 264), ppp. The HVR of embodiment 12.ppp (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 264), qqq. Embodiment 12. The HVR of qqq (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 264), rrr. The HVR of embodiment 12.rrr (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 264), sss. The HVR of embodiment 12.sss (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 269), ttt. Embodiment 12. The HVR of ttt (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 269), uuu. The HVR of embodiment 12.uuu (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 269), vvv. Embodiment 12. The HVR of vvv (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275), www. Embodiment 12. The HVR of www (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275), xxx. The HVR of embodiment 12.xxx (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275); yyy. Embodiment 12. The HVR of yyy (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275), zzz. Embodiment 12. The HVR of zzz (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275), aaaa. Embodiment 12. The HVR of aaaa (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275), bbbb. Embodiment 12. The HVR of bbbb (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275), cccc. Embodiment 12. The HVR of cccc (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275), dddd. The HVR of embodiment 12.dddd (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275), eeee. The HVR of embodiment 12. eeee (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 264), ffff. The HVR of embodiment 12.ffff (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275), gggg. Embodiment 12. The HVR of gggg (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275), hhhh. Embodiment 12. The HVR of hhhh (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275), iiii. The HVR of embodiment 12.iiii (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 416); jjjj. Embodiment 12. The HVR of jjjj (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 312), kkkk. Embodiment 12. An HVR of kkkk (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 312), IIIl. The HVR of embodiment 12.IIIl (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 312), mmmm. Embodiment 12. The HVR of mmmm (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 312), nnnn. The HVR of embodiment 12.nnnn (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 312), oooo. The HVR of embodiment 12.oooo (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 312), pppp. Embodiment 12. The HVR of pppp (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 312), qqqq. Embodiment 12. The HVR of qqqq (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 312), rrrr. Embodiment 12. The HVR of rrrr (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 312), ssss. The HVR of embodiment 12.ssss (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 312), or tttt. The HVR of embodiment 12.tttt (further comprising a VL comprising the amino acid sequence of SEQ ID NO: 312).

[0029] Embodiment 17 is the antibody of any one of embodiments 9 to 13, wherein the antibody comprises: a. A VH comprising the amino acid sequence of SEQ ID NO: 202 and a VL comprising the amino acid sequence of SEQ ID NO: 257; b. A VH comprising the amino acid sequence of SEQ ID NO: 203 and a VL comprising the amino acid sequence of SEQ ID NO: 258; c. A VH comprising the amino acid sequence of SEQ ID NO: 204 and a VL comprising the amino acid sequence of SEQ ID NO: 259; d. A VH comprising the amino acid sequence of SEQ ID NO: 205 and a VL comprising the amino acid sequence of SEQ ID NO: 260; e. A VH comprising the amino acid sequence of SEQ ID NO: 206 and a VL comprising the amino acid sequence of SEQ ID NO: 261; f. A VH comprising the amino acid sequence of SEQ ID NO: 207 and a VL comprising the amino acid sequence of SEQ ID NO: 262; g. A VH comprising the amino acid sequence of SEQ ID NO: 208 and a VL comprising the amino acid sequence of SEQ ID NO: 263; h. A VH comprising the amino acid sequence of SEQ ID NO: 209 and a VL comprising the amino acid sequence of SEQ ID NO: 264; i. a VH comprising the amino acid sequence of SEQ ID NO: 210 and a VL comprising the amino acid sequence of SEQ ID NO: 265; j. a VH comprising the amino acid sequence of SEQ ID NO: 211 and a VL comprising the amino acid sequence of SEQ ID NO: 266; k. A VH comprising the amino acid sequence of SEQ ID NO: 212 and a VL comprising the amino acid sequence of SEQ ID NO: 267; l. VH comprising the amino acid sequence of SEQ ID NO: 213 and VL comprising the amino acid sequence of SEQ ID NO: 268; m. a VH comprising the amino acid sequence of SEQ ID NO: 214 and a VL comprising the amino acid sequence of SEQ ID NO: 269; n. A VH comprising the amino acid sequence of SEQ ID NO: 215 and a VL comprising the amino acid sequence of SEQ ID NO: 270; o. a VH comprising the amino acid sequence of SEQ ID NO: 216 and a VL comprising the amino acid sequence of SEQ ID NO: 271; p. VH comprising the amino acid sequence of SEQ ID NO: 217 and VL comprising the amino acid sequence of SEQ ID NO: 272; q. a VH comprising the amino acid sequence of SEQ ID NO: 218 and a VL comprising the amino acid sequence of SEQ ID NO: 273; r. VH comprising the amino acid sequence of SEQ ID NO: 219 and VL comprising the amino acid sequence of SEQ ID NO: 274; s. a VH comprising the amino acid sequence of SEQ ID NO: 220 and a VL comprising the amino acid sequence of SEQ ID NO: 275; t. a VH comprising the amino acid sequence of SEQ ID NO: 209 and a VL comprising the amino acid sequence of SEQ ID NO: 276; u. VH comprising the amino acid sequence of SEQ ID NO: 221 and VL comprising the amino acid sequence of SEQ ID NO: 277; v. VH comprising the amino acid sequence of SEQ ID NO: 222 and VL comprising the amino acid sequence of SEQ ID NO: 278; w. VH comprising the amino acid sequence of SEQ ID NO: 223 and VL comprising the amino acid sequence of SEQ ID NO: 279; x. a VH comprising the amino acid sequence of SEQ ID NO: 224 and a VL comprising the amino acid sequence of SEQ ID NO: 280; y. VH comprising the amino acid sequence of SEQ ID NO: 225 and VL comprising the amino acid sequence of SEQ ID NO: 281; z. A VH comprising the amino acid sequence of SEQ ID NO: 226 and a VL comprising the amino acid sequence of SEQ ID NO: 282; aa. VH comprising the amino acid sequence of SEQ ID NO: 227 and VL comprising the amino acid sequence of SEQ ID NO: 283; bb. VH comprising the amino acid sequence of SEQ ID NO: 228 and VL comprising the amino acid sequence of SEQ ID NO: 284; cc. VH comprising the amino acid sequence of SEQ ID NO: 228 and VL comprising the amino acid sequence of SEQ ID NO: 285; dd. VH comprising the amino acid sequence of SEQ ID NO: 229 and VL comprising the amino acid sequence of SEQ ID NO: 286; ee. VH comprising the amino acid sequence of SEQ ID NO: 225 and VL comprising the amino acid sequence of SEQ ID NO: 287; ff. VH comprising the amino acid sequence of SEQ ID NO: 230 and VL comprising the amino acid sequence of SEQ ID NO: 288; gg. VH comprising the amino acid sequence of SEQ ID NO: 231 and VL comprising the amino acid sequence of SEQ ID NO: 289; hh. VH comprising the amino acid sequence of SEQ ID NO: 232 and VL comprising the amino acid sequence of SEQ ID NO: 290; ii. VH comprising the amino acid sequence of SEQ ID NO: 233 and VL comprising the amino acid sequence of SEQ ID NO: 291; jj. VH comprising the amino acid sequence of SEQ ID NO: 234 and VL comprising the amino acid sequence of SEQ ID NO: 292; kk. VH comprising the amino acid sequence of SEQ ID NO: 235 and VL comprising the amino acid sequence of SEQ ID NO: 293; ll. VH comprising the amino acid sequence of SEQ ID NO: 235 and VL comprising the amino acid sequence of SEQ ID NO: 294; mm. VH comprising the amino acid sequence of SEQ ID NO: 236 and VL comprising the amino acid sequence of SEQ ID NO: 295; nn. VH comprising the amino acid sequence of SEQ ID NO: 237 and VL comprising the amino acid sequence of SEQ ID NO: 296; oo. VH comprising the amino acid sequence of SEQ ID NO: 238 and VL comprising the amino acid sequence of SEQ ID NO: 297; pp. VH comprising the amino acid sequence of SEQ ID NO: 238 and VL comprising the amino acid sequence of SEQ ID NO: 298; qq. VH comprising the amino acid sequence of SEQ ID NO: 239 and VL comprising the amino acid sequence of SEQ ID NO: 299; rr. VH comprising the amino acid sequence of SEQ ID NO: 240 and VL comprising the amino acid sequence of SEQ ID NO: 300; ss. VH comprising the amino acid sequence of SEQ ID NO: 241 and VL comprising the amino acid sequence of SEQ ID NO: 301; tt. VH comprising the amino acid sequence of SEQ ID NO: 242 and VL comprising the amino acid sequence of SEQ ID NO: 302; VH comprising the amino acid sequence of SEQ ID NO: 243 and VL comprising the amino acid sequence of SEQ ID NO: 303; vv. VH comprising the amino acid sequence of SEQ ID NO: 244 and VL comprising the amino acid sequence of SEQ ID NO: 304; ww. VH comprising the amino acid sequence of SEQ ID NO: 245 and VL comprising the amino acid sequence of SEQ ID NO: 305; xx. VH comprising the amino acid sequence of SEQ ID NO: 246 and VL comprising the amino acid sequence of SEQ ID NO: 306; yy. VH comprising the amino acid sequence of SEQ ID NO: 247 and VL comprising the amino acid sequence of SEQ ID NO: 307; zz. VH comprising the amino acid sequence of SEQ ID NO: 248 and VL comprising the amino acid sequence of SEQ ID NO: 308; aaa. VH comprising the amino acid sequence of SEQ ID NO: 249 and VL comprising the amino acid sequence of SEQ ID NO: 309; bbb. VH comprising the amino acid sequence of SEQ ID NO: 250 and VL comprising the amino acid sequence of SEQ ID NO: 310; ccc. VH comprising the amino acid sequence of SEQ ID NO: 251 and VL comprising the amino acid sequence of SEQ ID NO: 311; ddd. VH comprising the amino acid sequence of SEQ ID NO: 252 and VL comprising the amino acid sequence of SEQ ID NO: 312; eee. VH comprising the amino acid sequence of SEQ ID NO: 253 and VL comprising the amino acid sequence of SEQ ID NO: 313; fff. VH comprising the amino acid sequence of SEQ ID NO: 254 and VL comprising the amino acid sequence of SEQ ID NO: 314; ggg. VH comprising the amino acid sequence of SEQ ID NO: 255 and VL comprising the amino acid sequence of SEQ ID NO: 315; hhh. VH comprising the amino acid sequence of SEQ ID NO: 256 and VL comprising the amino acid sequence of SEQ ID NO: 316; iii. VH comprising the amino acid sequence of SEQ ID NO: 233 and VL comprising the amino acid sequence of SEQ ID NO: 291; jjj. VH comprising the amino acid sequence of SEQ ID NO: 256 and VL comprising the amino acid sequence of SEQ ID NO: 317; kkk. VH comprising the amino acid sequence of SEQ ID NO: 361 and VL comprising the amino acid sequence of SEQ ID NO: 261; III. VH comprising the amino acid sequence of SEQ ID NO: 362 and VL comprising the amino acid sequence of SEQ ID NO: 261; mmm. VH comprising the amino acid sequence of SEQ ID NO: 363 and VL comprising the amino acid sequence of SEQ ID NO: 261; nnn. VH comprising the amino acid sequence of SEQ ID NO: 364 and VL comprising the amino acid sequence of SEQ ID NO: 261; ooo. VH comprising the amino acid sequence of SEQ ID NO: 365 and VL comprising the amino acid sequence of SEQ ID NO: 264; ppp. VH comprising the amino acid sequence of SEQ ID NO: 366 and VL comprising the amino acid sequence of SEQ ID NO: 264; qqq. VH comprising the amino acid sequence of SEQ ID NO: 367 and VL comprising the amino acid sequence of SEQ ID NO: 264; rrr. VH comprising the amino acid sequence of SEQ ID NO: 368 and VL comprising the amino acid sequence of SEQ ID NO: 264; sss. VH comprising the amino acid sequence of SEQ ID NO: 369 and VL comprising the amino acid sequence of SEQ ID NO: 269; ttt. VH comprising the amino acid sequence of SEQ ID NO: 370 and VL comprising the amino acid sequence of SEQ ID NO: 269; VH comprising the amino acid sequence of SEQ ID NO: 387 and VL comprising the amino acid sequence of SEQ ID NO: 269; VH comprising the amino acid sequence of SEQ ID NO: 388 and VL comprising the amino acid sequence of SEQ ID NO: 275; www. VH comprising the amino acid sequence of SEQ ID NO: 389 and VL comprising the amino acid sequence of SEQ ID NO: 275; xxx. VH comprising the amino acid sequence of SEQ ID NO: 390 and VL comprising the amino acid sequence of SEQ ID NO: 275; yyy. VH comprising the amino acid sequence of SEQ ID NO: 391 and VL comprising the amino acid sequence of SEQ ID NO: 275; zzz. VH comprising the amino acid sequence of SEQ ID NO: 392 and VL comprising the amino acid sequence of SEQ ID NO: 275; aaaa. VH comprising the amino acid sequence of SEQ ID NO: 393 and VL comprising the amino acid sequence of SEQ ID NO: 275; bbbb. VH comprising the amino acid sequence of SEQ ID NO: 394 and VL comprising the amino acid sequence of SEQ ID NO: 275; cccc. VH comprising the amino acid sequence of SEQ ID NO: 395 and VL comprising the amino acid sequence of SEQ ID NO: 275; dddd. VH comprising the amino acid sequence of SEQ ID NO: 396 and VL comprising the amino acid sequence of SEQ ID NO: 275; eeee. VH comprising the amino acid sequence of SEQ ID NO: 398 and VL comprising the amino acid sequence of SEQ ID NO: 264; ffff. VH comprising the amino acid sequence of SEQ ID NO: 399 and VL comprising the amino acid sequence of SEQ ID NO: 275; gggg. VH comprising the amino acid sequence of SEQ ID NO: 400 and VL comprising the amino acid sequence of SEQ ID NO: 275; hhhh. VH comprising the amino acid sequence of SEQ ID NO: 401 and VL comprising the amino acid sequence of SEQ ID NO: 275; iiii. VH comprising the amino acid sequence of SEQ ID NO: 402 and VL comprising the amino acid sequence of SEQ ID NO: 413; jjjj. VH comprising the amino acid sequence of SEQ ID NO: 403 and VL comprising the amino acid sequence of SEQ ID NO: 312; kkkk. VH comprising the amino acid sequence of SEQ ID NO: 404 and VL comprising the amino acid sequence of SEQ ID NO: 312; III. VH comprising the amino acid sequence of SEQ ID NO: 405 and VL comprising the amino acid sequence of SEQ ID NO: 312; mmmm. VH comprising the amino acid sequence of SEQ ID NO: 406 and VL comprising the amino acid sequence of SEQ ID NO: 312; nnnn. VH comprising the amino acid sequence of SEQ ID NO: 407 and VL comprising the amino acid sequence of SEQ ID NO: 312; oooo. VH comprising the amino acid sequence of SEQ ID NO: 408 and VL comprising the amino acid sequence of SEQ ID NO: 312; pppp. VH comprising the amino acid sequence of SEQ ID NO: 409 and VL comprising the amino acid sequence of SEQ ID NO: 312; VH comprising the amino acid sequence of SEQ ID NO: 410 and VL comprising the amino acid sequence of SEQ ID NO: 312; rrrr. VH comprising the amino acid sequence of SEQ ID NO: 411 and VL comprising the amino acid sequence of SEQ ID NO: 312; ssss. VH comprising the amino acid sequence of SEQ ID NO: 397 and VL comprising the amino acid sequence of SEQ ID NO: 312; tttt. VH comprising the amino acid sequence of SEQ ID NO: 412 and VL comprising the amino acid sequence of SEQ ID NO: 312.

[0030] Embodiment 18 is an isolated antibody that specifically binds to human SIRPA, comprising: a. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-1 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-1 (shown in Table 2)); b. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-2 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-2 (shown in Table 2)); c. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-3 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-3 (shown in Table 2)); d. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-4 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-4 (shown in Table 2)); e. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-5 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-5 (shown in Table 2)); f. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-6 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-6 (shown in Table 2)); g. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-7 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-7 (shown in Table 2)); h. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-8 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-8 (shown in Table 2)); i. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-9 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-9 (shown in Table 2)); j. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-10 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-10 (shown in Table 2)); k. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-11 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-11 (shown in Table 2)); l. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-12 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-12 (shown in Table 2)); m. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-13 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-13 (shown in Table 2)); n. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-14 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-14 (shown in Table 2)); o. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-15 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-15 (shown in Table 2)); p. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-16 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-16 (shown in Table 2)); q. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-17 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-17 (shown in Table 2)); r. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-18 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-18 (shown in Table 2)); s. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19 ​​(shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19 ​​(shown in Table 2)); t. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-20 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-20 (shown in Table 2)); u. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-21 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-21 (shown in Table 2)); v. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-22 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-22 (shown in Table 2)); w. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-23 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-23 (shown in Table 2)); x. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-24 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-24 (shown in Table 2)); y. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-25 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-25 (shown in Table 2)); z. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-26 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-26 (shown in Table 2)); aa. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-27 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-27 (shown in Table 2)); bb. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-28 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-28 (shown in Table 2)), cc. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-29 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-29 (shown in Table 2)), dd. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-30 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-30 (shown in Table 2)), ee. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-31 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-31 (shown in Table 2)); ff. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-32 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-32 (shown in Table 2)), gg. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-33 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-33 (shown in Table 2)), hh. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-34 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-34 (shown in Table 2)); ii. VH and VL, where VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-35 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-35 (shown in Table 2), jj. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-3+ (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-36 (shown in Table 2)); kk. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-37 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-37 (shown in Table 2)), 11. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-38 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-38 (shown in Table 2)); mm. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-39 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-39 (shown in Table 2)); nn. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-40 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-40 (shown in Table 2)), oo. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-41 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-41 (shown in Table 2)), pp. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-42 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-42 (shown in Table 2)); qq. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-43 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-43 (shown in Table 2)); rr. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-44 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-44 (shown in Table 2)); ss. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-45 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-45 (shown in Table 2)), tt. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-46 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-46 (shown in Table 2)), uu. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-47 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-47 (shown in Table 2)), vv. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-48 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-48 (shown in Table 2)); ww. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-49 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-49 (shown in Table 2)); xx. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-50 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-50 (shown in Table 2)); yy. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-51 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-51 (shown in Table 2)), zz. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-52 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-52 (shown in Table 2)), aaa. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-53 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-53 (shown in Table 2)); bbb. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-54 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-54 (shown in Table 2)); ccc. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-55 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-55 (shown in Table 2)), ddd. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56 (shown in Table 2)), eee. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-57 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-57 (shown in Table 2)); fff. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-58 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-58 (shown in Table 2)), ggg. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-59 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-59 (shown in Table 2)); hhh. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-60 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-60 (shown in Table 2)); iii. VH and VL, where VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-61 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-61 (shown in Table 2), jjj. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-62 (shown in Table 3), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-62 (shown in Table 2)); kkk. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-5-57 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-5-57 (shown in Table 6)); III. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-5-58 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-5-58 (shown in Table 6)); mmm. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-5-59 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-5-59 (shown in Table 6)); nnn. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-5-61 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-5-61 (shown in Table 6)); ooo. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-8-62 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-8-62 (shown in Table 6)), ppp. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-8-64 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-8-64 (shown in Table 6)); qqq. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-8-66 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-8-66 (shown in Table 6)); rrr. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-8-67 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-8-67 (shown in Table 6)), sss. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-13-68 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-13-68 (shown in Table 6)), ttt. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-13-69 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-13-69 (shown in Table 6)), uuu. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-13-71 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-13-71 (shown in Table 6)), vvv. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-72 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-72 (shown in Table 6)), www. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-73 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-73 (shown in Table 6)); xxx. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-74 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-74 (shown in Table 6)), yyy. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-75 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-75 (shown in Table 6)), zzz. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-76 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-76 (shown in Table 6)), aaaa. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-77 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-77 (shown in Table 6)); bbbb. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-78 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-78 (shown in Table 6)); cccc. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-79 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-79 (shown in Table 6)), dddd. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-80 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-80 (shown in Table 6)), eeee. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-81 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-81 (shown in Table 6)); ffff. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-82 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-82 (shown in Table 6)), gggg. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-83 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-83 (shown in Table 6)); hhhh. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-84 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-84 (shown in Table 6)); iiii. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-85 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-85 (shown in Table 6)); jjjj. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-86 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-86 (shown in Table 6)); kkkk. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-87 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-87 (shown in Table 6)); III. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-88 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-88 (shown in Table 6)); mmmm. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-89 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-89 (shown in Table 6)); nnnn. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-90 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-90 (shown in Table 6)), oooo. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-91 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-91 (shown in Table 6)), pppp. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-92 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-92 (shown in Table 6)); qqqq. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-93 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-93 (shown in Table 6)), rrrr. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-94 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-94 (shown in Table 6)); ssss. VH and VL, where VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-95 (shown in Table 7) and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-95 (shown in Table 6), or tttt. VH and VL (VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-96 (shown in Table 7), and VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-96 (shown in Table 6)).

[0031] Embodiment 19 is the antibody of any one of embodiments 1 to 17, wherein the antibody has one or more of the following properties: a. the antibody increases SIRPA activity, SIRPA signaling, CD47-induced SIRPA signaling, or any combination thereof, in macrophages, dendritic cells, and / or microglial cells; b. the antibody reduces phagocytic activity by phagocytes, reduces cytokine release (e.g., release of TNF-alpha) by dendritic cells, inhibits synapse loss in microglia-neuron co-cultures, inhibits synapse loss in a mouse model, or any combination thereof; c. the antibody has an affinity (KD) for human SIRPA of less than 1 μM, less than 100 nM, less than 10 nM, less than 1 nM, less than 0.1 nM, less than 0.01 nM, or less than 0.001 nM; d. the antibody has an affinity (KD) for human SIRPAv1 (SEQ ID NO: 1) of 1 nM to 50 nM, 0.3 nM to 2 nM, or 2 nM to 24 nM; e. the antibody has higher affinity for human SIRPA than for mouse SIRPA; f. The antibody does not bind to mouse SIRPA; g. The antibody has greater affinity for human SIRPA than for human SIRPB. h. The antibody does not bind to human SIRPB. i. the antibody binds to one or more amino acids of human SIRPAv1 (SEQ ID NO: 1) selected from D40, R54, and W68; j. The antibody has reduced binding affinity to human SIRPAv1 (SEQ ID NO: 1) by containing one or more of the following substitutions compared to wild-type SIRPAv1 consisting of SEQ ID NO: 1: D40A, R54A, W68A.

[0032] Embodiment 20 is the antibody of any one of embodiments 1 to 19, wherein the antibody is a monoclonal antibody.

[0033] Embodiment 21 is the antibody of any one of embodiments 1 to 20, wherein the antibody is a humanized antibody.

[0034] Embodiment 22 is the antibody of any one of embodiments 1 to 21, wherein the antibody is an antigen-binding fragment, such as a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment.

[0035] Embodiment 23 is the antibody of any one of embodiments 1 to 22, wherein the antibody is a bispecific or multispecific antibody.

[0036] Embodiment 24 is the antibody of any one of embodiments 1 to 23, wherein the antibody is of the IgG class, IgM class, or IgA class.

[0037] Embodiment 25 is the antibody of embodiment 24, wherein the antibody is of the IgG class and is of the human IgG1, IgG2, IgG3, or IgG4 isotype, or of the murine IgG1 or IgG2 isotype.

[0038] Embodiment 26 is the antibody of any one of embodiments 1 to 25, wherein the antibody binds to an inhibitory Fc receptor.

[0039] Embodiment 27 is the antibody of embodiment 26, wherein the inhibitory Fc receptor is inhibitory Fc gamma receptor IIB (FcgRIIB).

[0040] Embodiment 28 is the antibody of embodiment 27, wherein the antibody reduces cellular levels of FcgRIIB.

[0041] Embodiment 29 is a method for treating SIRPA, wherein the anti-SIRPA antibody has a human or mouse IgG1 isotype and is selected from the group consisting of N297A, D265A, D270A, L234A, L235A, G237A, P238D, L328E, E233D, G237D, H268D, P271G, A330R, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E , N297Q, P238S, P238A, A327Q, A327G, P329A, K322A, N325S, L328F, T394D, and any combination thereof, wherein the numbering of residues is according to EU numbering, or the antibody of any one of embodiments 1 to 28 comprises an amino acid deletion at a position corresponding to glycine 236 in the Fc region.

[0042] Embodiment 30 is the antibody of any one of embodiments 1 to 29, wherein the antibody comprises one or more amino acid substitutions at amino acid residues in the Fc region selected from the group consisting of C127S, L234A, L234F, L235A, L235E, S267E, K322A, N325S, L328F, A330S, P331S, E345R, E430G, S440Y, and any combination thereof, wherein the numbering of amino acid residues is according to EU or Kabat numbering.

[0043] Embodiment 31 is a pharmaceutical composition comprising the anti-SIRPA antibody of any one of Embodiments 1 to 30 and a pharmaceutically acceptable carrier.

[0044] Embodiment 32 is an isolated nucleic acid comprising a nucleic acid sequence encoding the anti-SIRPA antibody of any one of Embodiments 1 to 30.

[0045] Embodiment 33 is an isolated vector comprising the nucleic acid of embodiment 32.

[0046] Embodiment 34 is an isolated host cell comprising the nucleic acid of embodiment 32 or the vector of embodiment 33.

[0047] Embodiment 35 is a method for producing an antibody that binds to human SIRPA, comprising culturing the cell of embodiment 34 to produce the antibody.

[0048] Embodiment 36 is the method of embodiment 35, further comprising recovering the antibody produced by the cells.

[0049] Embodiment 37 is a method of treating a disease or disorder associated with inflammation, transplant rejection, autoimmunity, or cognitive impairment, the method comprising administering to an individual in need thereof a therapeutically effective amount of an anti-SIRPA antibody of any one of embodiments 1 to 30, thereby treating the disease or disorder.

[0050] Embodiment 38 is the method of embodiment 37, wherein the disease or disorder is selected from inflammation, enteritis, enteritis associated with colitis, rheumatoid arthritis, organ / graft transplant rejection, multiple sclerosis, synaptic pruning in neurons, synaptic loss in neurons, synaptic pruning by microglia, and cognitive impairment.

[0051] Embodiment 39 is a method of detecting the presence of SIRPA in a sample or an individual, the method comprising the anti-SIRPA antibody of any one of embodiments 1 to 30.

[0052] Embodiment 40 is the method of embodiment 39, further comprising quantitating antigen-bound anti-SIRPA antibodies. [Brief explanation of the drawings]

[0053] [Figure 1A]

[0023] Figure 1 shows an amino acid sequence alignment between the two most common alleles (v1 and v2) of the human SIRPA protein, showing the different residues within the ligand-binding domain. Accession numbers are NP542970 (SEQ ID NO: 1) and CAA71403 (SEQ ID NO: 2), respectively. [Figure 1B] 1 shows an amino acid sequence alignment between human SIRPAv1 protein (SEQ ID NO: 1) and human SIRPb1 (SEQ ID NO: 4) proteins, demonstrating homology between the two proteins. Accession numbers are NP542970 and O00241, respectively. [Figure 2] 1 shows an amino acid sequence alignment between the human SIRPA protein (SEQ ID NO: 1) and the mouse SIRPA protein (SEQ ID NO: 3), demonstrating the homology between the two proteins. Accession numbers are NP542970 and Q6P6I8, respectively. [Figure 3] 3 shows the relative MFI values ​​of the anti-SIRPA antibody of the present disclosure binding to Chinese hamster ovary cell line (CHO) overexpressing human SIRPA compared to CHO cells overexpressing mouse SIRPA. Results are expressed as fold over background. The background level is set to 1 on the y-axis. [Figure 4A] Figure 1 shows the induction of human SIRPA-dependent luciferase expression in a cell-based reporter assay. BWZ / NFAT-luciferase reporter cells (BWZ) were engineered to stably express the human SIRPA-DAP12 chimera (BWZ-HuSIRPA). Cells were stimulated overnight with full-length anti-SIRPA antibody or human IgG1 isotype control adsorbed onto a 96-well plate at 10 mg / mL. [Figure 4B] Figure 1 shows the induction of human SIRPb1-dependent luciferase expression in a cell-based reporter assay. BWZ / NFAT luciferase reporter cells (BWZ) were engineered to stably co-express human SIRPb1 and DAP12 (BWZ-HuSIRPb1). Cells were stimulated overnight with full-length anti-SIRPA antibody or a human IgG1 isotype control adsorbed onto a 96-well plate at 10 mg / mL. [Figure 5A] Epitope binning of anti-SIRPA antibodies relative to the CD47-blocking anti-SIRPA antibody clone SE7C2 (Santa Cruz Biotechnology) is shown. Results are shown as the relative MFI values ​​of PE-conjugated SE7C2 binding to BWZ-HuSIRPA cells preincubated with 10 mg / mL of test antibody or human IgG1 isotype control. Unlabeled cells are considered background signal and are set at 1 on the y-axis. [Figure 5B] Figure 1 shows the relative MFI values ​​of recombinant soluble CD47 binding to BWZ-HuSIRPA cells in the presence of potential ligand-blocking anti-SIRPA antibodies or a human IgG1 isotype control. Recombinant CD47 contains a C-terminal HIS tag, and surface-bound protein is detected with a PE-conjugated anti-HIS tag antibody. Results are expressed as fold over background, calculated by dividing the MFI values ​​of samples incubated with HuCD47 and antibody by the MFI value of cells stained with anti-HIS tag PE in the absence of HuCD47. [Figure 5C]Shown are the relative MFI values ​​of recombinant soluble CD47 binding to BWZ-HuSIRPA cells in the presence of ligand-enhanced anti-SIRPA antibodies SA-13 and SA-56, or a human IgG1 isotype control. [Figure 5D] Luminescence values ​​of BWZ-human SIRPA reporter cells incubated with plate-bound CD47 and the indicated test antibodies are shown. Results are presented as fold background, with the radiance value of unstimulated reporter cells set to 1 on the y-axis. [Figure 6A] Luminescence values ​​of BWZ-huSIRPA reporter cells co-cultured with Raji B cells in the presence of anti-SIRPA antibodies or isotype controls are shown. Results are presented as fold over background, with the radiance value of reporter cells treated with isotype controls mixed with Raji cells set to 1 on the y-axis. Reporter cells were treated with bin 2 anti-SIRPA antibodies SA-56 and SA-13, and for comparison, bin 1 anti-SIRPA antibodies 12D6 and 1H11. [Figure 6B] Luminescence values ​​of BWZ-huSIRPb1 reporter cells co-cultured with Raji B cells in the presence of anti-SIRPA antibodies or isotype controls are shown. Bin 2 anti-SIRPA antibodies, SA-56 and SA-13, are SIRPA-specific, whereas bin 1 anti-SIRPA antibodies 12D6 and 1H11 are SIRPA / b1 cross-reactive. [Figure 7A] 1 shows induction of human SIRPA-dependent luciferase expression in a cell-based reporter assay by affinity-matured anti-SIRPA antibodies derived from the parental anti-SIRPA antibodies SA-5 and SA-8. [Figure 7B] 1 shows the induction of human SIRPb1-dependent luciferase expression in a cell-based reporter assay by affinity-matured anti-SIRPA antibodies derived from the parental anti-SIRPA antibodies SA-5 and SA-8. [Figure 7C] 1 shows induction of human SIRPA-dependent luciferase expression in a cell-based reporter assay by affinity-matured anti-SIRPA antibodies derived from the parent anti-SIRPA antibody SA-56. [Figure 7D]Figure 1 shows the induction of human SIRPb1-dependent luciferase expression in a cell-based reporter assay by affinity-matured anti-SIRPA antibodies derived from the parental anti-SIRPA antibodies SA-19 ​​and SA-56. BWZ-huSIRPA and BWZ-huSIRPb1 cells were stimulated overnight with full-length anti-SIRPA antibodies or a human IgG1 isotype control adsorbed onto a 96-well plate at 10 mg / mL. AM4-5 is an anti-SIRPA / b1 cross-reactive antibody that served as a positive control. [Figure 8A] Luminescence values ​​of BWZ-huSIRPA reporter cells incubated in the presence of plate-bound CD47 and affinity-matured anti-SIRPA antibodies derived from the parental anti-SIRPA antibodies SA-5 and SA-8 are shown. [Figure 8B] Luminescence values ​​of BWZ-huSIRPA reporter cells incubated in the presence of plate-bound CD47 and affinity-matured anti-SIRPA antibodies derived from the parental anti-SIRPA antibody SA-19 ​​are shown. [Figure 8C] Luminescence values ​​of BWZ-huSIRPA reporter cells incubated in the presence of plate-bound CD47 and an affinity-matured anti-SIRPA antibody derived from the parental anti-SIRPA antibody SA-56 are shown. Results are presented as fold background, with the radiance value of unstimulated reporter cells set to 1 on the y-axis. AM4-5 is an anti-SIRPA / b1 cross-reactive antibody that blocks CD47 binding to SIRPA and serves as a positive control. [Figure 8D] Luminescence values ​​of BWZ-huSIRPA reporter cells incubated in the presence of plate-bound CD47 and an affinity-matured anti-SIRPA antibody derived from the parental anti-SIRPA antibody SA-56 are shown. Results are presented as fold background, with the radiance value of unstimulated reporter cells set to 1 on the y-axis. AM4-5 is an anti-SIRPA / b1 cross-reactive antibody that blocks CD47 binding to SIRPA and serves as a positive control. [Figure 9]Luminescence values ​​of BWZ-huSIRPA reporter cells co-cultured with Raji B cells in the presence of affinity-matured anti-SIRPA antibodies or isotype controls are shown. Results are presented as fold over background, with the radiance value of reporter cells treated with isotype controls mixed with Raji cells set to 1 on the y-axis. Reporter cells were treated with bin 2 anti-SIRPA antibodies derived from the parental anti-SIRPA antibody SA-56 (SA-85 = SA-56-85; SA-89 = SA-56-89; and SA-94 = SA-56-94). [Figure 10A] Residues critical for antigen binding by anti-SIRPA antibodies are shown. Residues (shown as black spheres) critical for binding of anti-SIRPA antibodies SA-56-90 and SA-56-94 (A) to antigen were identified as negative for experimental antibody binding but positive for control antibodies. Critical residues are shown in the Phyre2-derived model of SIRPA based on the human SIRPA crystal structure (PDB ID number 2WNG; Hatherley et al., 2009). [Figure 10B] The epitopes of the anti-SIRPA antibodies SA-56-90 and SA-56-94 (black spheres) are aligned with the CD47 binding site (white spheres) on the crystal structure of the D1 domain of SIRPA (PDB ID number 2UV3). [Figure 11] Figure 1 shows phagocytosis of Raji B cells by human macrophages. Monocyte-derived macrophages were treated overnight with 5 mg / mL of either isotype control or affinity-matured anti-SIRPA antibodies, SA-56-90 and SA-56-94. pHrodo-labeled Raji cells were added to the macrophages and incubated for 2 hours at 37°C. Phagocytosis was measured by counting the percent of the CD14+ / pHrodo+ macrophage population, with values ​​for isotype-treated macrophages set to 1 on the y-axis. [Figure 12]Figure 1 shows the release of TNFα by LPS-stimulated human dendritic cells in the presence of anti-SIRPA antibody SA-56-90. Monocyte-derived dendritic cells were seeded onto wells coated with either an isotype control, anti-SIRPA antibody (SA-56-90), or anti-SIRPb1 antibody (SB-1) and stimulated with 0.5 ng / mL LPS overnight at 37°C. DETAILED DESCRIPTION OF THE INVENTION

[0054] The present disclosure relates to anti-SIRPA antibodies (e.g., monoclonal antibodies); methods of making and using such antibodies; pharmaceutical compositions comprising such antibodies; nucleic acids encoding such antibodies; and host cells comprising nucleic acids encoding such antibodies.

[0055] The present disclosure provides anti-SIRPA antibodies that specifically recognize human SIRPA. The anti-SIRPA antibodies of the present disclosure recognize a unique epitope on the D1 domain of human SIRPA adjacent to the CD47 binding site. As a result of binding to this epitope, the anti-SIRPA antibodies provided herein enhance the interaction between human SIRPA and human CD47, thereby stimulating the inhibitory SIRPA signaling pathway in myeloid cells. Such agonistic anti-SIRPA antibodies of the present disclosure are useful for treating, preventing, or reducing the risk of diseases or conditions associated with decreased or diminished SIRPA expression, activity, or signaling.

[0056] The techniques and procedures described or referenced herein are generally well understood and commonly employed by those of skill in the art using conventional methodologies, such as, for example, widely used methodologies described in: Sambrook et al. Molecular Cloning: A Laboratory Manual 3rd edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (F.M. Usubel, et al. eds., (2003); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000).

[0057] I. Definition The terms "SIRPα" or "SIRPα polypeptide" or "SIRPA" or "SIRPA polypeptide" are used interchangeably herein and refer herein, unless otherwise indicated, to any naturally occurring SIRPA from any vertebrate source, e.g., mammals, e.g., primates (e.g., humans and cynomolgus monkeys) and rodents (e.g., mice and rats). In some embodiments, the term encompasses both wild-type and naturally occurring variant sequences, e.g., splice variants or allelic variants. In some embodiments, the term encompasses "full-length," unprocessed SIRPA, and any form of SIRPA that results from processing within a cell. In some embodiments, the SIRPA is human SIRPA. In some embodiments, the amino acid sequence of an exemplary SIRPA is Uniprot Accession No. P78324 as of April 25, 2018. In some embodiments, the amino acid sequence of an exemplary human SIRPAv1 is SEQ ID NO: 1. In some embodiments, the amino acid sequence of an exemplary human SIRPAv2 is GenBank CAA71403.

[0058] The terms "anti-SIRPA antibody," "antibody that binds to SIRPA," and "antibody that specifically binds to SIRPA" refer to an antibody that can bind to SIRPA with sufficient affinity to be useful as a diagnostic and / or therapeutic agent when the antibody targets SIRPA. In one embodiment, the extent of binding of an anti-SIRPA antibody to an unrelated, non-SIRPA polypeptide is less than about 10% of the binding of the antibody to SIRPA (e.g., as measured by radioimmunoassay (RIA)). In certain embodiments, an antibody that binds to MerTK has an affinity of less than 1 μM, less than 100 nM, less than 10 nM, less than 1 nM, less than 0.1 nM, less than 0.01 nM, or less than 0.001 nM (e.g., less than 10 -8 M or less, e.g., 10 -8 M~10 -13 M, e.g., 10 -9 M~10 -13 M) In certain embodiments, the anti-MerTK antibody binds to an epitope of MerTK that is conserved among MerTKs from different species.

[0059] With respect to the binding of an antibody to a target molecule, the term "specific binding" to or "specifically binds to" or "is specific for" a particular polypeptide or epitope on a particular polypeptide target refers to binding that is measurably different from non-specific interactions. Specific binding can be measured, for example, by determining the binding of a molecule compared to the binding of a control molecule. For example, specific binding can be determined by competition with a control molecule similar to the target, e.g., an excess of unlabeled target. In this case, specific binding is indicated when the binding of the labeled target to the probe is competitively inhibited by the excess of unlabeled target. As used herein, the term "specific binding" to or "specifically binds to" or "is specific for" a particular polypeptide or epitope on a particular polypeptide target refers to binding that is measurably different from non-specific interactions. -4 M or less, 10 -5 M or less, 10 -6 M or less, 10 -7 M or less, 10 -8 M or less, 10 -9 M or less, 10 -10 M or less, 10-11 M or less, 10 -12 KD for any target less than or equal to M, or 10 -4 M~10 -6 M or 10 -6 M~10 -10 M or 10 -7 M~10 -9 Affinity can be exhibited by a molecule having a KD in the range of M. As will be understood by those skilled in the art, affinity and KD values ​​are inversely related. High affinity for an antigen is measured by a low KD value. In one embodiment, the term "specific binding" refers to binding of a molecule to a particular polypeptide or an epitope on a particular polypeptide without substantially binding to any other polypeptides or polypeptide epitopes.

[0060] The term "immunoglobulin" (Ig) is used interchangeably herein with "antibody." The term "antibody" is used herein in the broadest sense and specifically encompasses monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), such as those formed from at least two intact antibodies, and antigen-binding antibody fragments, so long as they exhibit the desired biological activity.

[0061] "Native antibodies" are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light ("L") chains and two identical heavy ("H") chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain contains at one end a variable domain (V H ), followed by several constant domains. Each light chain has at one end a variable domain (V L ) and at the other end a constant domain, with the light-chain constant domain aligned with the first constant domain of the heavy chain and the light-chain variable domain aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light-chain variable domain and the heavy-chain variable domain.

[0062] For the structure and properties of different classes of antibodies, see, e.g., Basic and Clinical Immunology, 8th Ed., Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6.

[0063] The light chains of any vertebrate species can be assigned to one of two clearly distinct types, called kappa ("κ") and lambda ("λ"), based on the amino acid sequence of their constant domains. Depending on the amino acid sequence of the constant domain (CH) of the heavy chain, immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, which have heavy chains called alpha ("α"), delta ("δ"), epsilon ("ε"), gamma ("γ"), and mu ("μ"), respectively. The gamma and alpha classes are further divided into subclasses (isotypes) based on relatively minor differences in CH sequence and function; for example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known and are generally described in, for example, Abbas et al., Cellular and Molecular Immunology, 4 th ed.(WBSaunders Co.,2000).

[0064] The "variable region" or "variable domain" of an antibody, such as the anti-MerTK antibody of the present disclosure, refers to the amino-terminal domains of the heavy or light chain of the antibody. The variable domains of the heavy and light chains, respectively, are referred to as "V H " and "V L These domains are generally the most variable parts of an antibody (compared to other antibodies of the same class) and contain the antigen-binding sites.

[0065] The term "variable" refers to the fact that the sequences of certain segments of the variable domains vary significantly among antibodies, such as the anti-MerTK antibodies of the present disclosure. The variable domains mediate antigen binding and define the specificity of a particular antibody for a particular antigen. However, variability is not uniformly distributed throughout the span of the variable domains. Instead, it is concentrated in three segments called hypervariable regions (HVRs) in both the light-chain and heavy-chain variable domains. The more highly conserved portions of the variable domains are called framework regions (FRs). Naturally occurring heavy- and light-chain variable domains each contain four FR regions, which primarily adopt a beta-sheet structure connected by three HVRs that form loops connecting the beta-sheet structure and, in some cases, form part of the beta-sheet structure. The HVRs of each chain are held together in close proximity by the FR regions and, together with the HVRs from the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institutes of Health, Bethesda, MD (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation in antibody-dependent cellular toxicity.

[0066] As used herein, the term "monoclonal antibody" refers to an antibody, such as a monoclonal anti-SIRPA antibody of the present disclosure, obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations and / or post-translational modifications (e.g., isomerization, amidation, etc.) that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they are synthesized by hybridoma culture, uncontaminated by other immunoglobulins. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous antibody population and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including, but not limited to, one or more of the following methods: immunization of animals, including, but not limited to, rats, mice, rabbits, guinea pigs, hamsters, and / or chickens, with one or more of DNA(s), virus-like particles, polypeptide(s), and / or cell(s); hybridoma methods; B-cell cloning methods; recombinant DNA methods; and techniques for producing human or human-like antibodies in animals that possess some or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences.

[0067] The terms "full length antibody," "intact antibody," or "whole antibody" are used interchangeably to refer to an antibody, such as an anti-SIRPA antibody of the present disclosure, in substantially intact form, as opposed to an antibody fragment. Specifically, a whole antibody includes an antibody having a heavy chain and a light chain, including an Fc region. The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof. In some cases, an intact antibody may have one or more effector functions.

[0068] "Antibody fragment" refers to a molecule other than an intact antibody that contains a portion of the intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies (see U.S. Pat. No. 5,641,870, Example 2; Zapata et al., Protein Eng. 8(10):1057-1062 (1995)); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[0069] Papain digestion of antibodies, such as the anti-SIRPA antibodies of the present disclosure, produces two identical antigen-binding fragments called "Fab" fragments and a residual "Fc" fragment, a name reflecting its ability to be readily crystallized. The Fab fragment contains the variable region domain of the heavy chain (V H ) and the first constant domain of one heavy chain (C H Fab fragments are composed of an entire light chain with a single F(ab')2 fragment containing one or more cysteines from the antibody hinge region. Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab')2 fragment which roughly corresponds to two disulfide-linked Fab fragments with different antigen-binding activities and is still capable of antigen cross-linking. The Fab' fragment contains one or more cysteines from the antibody hinge region, C(ab')2. H F(ab')2 antibody fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of one domain. Fab'-SH is the designation used herein for Fab' in which the cysteine ​​residue(s) in the constant domains bear a free thiol group. F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical bonds for antibody fragments are also known.

[0070] The Fc fragment contains the carboxy-terminal portions of both heavy chains linked by disulfides. The effector functions of an antibody are determined by the sequences in the Fc region, which is also recognized by Fc receptors (FcRs) found on certain types of cells.

[0071] The term "diabody" refers to a V diabody in which inter-chain (rather than intra-chain) pairing of variable domains is achieved. H Domain and V L These refer to small antibody fragments prepared by constructing sFv fragments (see previous paragraph) with a short linker (about 5-10 residues) between the domains, thereby obtaining bivalent fragments, i.e., fragments with two antigen-binding sites. Bispecific diabodies are small antibody fragments prepared by combining the V of two antibodies. H and V L It is a heterodimer of two "crossover" sFv fragments in which the domains are present on different polypeptide chains.

[0072] As used herein, "chimeric antibody" refers to antibodies (immunoglobulins), such as the chimeric anti-SIRPA antibodies of the present disclosure, in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical to or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies (so long as they exhibit the desired biological activity). Chimeric antibodies of interest herein include PRIMATIZED® antibodies, in which the antigen-binding region of the antibody is derived from, for example, an antibody produced by immunizing macaque monkeys with the antigen of interest. As used herein, "humanized antibody" is used as a subset of "chimeric antibody."

[0073] A "humanized" form of a non-human (e.g., murine) antibody, e.g., a humanized form of an anti-MerTK antibody of the present disclosure, is a chimeric antibody comprising amino acid residues from non-human HVRs and human FRs. In certain embodiments, a humanized antibody will comprise substantially all of at least one, and usually two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody (e.g., a non-human antibody) refers to an antibody that has undergone humanization.

[0074] A "human antibody" is one that has an amino acid sequence that corresponds to that of an antibody, such as the anti-SIRPA antibody of the present disclosure, that has been produced by a human and / or that 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 various techniques known in the art, including phage display libraries and yeast display libraries. Human antibodies can be prepared by administering antigen to transgenic animals, e.g., immunized xeno-mouse, that have been engineered to produce such antibodies in response to antigen challenge but whose endogenous gene loci have been disabled, and can also be generated by human B-cell hybridoma technology.

[0075] The terms "hypervariable region," "HVR," or "HV," as used herein, refer to the regions of an antibody variable domain, such as those of the anti-MerTK antibodies of the present disclosure, that are hypervariable in sequence and / or form structurally defined loops. Generally, antibodies contain six HVRs (HVs). H (H1, H2, H3) and V LHVRs are composed of three heavy chains (L1, L2, and L3). In natural antibodies, H3 and L3 show the most diversity among the six HVRs, and H3 in particular is thought to play a unique role in conferring excellent specificity to antibodies. Naturally occurring camelid antibodies, which consist only of heavy chains, are functional and stable in the absence of light chains.

[0076] Many HVR delineations are in use and are encompassed herein. In some embodiments, HVRs may be Kabat complementarity-determining regions (CDRs), which are based on sequence variability and are the most commonly used (Kabat et al., supra). In some embodiments, HVRs may be Chothia CDRs. Alternatively, Chothia refers to the location of structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). In some embodiments, HVRs may be AbM HVRs. AbM HVRs represent a compromise between Kabat CDRs and Chothia structural loops and are used in Oxford Molecular's AbM antibody modeling software. In some embodiments, HVRs may be "contact" HVRs. "Contact" HVRs are based on analysis of available complex crystal structures. The respective residues of these HVRs are shown below: [Table 1]

[0077] HVRs may also include "extended HVRs" such as: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) of the VL; and 26-35 (H1), 50-65 or 49-65 (preferred embodiment) (H2), and 93-102, 94-102, or 95-102 (H3) of the VH. The variable domain residues are numbered according to Kabat et al., supra, for each of these extended HVR definitions. HVRs for particular antibodies herein may also be provided in the tables of this disclosure.

[0078] "Framework" or "FR" residues are those variable domain residues other than the HVR residues as herein defined.

[0079] As used herein, an "acceptor human framework" refers to a V-framework derived from a human immunoglobulin framework or a human consensus framework. L or V H A framework comprising the amino acid sequence of a framework. An acceptor human framework "derived" from a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence or may contain pre-existing amino acid sequence changes. In some embodiments, the number of pre-existing amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. When pre-existing amino acid changes are present in the VH, those preferred changes occur at only three, two, or one of positions 71H, 73H, and 78H; for example, the amino acid residues at those positions may be 71A, 73T, and / or 78A. In one embodiment, the VL acceptor human framework comprises a VL. L It is identical in sequence to a human immunoglobulin framework sequence or a human consensus framework sequence.

[0080] The "human consensus framework" is based on human immunoglobulin V L or V H A framework representing the most commonly occurring amino acid residues in a selection of framework sequences. Generally, human immunoglobulin V L or V H The selection of sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is as follows: Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). LExamples for V include subgroups that may be subgroups kappa I, kappa II, kappa III, or kappa IV of Kabat et al., supra. H For example, the subgroup may be subgroup I, subgroup II, or subgroup III of Kabat et al., supra.

[0081] For example, an "amino acid modification" at a particular position of an anti-SIRPA antibody of the present disclosure refers to a substitution or deletion of the particular residue, or an insertion of at least one amino acid residue adjacent to the particular residue. An insertion "adjacent to" a particular residue means an insertion within 1 to 2 residues thereof. The insertion may be on the N-terminal or C-terminal side of the specified residue. A preferred amino acid modification herein is a substitution.

[0082] An "Fv" is the minimum antibody fragment that contains a complete antigen-recognition and binding site. This fragment consists of a dimer of one heavy-chain and one light-chain variable domain in tight, non-covalent association. Extending from the folding of these two domains are six hypervariable loops (three loops from each H and L chain), which contribute antigen-binding amino acid residues and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three antigen-specific HVRs) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.

[0083] A "single-chain Fv," also abbreviated as "sFv" or "scFv," is an antibody fragment comprising the VH and VL antibody domains joined in a single polypeptide chain. Preferably, the sFv polypeptide further comprises a V H Domains and V L A polypeptide linker is included between the domains which enables the sFv to form the desired structure for antigen binding.

[0084] Antibody "effector functions" refer to those biological activities attributable to the Fc region of an antibody (a native sequence Fc region or amino acid sequence variant Fc region), and vary with the antibody isotype.

[0085] The term "Fc 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 the Fc region of an immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is usually defined to stretch from the amino acid residue at position Cys226 or Pro230 to its carboxyl terminus. The C-terminal lysine of the Fc region (residue 447 (according to the EU numbering system)) can be removed, for example, during antibody production or purification, or by recombinantly engineering the nucleic acid encoding the antibody heavy chain. Thus, an intact antibody composition 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 that contain and do not contain the K447 residue. Suitable native-sequence Fc regions for use in the antibodies of the present disclosure include human IgG1, IgG2, IgG3, and IgG4.

[0086] A "native-sequence Fc region" comprises an amino acid sequence identical to that of an Fc region found in nature. Native-sequence human Fc regions include native-sequence human IgG1 Fc regions (non-A and A allotypes); native-sequence human IgG2 Fc regions; native-sequence human IgG3 Fc regions; and native-sequence human IgG4 Fc regions, as well as naturally occurring variants thereof.

[0087] A "variant Fc region" comprises an amino acid sequence that differs from that of a native-sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitution(s). Preferably, the variant Fc region has at least one amino acid substitution compared to a native-sequence Fc region or the Fc region of a parent polypeptide, e.g., about one to about ten amino acid substitutions, preferably about one to about five amino acid substitutions, in the native-sequence Fc region or the Fc region of a parent polypeptide. A variant Fc region herein preferably has at least 80% homology with a native-sequence Fc region and / or the Fc region of a parent polypeptide, most preferably at least 90% homology thereto, and more preferably at least 95% homology thereto.

[0088] "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. A preferred FcR is a native-sequence human FcR. Furthermore, a preferred FcR is one that binds IgG antibodies (gamma receptors) and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses (including allelic variants and alternatively spliced ​​forms of these receptors). FcγRII receptors include FcγRIIA (an "activating receptor") and FcγRIIB (an "inhibiting 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. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif ("ITIM") in its cytoplasmic domain. Other FcRs, including those identified in the future, are encompassed by the term "FcR" herein. FcRs may also extend the serum half-life of antibodies.

[0089] As used herein, "percent (%) amino acid sequence identity" and "homology" with respect to a peptide, polypeptide, or antibody sequence refer to the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in a particular peptide or polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity (conservative substitutions are not considered part of sequence identity). Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways that are within the skill of those in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN™ (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms known in the art necessary to achieve maximum alignment over the full length of the sequences being compared.

[0090] The term "competition," when used in the context of antibodies competing for the same or overlapping epitope, refers to competition between the antibodies as determined in an assay in which the antibody being tested prevents or inhibits (e.g., reduces) specific binding of a reference molecule (e.g., a ligand or reference antibody) to a common antigen (e.g., SIRPA or a fragment thereof). To determine whether an antibody competes with another antibody, numerous types of competitive binding assays can be used, such as solid-phase direct or indirect radioimmunoassays (RIA), solid-phase direct or indirect enzyme immunoassays (EIA), sandwich competition assays (see, e.g., Stahl et al., 1983, Methods in Enzymology 9:242-253); solid-phase direct biotin-avidin EIA (see, e.g., Kirkland et al., 1986, J. Immunol. 137:3614-3619); solid-phase direct label assay; solid-phase direct label sandwich assay (see, e.g., Harlow and Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Press); solid-phase direct label RIA using 1-125 label (see, e.g., Morel et al., 1988, Molec. Immunol. 25:7-15); solid-phase direct biotin-avidin EIA (see, e.g., Cheung, et al., al., 1990, Virology 176:546-552); and direct labeling RIA (Moldenhauer et al., 1990, Scand. J. Immunol. 32:77-82) can be used. Typically, such assays involve the use of purified antigen bound to a solid surface, or cells bearing either of these (unlabeled, labeled test antibody and labeled reference antibody). Competitive inhibition is measured by determining the amount of label bound to the solid surface or cells in the presence of the test antibody. Typically, the test antibody is present in excess. Antibodies identified by competitive assays (competing antibodies) include antibodies that bind to the same epitope as the reference antibody and antibodies that bind to adjacent epitopes sufficiently close to the epitope bound by the reference antibody so that steric hindrance occurs.Typically, a competing antibody, when present in excess, inhibits (e.g., reduces) specific binding of a reference antibody to a common antigen by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97.5%, and / or nearly 100%.

[0091] As used herein, an "interaction" between a SIRPA polypeptide and a second polypeptide includes, but is not limited to, protein-protein interactions, physical interactions, chemical interactions, bonds, covalent bonds, and ionic bonds. As used herein, an antibody "inhibits an interaction" between two polypeptides if the antibody disrupts, reduces, or completely eliminates the interaction between the two polypeptides. An antibody of the present disclosure "inhibits an interaction" between two polypeptides if the antibody binds to one of the two polypeptides. In some embodiments, the interaction can be inhibited by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97.5%, and / or nearly 100%.

[0092] The term "epitope" includes any determinant capable of binding by an antibody. An epitope is the region of an antigen bound by an antibody targeting that antigen, and, if the antigen is a polypeptide, includes specific amino acids that make direct contact with the antibody. In most cases, epitopes reside on polypeptides, but in some cases, they may reside on other types of molecules, such as nucleic acids. Epitopes may include chemically active surface groups of molecules, such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and may have specific three-dimensional structural characteristics and / or specific charge characteristics. In general, antibodies specific for a particular target antigen preferentially recognize epitopes on the target antigen in a complex mixture of polypeptides and / or macromolecules.

[0093] An "agonist" or "activating" antibody is an antibody that induces (eg, increases) one or more activities or functions of an antigen after the antibody binds to the antigen.

[0094] An "isolated" antibody, such as an isolated anti-SIRPA antibody of the present disclosure, is an antibody that has been identified, separated, and / or recovered from components (e.g., natural or recombinant) of its production environment. Preferably, an isolated antibody is free of association with all other contaminating components from its production environment. Contaminating components from its production environment, such as those arising from recombinantly transfected cells, are substances that would normally interfere with research, diagnostic, or therapeutic uses of the antibody and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In preferred embodiments, the antibody is purified: (1) to greater than 95% by weight, and in some embodiments, greater than 99% by weight, of the antibody, as determined, for example, by the Lowry method; (2) sufficiently to obtain at least 15 residues of N-terminal or internal amino acid sequence using a spinning cup sequenator; or (3) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver staining. Because at least one component of the antibody's natural environment will be absent, an isolated antibody includes the antibody in situ within recombinant T cells. Ordinarily, however, isolated polypeptide or antibody will be prepared by at least one purification step.

[0095] An "isolated" nucleic acid molecule encoding an antibody, such as an anti-SIRPA antibody of the present disclosure, is a nucleic acid molecule that has been identified and separated from at least one contaminant nucleic acid molecule with which it is normally associated in the environment in which it is produced. Preferably, the isolated nucleic acid is free from association with all components associated with the production environment. Isolated nucleic acid molecules encoding the polypeptides and antibodies of the present disclosure are in a form other than that in which they are found in nature or in the environment in which they are found. Thus, isolated nucleic acid molecules are distinguished from nucleic acids encoding the polypeptides and antibodies of the present disclosure that naturally occur in cells.

[0096] As used herein, the term "vector" is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid," which refers to a circular double-stranded DNA into which additional DNA segments can be ligated. Another type of vector is a phage vector. Another kind of vector is a viral vector, into which additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors" or simply, "expression vectors." In general, expression vectors useful in recombinant DNA techniques are often in the form of plasmids. As the plasmid is the most commonly used form of vector, "plasmid" and "vector" may be used interchangeably herein.

[0097] "Polynucleotide" or "nucleic acid," used interchangeably herein, refer to a polymer of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or a synthetic reaction.

[0098] A "host cell" includes an individual cell or cell culture that can be or has been the recipient of a vector(s) for incorporating a polynucleotide insert. A host cell includes the progeny of a single host cell, although the progeny may not necessarily be completely identical (in morphology or genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with a polynucleotide(s) of the invention.

[0099] As used herein, a "carrier" includes a pharmaceutically acceptable carrier, excipient, or stabilizer that is non-toxic to cells or mammals exposed at the dosages and concentrations employed.

[0100] As used herein, the term "treatment" refers to a clinical intervention designed to alter the natural course of a treated individual's clinical pathology. Desirable effects of treatment include reducing the rate of progression, improving or alleviating the condition, and remission or improving the prognosis of a particular disease, disorder, or condition. For example, an individual is successfully "treated" if one or more symptoms associated with a particular disease, disorder, or condition are alleviated or eliminated.

[0101] An "effective amount" refers to at least an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. An effective amount may be provided in one or more administrations. An effective amount is also an amount in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. In therapeutic applications, beneficial or desired results include clinical results, such as a reduction in one or more symptoms attributable to the disease, an improvement in the quality of life of those suffering from the disease, a reduction in the dosage of other drugs required to treat the disease, augmentation of other drug therapies, e.g., by targeting, a delay in disease progression, and / or an extension of survival. An effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve a therapeutic treatment directly or indirectly. As understood in a clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if a desired result can be obtained or is achieved in combination with one or more other agents.

[0102] An "individual" for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as dogs, horses, rabbits, cows, pigs, hamsters, gerbils, mice, ferrets, rats, cats, etc. In some embodiments, the individual is a human.

[0103] As used herein, administration "in combination with" another compound or composition includes simultaneous administration and / or administration at different times. Concomitant administration also includes administration as a co-formulation or as separate compositions (including different dosing frequencies or intervals), and using the same or different routes of administration. In some embodiments, concomitant administration is administration as part of the same treatment regimen.

[0104] The term "about" as used herein refers to the normal error range for the respective value, which is readily known to one of ordinary skill in the art. The reference to "about" before a value or parameter herein includes (and describes) embodiments that are directed to the value or parameter itself.

[0105] As used herein and in the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. For example, a reference to an "antibody" is a reference to one to many antibodies, such as molar amounts, and includes equivalents thereof known to those skilled in the art, and so forth.

[0106] It is understood that aspects and embodiments of the present disclosure described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0107] II. Anti-SIRPA antibody Provided herein are anti-SIRPA antibodies. The antibodies provided herein are useful, for example, for the diagnosis or treatment of SIRPA-associated disorders.

[0108] SIRPA is a single-pass type I membrane protein. Within the amino acid sequence of human SIRPA (SEQ ID NO: 1), the extracellular domain is located at amino acid residues 31-373; the transmembrane domain is located at amino acid residues 374-394; and the intracellular domain is located at amino acid residues 395-504. Human SIRPA contains one V set and two C1 sets of Ig superfamily (IgSF) domains, referred to as the D1 domain, D2 domain, and D3 domain, respectively. The D1 domain contains amino acid residues 32-137 of human SIRPA; the D2 domain contains amino acid residues 148-247 of human SIRPA; and the D3 domain contains amino acid residues 254-348 of human SIRPA. As will be appreciated by those skilled in the art, the starting and ending residues of domains of the present disclosure may vary depending on the computer modeling program or method used to determine the domains.

[0109] In some embodiments, the anti-SIRPA antibody of the present disclosure can bind to a conformational epitope. In some embodiments, the anti-SIRPA antibody of the present disclosure can bind to a discontinuous SIRPA epitope. In some embodiments, the discontinuous SIRPA epitope comprises two or more peptides, three or more peptides, four or more peptides, five or more peptides, six or more peptides, seven or more peptides, eight or more peptides, nine or more peptides, or ten or more peptides. In some embodiments, the anti-SIRPA antibody of the present disclosure can bind to a SIRPA epitope comprising one or more peptides. As disclosed herein, a SIRPA epitope may comprise 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or 20 or more amino acid residues of the amino acid sequence of SEQ ID NO: 1, or one or more peptides comprising 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or 20 or more amino acid residues on a mammalian SIRPA protein corresponding to the amino acid sequence of SEQ ID NO: 1.

[0110] Evidence provided herein demonstrates that anti-SIRPA antibodies of the present disclosure bind to the D1 domain of human SIRPAv1. Accordingly, in some embodiments, anti-SIRPA antibodies of the present disclosure bind to the D1 domain of human SIRPA. In some embodiments, anti-SIRPA antibodies of the present disclosure bind to the D1 domain of human SIRPAv1. In some embodiments, anti-SIRPA antibodies of the present disclosure bind to a region comprising amino acid residues 32-137 of SEQ ID NO: 1. In some embodiments, anti-SIRPA antibodies of the present disclosure bind to amino acid residues within human SIRPA, and the human SIRPA amino acid residues involved in binding by anti-SIRPA antibodies of the present disclosure include amino acid residues D40, R54, and W68 of SEQ ID NO: 1.

[0111] Evidence provided herein demonstrates that anti-SIRPA antibodies of the present disclosure increase the binding of CD47 to SIRPA. In some embodiments, anti-SIRPA antibodies of the present disclosure increase the binding of CD47 to SIRPA. In some embodiments, anti-SIRPA antibodies of the present disclosure increase the binding of CD47 to human SIRPA. In some embodiments, anti-SIRPA antibodies of the present disclosure increase the binding of CD47 to human SIRPAv1. In some embodiments, anti-SIRPA antibodies of the present disclosure bind to the D1 domain of SIRPA and increase the binding of CD47 to SIRPA. In some embodiments, anti-SIRPA antibodies of the present disclosure bind to a region comprising amino acid residues 32-137 of SEQ ID NO: 1 and increase the binding of CD47 to SIRPA. In yet other embodiments, the anti-SIRPA antibodies of the present disclosure bind to specific amino acid residues within SIRPA, and the SIRPA amino acid residues involved in binding by the anti-SIRPA antibodies of the present disclosure include amino acid residues D40, R54, and W68 of SEQ ID NO: 1, and further, the anti-SIRPA antibodies increase binding of CD47 to SIRPA.

[0112] In one aspect, the present disclosure provides an isolated (e.g., monoclonal) antibody that binds to an epitope within a SIRPA protein or polypeptide of the present disclosure. SIRPA proteins or polypeptides of the present disclosure include, but are not limited to, mammalian SIRPA proteins or polypeptides, human SIRPA proteins or polypeptides, mouse (murine) SIRPA proteins or polypeptides, and cynomolgus monkey SIRPA proteins or polypeptides. SIRPA proteins and polypeptides of the present disclosure include naturally occurring variants of SIRPA. In some embodiments, the SIRPA proteins and polypeptides of the present disclosure are membrane-bound. In some embodiments, the SIRPA proteins and polypeptides of the present disclosure are the soluble extracellular domain of SIRPA.

[0113] A. Competitive inhibition of binding In some embodiments, the anti-SIRPA antibodies of the present disclosure bind to an epitope of human SIRPA that is the same as or overlaps with the SIRPA epitope bound by at least one antibody selected from any of the antibodies provided herein.

[0114] In some embodiments, the anti-SIRPA antibody competes with another antibody for binding to SIRPA. Suitable competition or SIRPA binding assays known in the art, such as BIAcore® analysis (surface plasmon resonance), ELISA assays, or flow cytometry, demonstrate that the anti-SIRPA antibody competes with SA-1, SA-2, SA-3, SA-4, SA-5 (including SA-5-57, SA-5-58, SA-5-59, and SA-5-61), SA-6, SA-7, SA-8 (including SA-8-62, SA-8-64, SA-8-66, and SA-8-67), SA- 9, SA-10, SA-11, SA-12, SA-13 (including SA-13-6, SA-13-69, and SA-13-71), SA-14, SA-15, SA-16, SA-17, SA-18, SA-19 ​​(SA-19-72, SA-19-7 3, SA-19-74, SA-19-75, SA-19-76, SA-19-77, SA-19-78, SA-19-79, SA-19-80, SA-19-81, SA-19-82, SA-19-83, and SA-19-84), SA- 20, SA-21, SA-22, SA-23, SA-24, SA-25, SA-26, SA-27, SA-28, SA-29, SA-30, SA-31, SA-32, SA-33, SA-34, SA-35, SA-36, SA-37, SA-3 8, SA-39, SA-40, SA-41, SA-42, SA-43, SA-44, SA-45, SA-46, SA-47, SA-48, SA-49, SA-50, SA-51, SA-52, SA-53, SA-54, SA-55, SA-56( The antibody may be utilized to determine whether or not a antibody competes for binding to SIRPA with one or more antibodies selected from SA-56-85, SA-56-86, SA-56-87, SA-56-88, SA-56-89, SA-56,90, SA-56,91, SA-56-92, SA-56-93, SA-56-94, SA-56-95, and SA-56-96), SA-57, SA-58, SA-59, SA-60, SA-61, and SA-62, and any combination thereof.In an exemplary competitive assay, immobilized SIRPA or cells expressing SIRPA on their cell surface are incubated in a solution containing a first labeled antibody (e.g., human or non-human primate) that binds to SIRPA and a second unlabeled antibody being tested for its ability to compete with the first antibody for binding to SIRPA. The second antibody may be present in hybridoma supernatant. As a control, immobilized SIRPA or cells expressing SIRPA are incubated in a solution containing the first labeled antibody but not the second unlabeled antibody. After incubation under conditions that allow binding of the first antibody to SIRPA, excess unbound antibody is removed and the amount of label associated with immobilized SIRPA or cells expressing SIRPA is measured. If the amount of label associated with immobilized SIRPA or cells expressing SIRPA is substantially reduced in the test sample compared to the control sample, this indicates that the second antibody competes with the first antibody for binding to SIRPA. See Harlow and Lane (1988) Antibodies: A Laboratory Manual ch. 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).

[0115] In some embodiments, SIRPA is expressed in cells. In some embodiments, SIRPA is expressed in phagocytes, including but not limited to macrophages and dendritic cells. In some embodiments, SIRPA is expressed in monocytes, natural killer cells, natural killer T cells, microglia, endothelial cells, and megakaryocytes.

[0116] Evidence provided herein demonstrates that anti-SIRPA antibodies of the present disclosure are effective in reducing phagocytic activity by phagocytes. In some embodiments, anti-SIRPA antibodies of the present disclosure reduce phagocytic activity by phagocytes. In some embodiments, anti-SIRPA antibodies of the present disclosure reduce phagocytosis of tumor cells by phagocytes. In some embodiments, the phagocytes are macrophages. In some embodiments, the phagocytes are dendritic cells.

[0117] The present disclosure demonstrates that the anti-SIRPA antibodies described herein are effective in increasing SIRPA activity and SIRPA signaling in cells. Evidence is also provided herein demonstrating that the anti-SIRPA antibodies of the present disclosure are effective in increasing CD47-induced (or CD47-mediated) SIRPA signaling in cells. Thus, in some embodiments, the anti-SIRPA antibodies of the present disclosure are effective in increasing SIRPA activity in cells. In some embodiments, the anti-SIRPA antibodies of the present disclosure are effective in increasing SIRPA signaling in cells. In other embodiments, the anti-SIRPA antibodies of the present disclosure increase CD47-induced SIRPA signaling (e.g., CD47-mediated SIRPA signaling) in cells. In some embodiments, the anti-SIRPA antibodies of the present disclosure increase SIRPA activity in macrophages, dendritic cells, and / or microglial cells. In some embodiments, the anti-SIRPA antibodies of the present disclosure increase SIRPA signaling in macrophages, dendritic cells, and / or microglial cells. In some embodiments, the anti-SIRPA antibodies of the present disclosure increase CD47-induced or CD47-mediated SIRPA signaling in macrophages, dendritic cells, and / or microglial cells.

[0118] In some embodiments, the anti-SIRPA antibodies of the present disclosure increase synapse density. In some embodiments, the anti-SIRPA antibodies of the present disclosure increase synapse density in the brain. In some embodiments, the anti-SIRPA antibodies of the present disclosure increase synapse density in neurons.

[0119] In some embodiments, the anti-SIRPA antibodies of the present disclosure reduce synapse loss.

[0120] Synapsins are a family of neuron-specific phosphoproteins involved in the control of neurotransmitter release at synapses. Synapsins are thought to be involved in regulating the number of synaptic vesicles available for release via exocytosis. (See, e.g., Mirza and Zahid, 2018, Neurosci Bull, 34:349-358). Provided herein are anti-SIRPA antibodies that are effective in increasing synapsin levels. In some embodiments, the anti-SIRPA antibodies of the present disclosure increase synapsin levels in neurons.

[0121] The postsynaptic density (PSD) is an electron-dense region localized at the postsynaptic site of excitatory synapses. Postsynaptic density-95 (PSD-95) is one of the most abundant proteins in the PSD and is involved in promoting synaptic maturation and regulating synaptic strength and plasticity. Provided herein are anti-SIRPA antibodies that are effective in increasing PSD-95 levels in neurons. In some embodiments, the anti-SIRPA antibodies of the present disclosure increase PSD-95 levels in neurons. In some embodiments, the anti-SIRPA antibodies of the present disclosure increase synapsin levels and increase PSD-95 levels in neurons.

[0122] The evidence provided herein demonstrates that anti-SIRPA antibodies of the present disclosure are effective in reducing cytokine release from dendritic cells. In particular, the present disclosure shows that anti-SIRPA antibodies of the present disclosure reduce TNFα release from dendritic cells. In some embodiments, anti-SIRPA antibodies of the present disclosure reduce cytokine release from dendritic cells. In some embodiments, anti-SIRPA antibodies of the present disclosure reduce TNFα release from dendritic cells. In some embodiments, anti-SIRPA antibodies of the present disclosure reduce TNFα release by about 42% compared to that observed in the absence of the anti-SIRPA antibodies of the present disclosure.

[0123] B. Exemplary Antibodies and Other Specific Antibody Embodiments The present disclosure provides anti-SIRPA antibodies. In some embodiments, provided herein are anti-SIRPA antibodies comprising at least one, two, three, four, five, or six HVRs selected from the following: (a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 7 to 28; (b) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 29 to 40; (c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41 to 101; (d) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 102 to 122; (e) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 123 to 146; and (f) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 147 to 201.

[0124] In some embodiments, at least one, at least two, or all three V selected from the following: L Anti-SIRPA antibodies comprising HVR sequences are provided herein: (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 7 to 28; (b) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 29 to 40; and (c) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41 to 101.

[0125] In some embodiments, at least one, at least two, or all three V selected from the following: H Anti-SIRPA antibodies comprising HVR sequences are provided herein: (a) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 102 to 122; (b) HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 123 to 146; and (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 147 to 201.

[0126] In some embodiments, provided herein are anti-SIRPA antibodies comprising: (a) at least one, at least two, or all three V selected from the following: L V containing HVR sequences LDomains: (i) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 7 to 28, (ii) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 29 to 40, and (iii) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41 to 101, and (b) at least one, at least two, or all three V selected from the following: H V containing HVR sequences H Domains: (i) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 102 to 122, (ii) HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 123 to 146, and (iii) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 147 to 201.

[0127] In some embodiments, provided herein are anti-SIRPA antibodies comprising: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 41; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 102; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 8; (b) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 30. (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 148; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 43; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 104; (e) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 125 -H2; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 149; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 44; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 105; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 150; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32 L2; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 151; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 46; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 126;and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 152; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 47; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 127; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 47; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 127; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 154; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 49; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 155. (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 34; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 50; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 126; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 156; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 51. (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 102; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 157; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 52; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 108; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 129; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 158;(a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 53; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 15; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54; (d) SEQ ID NO: 10 (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 55; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 110; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 161; ... the amino acid sequence of SEQ ID NO: 7 (b) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 31; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 56; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 111; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 132; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 162; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 16; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 110. -H1; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 133; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 163; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 58; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 164; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11;(b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (e) SEQ ID NO: 1 (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 8; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 61; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 113; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 135; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 166; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33 (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 62; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 130; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 167; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 17; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 37; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114; (e) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 136. (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 168; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 64; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 169; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33;(c) HVR-L3 having the amino acid sequence of SEQ ID NO: 65; (d) HVR-H1 having the amino acid sequence of SEQ ID NO: 110; (e) HVR-H2 having the amino acid sequence of SEQ ID NO: 138; and (f) HVR-H3 having the amino acid sequence of SEQ ID NO: 170; (a) HVR-L1 having the amino acid sequence of SEQ ID NO: 18; (b) HVR-L2 having the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 having the amino acid sequence of SEQ ID NO: 66; (d) HVR-H1 having the amino acid sequence of SEQ ID NO: 111; (e) HVR-H2 having the amino acid sequence of SEQ ID NO: 132; and (f) HVR-H3 having the amino acid sequence of SEQ ID NO: 171 HVR-H3 comprising the amino acid sequence of SEQ ID NO: 14; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 67; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 139; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 172; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 68; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 116; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 173; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 116; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 173; (a) (b) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 70; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 174; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 71; (d) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 110. (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 138; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 170; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 175 ... (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 73; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 110; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 133; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 176; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 118;(e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 141; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 119; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 129; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 178; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 22; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 119; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 129; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 76; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 113; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 135; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 179; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 77; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 116; (e) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 139. (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 16; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 116; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 139; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 180; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33. (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 79; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 120; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 129; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 181; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 80; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 119; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 142;and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 182; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 16; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 25; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36 (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 82; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 83; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 122; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 139; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 184; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 144; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 185; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38 (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 85; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 141; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 186; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 86; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 104; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 125;and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 187; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 119; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 129; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 188; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30 (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 88; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 189; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 89; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 130; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 190; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 144; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 191; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38 (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 91; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 110; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 138; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 192; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 40; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 92; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 141;and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 193; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 116; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 145; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 194; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 94; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 139; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 195; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 27; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 95; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 112; (e) SEQ ID NO: 1 (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 130; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 197; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31. (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 97; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 122; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 139; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 198; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 98; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 122; (e) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 139. (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 200; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 29;(c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 100; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 144; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 119; (e) sequence HVR-H2 comprising the amino acid sequence of SEQ ID NO: 129; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 178; and (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 28; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 101; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 144; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201.

[0128] In another embodiment, the anti-SIRPA antibody comprises a light chain variable domain (V) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 257-317. L In certain embodiments, the V has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 257-317. LThe sequence contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-SIRPA antibody comprising the sequence retains the ability to bind to SIRPA. In certain embodiments, a total of 1 to 10 amino acids are selected from the group consisting of SEQ ID NOs: 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352 88, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, or 317. In certain embodiments, a total of 1 to 5 amino acids are selected from the group consisting of SEQ ID NOs: 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353 8, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, or 317. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., the FRs).Optionally, the anti-SIRPA antibody is selected from the group consisting of SEQ ID NOs: 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285 , 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, or 317 V. L In certain embodiments, V L comprises one, two, or three HVRs selected from the following: (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 7 to 28, (b) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 29 to 40, and (c) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41 to 101.

[0129] In another embodiment, the antibody comprises a heavy chain variable domain (V) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 202-256. H In certain embodiments, an anti-SIRPA antibody is provided, comprising a V having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 202-256. HThe sequence contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-SIRPA antibody comprising the sequence retains the ability to bind to SIRPA. In some embodiments, a total of 1 to 10 amino acids are selected from the group consisting of SEQ ID NOs: 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, or 257. In certain embodiments, a total of 1 to 5 amino acids are selected from the group consisting of SEQ ID NOs: 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, Substitutions, insertions, and / or deletions are made in 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, or 257. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., the FRs). Optionally, the anti-SIRPA antibody comprises a V of SEQ ID NO: 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, or 257. H In certain embodiments, V Hcomprises one, two, or three HVRs selected from (a) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 102 to 122, (b) HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 123 to 146, and (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 147 to 201.

[0130] In some embodiments, the antibody is a V such as any of the embodiments provided above. L and V such as in any of the embodiments provided above. H In some embodiments, the antibody comprises a V such as any of the embodiments provided above. L and V such as in any of the embodiments provided above. H In one embodiment, the antibody comprises a V of SEQ ID NOs: 257-317. L Sequences and V of SEQ ID NOs: 202 to 256 H sequences (including post-translational modifications of those sequences).

[0131] In some embodiments, the light chain variable domain (V L ) and heavy chain variable domain (V H ) and V L and V H is selected from the group consisting of: V comprising the amino acid sequence of SEQ ID NO: 257 L and V comprising the amino acid sequence of SEQ ID NO: 202 H V comprising the amino acid sequence of SEQ ID NO: 258 L and V comprising the amino acid sequence of SEQ ID NO: 203 H V comprising the amino acid sequence of SEQ ID NO: 259 L and V comprising the amino acid sequence of SEQ ID NO: 204 H V comprising the amino acid sequence of SEQ ID NO: 260 L and V comprising the amino acid sequence of SEQ ID NO: 205 H V comprising the amino acid sequence of SEQ ID NO: 261 L and V comprising the amino acid sequence of SEQ ID NO: 206 HV comprising the amino acid sequence of SEQ ID NO: 262 L and V comprising the amino acid sequence of SEQ ID NO: 207 H V comprising the amino acid sequence of SEQ ID NO: 263 L and V comprising the amino acid sequence of SEQ ID NO: 208 H V comprising the amino acid sequence of SEQ ID NO: 264 L and V comprising the amino acid sequence of SEQ ID NO: 209 H V comprising the amino acid sequence of SEQ ID NO: 265 L and V comprising the amino acid sequence of SEQ ID NO: 210 H V comprising the amino acid sequence of SEQ ID NO: 266 L and V comprising the amino acid sequence of SEQ ID NO: 211 H V comprising the amino acid sequence of SEQ ID NO: 267 L and V comprising the amino acid sequence of SEQ ID NO: 212 H V comprising the amino acid sequence of SEQ ID NO: 268 L and V comprising the amino acid sequence of SEQ ID NO: 213 H V comprising the amino acid sequence of SEQ ID NO: 269 L and V comprising the amino acid sequence of SEQ ID NO: 214 H V comprising the amino acid sequence of SEQ ID NO: 270 L and V comprising the amino acid sequence of SEQ ID NO: 215 H V comprising the amino acid sequence of SEQ ID NO: 271 L and V comprising the amino acid sequence of SEQ ID NO: 216 H V comprising the amino acid sequence of SEQ ID NO: 272 L and V comprising the amino acid sequence of SEQ ID NO: 217 H V comprising the amino acid sequence of SEQ ID NO: 273 L and V comprising the amino acid sequence of SEQ ID NO: 218 H V comprising the amino acid sequence of SEQ ID NO: 274 L and V comprising the amino acid sequence of SEQ ID NO: 219 H V comprising the amino acid sequence of SEQ ID NO: 275 L and V comprising the amino acid sequence of SEQ ID NO: 220 H V comprising the amino acid sequence of SEQ ID NO: 276 L and V comprising the amino acid sequence of SEQ ID NO: 209 H V comprising the amino acid sequence of SEQ ID NO: 277L and V comprising the amino acid sequence of SEQ ID NO: 221 H V comprising the amino acid sequence of SEQ ID NO: 278 L and V comprising the amino acid sequence of SEQ ID NO: 222 H V comprising the amino acid sequence of SEQ ID NO: 279 L and V comprising the amino acid sequence of SEQ ID NO: 223 H V comprising the amino acid sequence of SEQ ID NO: 280 L and V comprising the amino acid sequence of SEQ ID NO: 224 H V comprising the amino acid sequence of SEQ ID NO: 281 L and V comprising the amino acid sequence of SEQ ID NO: 225 H V comprising the amino acid sequence of SEQ ID NO: 282 L and V comprising the amino acid sequence of SEQ ID NO: 226 H V comprising the amino acid sequence of SEQ ID NO: 283 L and V comprising the amino acid sequence of SEQ ID NO: 227 H V comprising the amino acid sequence of SEQ ID NO: 284 L and V comprising the amino acid sequence of SEQ ID NO: 228 H V comprising the amino acid sequence of SEQ ID NO: 285 L and V comprising the amino acid sequence of SEQ ID NO: 228 H V comprising the amino acid sequence of SEQ ID NO: 286 L and V comprising the amino acid sequence of SEQ ID NO: 229 H V comprising the amino acid sequence of SEQ ID NO: 287 L and V comprising the amino acid sequence of SEQ ID NO: 225 H V comprising the amino acid sequence of SEQ ID NO: 288 L and V comprising the amino acid sequence of SEQ ID NO: 230 H V comprising the amino acid sequence of SEQ ID NO: 289 L and V comprising the amino acid sequence of SEQ ID NO: 231 H V comprising the amino acid sequence of SEQ ID NO: 290 L and V comprising the amino acid sequence of SEQ ID NO: 232 H V comprising the amino acid sequence of SEQ ID NO: 291 L and V comprising the amino acid sequence of SEQ ID NO: 233 H V comprising the amino acid sequence of SEQ ID NO: 292 Land V comprising the amino acid sequence of SEQ ID NO: 234 H V comprising the amino acid sequence of SEQ ID NO: 293 L and V comprising the amino acid sequence of SEQ ID NO: 235 H V comprising the amino acid sequence of SEQ ID NO: 294 L and V comprising the amino acid sequence of SEQ ID NO: 235 H V comprising the amino acid sequence of SEQ ID NO: 295 L and V comprising the amino acid sequence of SEQ ID NO: 236 H V comprising the amino acid sequence of SEQ ID NO: 296 L and V comprising the amino acid sequence of SEQ ID NO: 237 H V comprising the amino acid sequence of SEQ ID NO: 297 L and V comprising the amino acid sequence of SEQ ID NO: 238 H V comprising the amino acid sequence of SEQ ID NO: 298 L and V comprising the amino acid sequence of SEQ ID NO: 238 H V comprising the amino acid sequence of SEQ ID NO: 299 L and V comprising the amino acid sequence of SEQ ID NO: 239 H V comprising the amino acid sequence of SEQ ID NO: 300 L and V comprising the amino acid sequence of SEQ ID NO: 240 H V comprising the amino acid sequence of SEQ ID NO: 301 L and V comprising the amino acid sequence of SEQ ID NO: 241 H V comprising the amino acid sequence of SEQ ID NO: 302 L and V comprising the amino acid sequence of SEQ ID NO: 242 H V comprising the amino acid sequence of SEQ ID NO: 303 L and V comprising the amino acid sequence of SEQ ID NO: 243 H V comprising the amino acid sequence of SEQ ID NO: 304 L and V comprising the amino acid sequence of SEQ ID NO: 244 H V comprising the amino acid sequence of SEQ ID NO: 305 L and V comprising the amino acid sequence of SEQ ID NO: 245 H V comprising the amino acid sequence of SEQ ID NO: 306 L and V comprising the amino acid sequence of SEQ ID NO: 246 H V comprising the amino acid sequence of SEQ ID NO: 307 L and V comprising the amino acid sequence of SEQ ID NO: 247H V comprising the amino acid sequence of SEQ ID NO: 308 L and V comprising the amino acid sequence of SEQ ID NO: 248 H V comprising the amino acid sequence of SEQ ID NO: 309 L and V comprising the amino acid sequence of SEQ ID NO: 249 H V comprising the amino acid sequence of SEQ ID NO: 310 L and V comprising the amino acid sequence of SEQ ID NO: 250 H V comprising the amino acid sequence of SEQ ID NO: 311 L and V comprising the amino acid sequence of SEQ ID NO: 251 H V comprising the amino acid sequence of SEQ ID NO: 312 L and V comprising the amino acid sequence of SEQ ID NO: 252 H V comprising the amino acid sequence of SEQ ID NO: 313 L and V comprising the amino acid sequence of SEQ ID NO: 253 H V comprising the amino acid sequence of SEQ ID NO: 314 L and V comprising the amino acid sequence of SEQ ID NO: 254 H V comprising the amino acid sequence of SEQ ID NO: 315 L and V comprising the amino acid sequence of SEQ ID NO: 255 H V comprising the amino acid sequence of SEQ ID NO: 316 L and V comprising the amino acid sequence of SEQ ID NO: 256 H V comprising the amino acid sequence of SEQ ID NO: 291 L and V comprising the amino acid sequence of SEQ ID NO: 233 H and V comprising the amino acid sequence of SEQ ID NO: 317. L and V comprising the amino acid sequence of SEQ ID NO: 256 H .

[0132] In some embodiments, provided herein are anti-SIRPA antibodies comprising at least one, two, three, four, five, or six HVRs selected from the following: (a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 11, 12, and 14; (b) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 32 and 33; (c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 48, 53, 59, and 96; (d) an HVR-L4 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 103, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 346, 347, 348, and 349. (e) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 125, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, and 345; and (f) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 154, 159, 165, 197, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, and 386.

[0133] In some embodiments, at least one, at least two, or all three V selected from the following: L Provided herein are anti-SIRPA antibodies comprising HVR sequences: (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 11, 12, and 14; (b) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 32 and 33; and (c) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 48, 53, 59, and 96.

[0134] In some embodiments, at least one, at least two, or all three V selected from the following: HProvided herein are anti-SIRPA antibodies comprising HVR sequences: (a) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 103, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 346, 347, 348, and 349; (b) SEQ ID NOs: 125, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, (c) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 154, 159, 165, 197, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, and 386.

[0135] In some embodiments, provided herein are anti-SIRPA antibodies comprising: (a) at least one, at least two, or all three V selected from the following: L V containing HVR sequences L Domains: (i) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 11, 12, and 14, (ii) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 32 and 33, and (iii) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 48, 53, 59, and 96, and (b) at least one, at least two, or all three V selected from the following: H V containing HVR sequences HDomains: (i) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 103, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 346, 347, 348, and 349; (ii) SEQ ID NOs: 125, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, and 345. and (iii) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 154, 159, 165, 197, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, and 386.

[0136] In some embodiments, provided herein are anti-SIRPA antibodies comprising: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 318; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 329; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 350; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32 (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 318; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 330; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 351; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 319; (e) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 331 H2; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 352; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 318; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 353; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33 2; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 320; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 332; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 371; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 320; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 332;and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 154; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 333; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 154; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33 (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 320; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 334; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 154; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 53; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 321; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 372; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 53; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 321; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 335; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 373; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32 (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 53; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 322; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 323; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 336;and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 354; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 323; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 336; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 355; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33 (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 346; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 336; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 356; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 337; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 357; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 337; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 374; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33 (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 347; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 338; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 337;and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 375; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 339; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 376; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33 (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 336; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 377; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 348; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 337; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 378; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 323; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 336; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 379; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33 (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 349; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 340; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 380; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 337;and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 381; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 324; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 341; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 197; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32 (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 325; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 342; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 197; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 325; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 341; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 382; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 325; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 343; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 383; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32 (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 325; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 341; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 197; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 326; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 341;and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 197; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 327; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 341; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 384; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 325; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 341; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 385 (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 325; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 341; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 386; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 325; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 341; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 358; (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 327; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: HVR-H2 comprising the amino acid sequence of SEQ ID NO: 3244; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 359; and (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 328; (e) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 345; and (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 360.

[0137] In another embodiment, the anti-SIRPA antibody comprises a light chain variable domain (V) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 257-317. L In certain embodiments, the V has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 261, 264, 269, 275, 213, and 413. L The sequence contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, but an anti-SIRPA antibody comprising the sequence retains the ability to bind to SIRPA. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 261, 264, 269, 275, 213, or 413. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 261, 264, 269, 275, 213, or 413. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FRs). Optionally, the anti-SIRPA antibody may contain a VVR of SEQ ID NO: 261, 264, 269, 275, 213, or 413, including post-translational modifications of that sequence. L In certain embodiments, V L comprises one, two, or three HVRs selected from: (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 11, 12, and 14; (b) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 32 and 33; and (c) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 48, 53, 59, and 96.

[0138] In another aspect, an anti-SIRPA antibody is provided, wherein the antibody comprises a heavy chain variable domain (V) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, and 412. H In certain embodiments, a V has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, and 412. HThe sequence contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, but an anti-SIRPA antibody comprising the sequence retains the ability to bind to SIRPA. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in SEQ ID NO: 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, or 412. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, or 412. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FRs). Optionally, the anti-SIRPA antibody comprises the V of SEQ ID NO: 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, or 412. H In certain embodiments, V H(a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 103, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 346, 347, 348, and 349; (b) an amino acid sequence selected from the group consisting of SEQ ID NOs: 125, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, and 345; and (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 154, 159, 165, 197, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, and 386.

[0139] In some embodiments, the antibody is a V such as any of the embodiments provided above. L and V such as in any of the embodiments provided above. H In some embodiments, the antibody comprises a V such as any of the embodiments provided above. L and V such as in any of the embodiments provided above. H In one embodiment, the antibody comprises a V of SEQ ID NOs: 261, 264, 269, 275, 213, and 413. L and V of SEQ ID NOs: 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, and 412. H sequences, including post-translational modifications of those sequences.

[0140] In some embodiments, the light chain variable domain (V L ) and heavy chain variable domain (VH ) and V L and V H is selected from the group consisting of: V comprising the amino acid sequence of SEQ ID NO: 261 L and V comprising the amino acid sequence of SEQ ID NO: 361 H V comprising the amino acid sequence of SEQ ID NO: 261 L and V comprising the amino acid sequence of SEQ ID NO: 362 H V comprising the amino acid sequence of SEQ ID NO: 261 L and V comprising the amino acid sequence of SEQ ID NO: 363 H V comprising the amino acid sequence of SEQ ID NO: 261 L and V comprising the amino acid sequence of SEQ ID NO: 364 H V comprising the amino acid sequence of SEQ ID NO: 264 L and V comprising the amino acid sequence of SEQ ID NO: 365 H V comprising the amino acid sequence of SEQ ID NO: 264 L and V comprising the amino acid sequence of SEQ ID NO: 366 H V comprising the amino acid sequence of SEQ ID NO: 264 L and V comprising the amino acid sequence of SEQ ID NO: 367 H V comprising the amino acid sequence of SEQ ID NO: 264 L and V comprising the amino acid sequence of SEQ ID NO: 368 H V comprising the amino acid sequence of SEQ ID NO: 269 L and V comprising the amino acid sequence of SEQ ID NO: 369 H V comprising the amino acid sequence of SEQ ID NO: 269 L and V comprising the amino acid sequence of SEQ ID NO: 370 H V comprising the amino acid sequence of SEQ ID NO: 269 L and V comprising the amino acid sequence of SEQ ID NO: 387 H V comprising the amino acid sequence of SEQ ID NO: 275 L and V comprising the amino acid sequence of SEQ ID NO: 388 H V comprising the amino acid sequence of SEQ ID NO: 275 L and V comprising the amino acid sequence of SEQ ID NO: 389 H V comprising the amino acid sequence of SEQ ID NO: 275 L and V comprising the amino acid sequence of SEQ ID NO: 390 HV comprising the amino acid sequence of SEQ ID NO: 275 L and V comprising the amino acid sequence of SEQ ID NO: 391 H V comprising the amino acid sequence of SEQ ID NO: 275 L and V comprising the amino acid sequence of SEQ ID NO: 392 H V comprising the amino acid sequence of SEQ ID NO: 275 L and V comprising the amino acid sequence of SEQ ID NO: 393 H V comprising the amino acid sequence of SEQ ID NO: 275 L and V comprising the amino acid sequence of SEQ ID NO: 394 H V comprising the amino acid sequence of SEQ ID NO: 275 L and V comprising the amino acid sequence of SEQ ID NO: 395 H V comprising the amino acid sequence of SEQ ID NO: 275 L and V comprising the amino acid sequence of SEQ ID NO: 396 H V comprising the amino acid sequence of SEQ ID NO: 264 L and V comprising the amino acid sequence of SEQ ID NO: 398 H V comprising the amino acid sequence of SEQ ID NO: 275 L and V comprising the amino acid sequence of SEQ ID NO: 399 H V comprising the amino acid sequence of SEQ ID NO: 275 L and V comprising the amino acid sequence of SEQ ID NO: 400 H V comprising the amino acid sequence of SEQ ID NO: 275 L and V comprising the amino acid sequence of SEQ ID NO: 401 H V comprising the amino acid sequence of SEQ ID NO: 413 L and V comprising the amino acid sequence of SEQ ID NO: 402 H V comprising the amino acid sequence of SEQ ID NO: 312 L and V comprising the amino acid sequence of SEQ ID NO: 403 H V comprising the amino acid sequence of SEQ ID NO: 312 L and V comprising the amino acid sequence of SEQ ID NO: 404 H V comprising the amino acid sequence of SEQ ID NO: 312 L and V comprising the amino acid sequence of SEQ ID NO: 405 H V comprising the amino acid sequence of SEQ ID NO: 312 L and V comprising the amino acid sequence of SEQ ID NO: 406 H V comprising the amino acid sequence of SEQ ID NO: 312L and V comprising the amino acid sequence of SEQ ID NO: 407 H V comprising the amino acid sequence of SEQ ID NO: 312 L and V comprising the amino acid sequence of SEQ ID NO: 408 H V comprising the amino acid sequence of SEQ ID NO: 312 L and V comprising the amino acid sequence of SEQ ID NO: 409 H V comprising the amino acid sequence of SEQ ID NO: 312 L and V comprising the amino acid sequence of SEQ ID NO: 410 H V comprising the amino acid sequence of SEQ ID NO: 312 L and V comprising the amino acid sequence of SEQ ID NO: 411 H V comprising the amino acid sequence of SEQ ID NO: 312 L and V comprising the amino acid sequence of SEQ ID NO: 397 H and V comprising the amino acid sequence of SEQ ID NO: 312. L and V comprising the amino acid sequence of SEQ ID NO: 412 H .

[0141] In some embodiments, the anti-SIRPA antibodies of the disclosure are selected from the group consisting of SA-1, SA-2, SA-3, SA-4, SA-5 (including SA-5-57, SA-5-58, SA-5-59, and SA-5-61), SA-6, SA-7, SA-8 (including SA-8-62, SA-8-64, SA-8-66, and SA-8-67), SA-9, SA-10, SA-11, SA-12, SA-13 (including SA-13-6, SA-13- 69, and SA-13-71), SA-14, SA-15, SA-16, SA-17, SA-18, SA-19 ​​(SA-19-72, SA-19-73, SA-19-74, SA-19-75, SA-19-76, S A-19-77, SA-19-78, SA-19-79, SA-19-80, SA-19-81, SA-19-82, SA-19-83, and SA-19-84), SA-20, SA-21, SA-22, SA-23 , SA-24, SA-25, SA-26, SA-27, SA-28, SA-29, SA-30, SA-31, SA-32, SA-33, SA-34, SA-35, SA-36, SA-37, SA-38, SA-39, SA- 40, SA-41, SA-42, SA-43, SA-44, SA-45, SA-46, SA-47, SA-48, SA-49, SA-50, SA-51, SA-52, SA-53, SA-54, SA-55, SA-56(S SA-56-85, SA-56-86, SA-56-87, SA-56-88, SA-56-89, SA-56, 90, SA-56, 91, SA-56-92, SA-56-93, SA-56-94, SA-56-95, and SA-56-96), SA-57, SA-58, SA-59, SA-60, SA-61, and SA-62, and any combination thereof.

[0142] In some embodiments, the anti-SIRPA antibodies of the disclosure are SA-1, SA-2, SA-3, SA-4, SA-5 (including SA-5-57, SA-5-58, SA-5-59, and SA-5-61), SA-6, SA-7, SA-8 (including SA-8-62, SA-8-64, SA-8-66, and SA-8-67), SA-9, SA-10, SA-11, SA-12, SA-13 (including SA-13-6, SA-13-69, and SA-13-71). ), SA-14, SA-15, SA-16, SA-17, SA-18, SA-19 ​​(SA-19-72, SA-19-73, SA-19-74, SA-19-75, SA-19-76, SA-19-77, SA-19-78 , SA-19-79, SA-19-80, SA-19-81, SA-19-82, SA-19-83, and SA-19-84), SA-20, SA-21, SA-22, SA-23, SA-24, SA-25, SA-2 6, SA-27, SA-28, SA-29, SA-30, SA-31, SA-32, SA-33, SA-34, SA-35, SA-36, SA-37, SA-38, SA-39, SA-40, SA-41, SA-42, SA -43, SA-44, SA-45, SA-46, SA-47, SA-48, SA-49, SA-50, SA-51, SA-52, SA-53, SA-54, SA-55, SA-56(SA-56-85, SA-56-86, S and SA-56-94, SA-56-95, and SA-56-96), SA-57, SA-58, SA-59, SA-60, SA-61, and SA-62. Detailed exemplary methods for mapping antibody-binding epitopes are provided in Morris (1996) "Epitope Mapping Protocols," in Methods in Molecular Biology, vol. 66 (Humana Press, Totowa, NJ).

[0143] In some embodiments, the anti-SIRPA antibody according to any of the above embodiments is a monoclonal antibody, including a humanized antibody and / or a human antibody. In some embodiments, the anti-SIRPA antibody is an antibody fragment, e.g., an Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In some embodiments, the anti-SIRPA antibody is a substantially full-length antibody, e.g., an IgG1 antibody, an IgG2a antibody, or other antibody class or isotype as defined herein.

[0144] In some embodiments, an anti-SIRPA antibody according to any of the above embodiments may incorporate any of the features, alone or in combination, as described in Sections 1-7 below.

[0145] C. Anti-SIRPA antibody binding affinity In some embodiments of any of the anti-SIRPA antibodies provided herein, the antibody has a cytotoxicity of less than 1 μM, less than 100 nM, less than 10 nM, less than 1 nM, less than 0.1 nM, less than 0.01 nM, or less than 0.001 nM (e.g., less than 10 -8 M or less, e.g., 10 -8 M~10 -13 M, e.g., 10 -9 M~10 -13 Dissociation constant (K D ). The dissociation constant can be determined by any analytical technique, for example, any biochemical or biophysical technique, such as ELISA, surface plasmon resonance (SPR), biolayer interferometry (see, e.g., the Octet System by ForteBio), isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC), circular dichroism (CD), stopped-flow analysis, and colorimetric or fluorescent protein melting analysis. In one embodiment, Kd is measured by a radiolabeled antigen binding assay (RIA). In some embodiments, an RIA is performed on a Fab version of the antibody of interest and its antigen, for example, as described in Chen et al. J. Mol. Biol. 293:865-881 (1999). In some embodiments, the K Dis measured using a BIACORE® surface plasmon resonance assay, e.g., using a BIACORE®-2000 or BIACORE®-3000 (BIAcore, Inc., Piscataway, NJ), performed at 25°C with an immobilized antigen CM5 chip of approximately 10 response units (RU). In some embodiments, K D is determined using a monovalent antibody (e.g., Fab) or a full-length antibody. In some embodiments, K D is determined using the monovalent form of the full-length antibody.

[0146] In some embodiments, the anti-SIRPA antibodies of the present disclosure bind to human SIRPAv1 (SEQ ID NO: 1) and have a K D In some embodiments, the anti-SIRPA antibodies of the present disclosure bind to human SIRPAv1 and have a K of about 0.3 nM to about 2 nM. D In some embodiments, the anti-SIRPA antibodies herein bind to human SIRPAv1 and have a K of about 2.8 nM to about 24 nM. D is 1 nM to 50 nM, 0.3 nM to 2 nM, or 2 nM to 24 nM. In some embodiments, the anti-SIRPA antibody herein binds to human SIRPA with higher affinity than to mouse SIRPA. In some embodiments, an anti-SIRPA antibody that specifically binds to human SIRPA does not specifically bind to SIRPB and / or does not specifically bind to mouse SIRPA. In some embodiments, the antibody herein recognizes one or more of D40, R54, and W68 in D1 of human SIRPA. In some embodiments, when one or more of these amino acid residues are mutated to alanine, the affinity of the antibody for human SIRPA is significantly reduced.

[0147] D. Antibody Fragments In some embodiments of any of the antibodies provided herein, the antibody is an antibody fragment. Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab')2, Fv, and scFv fragments, as well as other fragments described below. For a review of specific antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, e.g., WO 93 / 16185, and U.S. Pat. Nos. 5,571,894 and 5,587,458. For a discussion of Fab and F(ab')2 fragments that contain salvage receptor-binding epitope residues and have increased in vivo half-lives, see U.S. Pat. No. 5,869,046.

[0148] Diabodies are antibody fragments with two antigen-binding sites that can be bivalent or bispecific. See, for example, EP 404097; WO 1993 / 01161; Hudson et al. Nat. Med. 9:129-134 (2003). Triabodies and tetrabodies are also described in Hudson et al. Nat. Med. 9:129-134 (2003). Single-domain antibodies are antibody fragments that contain all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In certain embodiments, single-domain antibodies are human single-domain antibodies (see, for example, U.S. Pat. No. 6,248,516).

[0149] Antibody fragments can be produced in a variety of ways, including, but not limited to, proteolytic digestion of intact antibodies and production by recombinant host cells (e.g., E. coli or phage), as described herein.

[0150] E. Chimeric and Humanized Antibodies In some embodiments of any of the antibodies provided herein, the antibody is a chimeric antibody. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567. In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region. In a further example, a chimeric antibody is a "class-switched" antibody in which the class or subclass has been changed from that of the parent antibody. The chimeric antibody includes an antigen-binding fragment thereof.

[0151] In some embodiments of any of the antibodies provided herein, the antibody is a humanized antibody. Typically, non-human antibodies are humanized to reduce immunogenicity in humans while retaining the specificity and affinity of the parent non-human antibody. In certain embodiments, humanized antibodies are substantially non-immunogenic in humans. In certain embodiments, humanized antibodies have substantially the same affinity for a target as an antibody from another species from which the humanized antibody is derived. See, e.g., U.S. Patent Nos. 5,530,101, 5,693,761, 5,693,762, and 5,585,089. In certain embodiments, amino acids in antibody variable domains are identified that can be modified to reduce immunogenicity without reducing the native affinity of the antigen-binding domain. See, e.g., U.S. Patent Nos. 5,766,886 and 5,869,619. Generally, humanized antibodies comprise one or more variable domains in which HVRs (or portions thereof) are derived from a non-human antibody and FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody will optionally also comprise at least a portion of a human constant region. In some embodiments, some FR residues of a humanized antibody are substituted by corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues were derived), e.g., to restore or improve antibody specificity or affinity.

[0152] Humanized antibodies and methods for their production are reviewed, for example, in Almagro et al. Front. Biosci. 13:161 9-1633 (2008) and further described, for example, in U.S. Pat. Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409. 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 a particular subgroup 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 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)).

[0153] F. Human Antibodies In some embodiments of any of the antibodies provided herein, the antibody is a human antibody. Human antibodies can be produced using various techniques known in the art. Human antibodies are generally described in: van Dijk et al. Curr. Opin. Pharmacol. 5:368-74 (2001) and Lonberg Curr. Opin. Immunol. 20:450-459 (2008).

[0154] Human antibodies can be prepared by administering immunogens to transgenic animals that have been engineered to produce intact human antibodies or intact antibodies with human variable regions in response to antigen challenge. Mouse strains deficient in mouse antibody production with large fragments of the human Ig loci can be engineered, anticipating that the mice will produce human antibodies in the absence of mouse antibodies. Large human Ig fragments can preserve the diversity of large variable genes and the proper regulation of antibody production and expression. By taking advantage of the mouse mechanisms for antibody diversification and selection and the lack of immune tolerance to human proteins, the human antibody repertoire recapitulated in these mouse strains can yield high-affinity, fully human antibodies against any antigen of interest, including human antigens. Hybridoma technology can be used to produce and select antigen-specific human MAbs with desired specificity. Certain exemplary methods are described in U.S. Pat. No. 5,545,807, EP 546073, and EP 546073. See, for example, U.S. Pat. Nos. 6,075,181 and 6,150,584 (describing XENOMOUSE™ technology); U.S. Pat. No. 5,770,429 (describing HUMAB® technology); U.S. Pat. No. 7,041,870 (describing KM MOUSE® technology), and U.S. Patent Application Publication No. US2007 / 0061900 (describing VELOCIMOUSE® technology). The human variable regions from intact antibodies produced by such animals can be further modified, for example, by combining with a different human constant region.

[0155] Human antibodies can also be produced using hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for producing human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol. 133:3001 (1984) 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). Additional methods include those described, for example, in U.S. Pat. No. 7,189,826, which describes the production of monoclonal human IgM antibodies from hybridoma cell lines. Human hybridoma technology (Trioma technology) is also described in Vollmers et al., Histology and Histopathology 20(3):927-937 (2005) and Vollmers et al., Methods and Findings in Experimental and Clinical Pharmacology 27(3):185-91 (2005). Human antibodies can also be generated by isolating Fv clone variable domain sequences selected from a human-derived phage display library. Such variable domain sequences can then be combined with desired human constant domains. Techniques for selecting human antibodies from antibody libraries are described below.

[0156] In some embodiments of any of the antibodies provided herein, the antibody is a human antibody isolated by in vitro methods and / or screening of combinatorial libraries for antibodies with the desired activity(ies). Suitable examples include, but are not limited to, phage display (CAT, Morphosys, Dyax, Biosite / Medarex, Xoma, Symphogen, Alexion (formerly Proliferon), Affimed), ribosome display (CAT), yeast display (Adimab), and the like. In certain phage display methods, repertoires of VH and VL genes are individually cloned by polymerase chain reaction (PCR) and randomly recombined into phage libraries, which can then be screened for antigen-binding phage, as described in Winter et al. Ann. Rev. Immunol. 12:433-455 (1994). For example, various methods are known in the art for generating phage display libraries and screening such libraries for antibodies with the desired binding characteristics. See also: Sidhu et al. J. Mol. Biol. 338(2):299-310, 2004; Lee et 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(-2):119-132 (2004). Phages typically display antibody fragments as either single-chain Fv (scFv) fragments or Fab fragments. Libraries from immunized sources provide high-affinity antibodies against the immunogen without the need to construct hybridomas. Alternatively, as described by Griffiths et al. EMBO J. 12:725-734 (1993), naive repertoires can be cloned (e.g., from humans) to provide a single source of antibodies against a wide range of non-self and even self antigens without immunization.Finally, naive libraries can also be synthetically generated by cloning unrearranged V gene segments from stem cells, encoding the highly variable HVR3 region, and using PCR primers containing random sequences to achieve in vitro rearrangement, as described by Hoogenboom et al. 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 Publication Nos. 2007 / 0292936 and 2009 / 0002360. Antibodies isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.

[0157] G. Constant region containing the Fc region In some embodiments of any of the antibodies provided herein, the antibody comprises an Fc. In some embodiments, the Fc is a human IgG1, IgG2, IgG3, and / or IgG4 isotype. In some embodiments, the antibody is of the IgG class, IgM class, or IgA class.

[0158] In certain embodiments of any of the antibodies provided herein, the antibody has an IgG2 isotype. In some embodiments, the antibody contains a human IgG2 constant region. In some embodiments, the human IgG2 constant region comprises an Fc region. In some embodiments, the antibody induces one or more SIRPA activities, or does so independently of binding to an Fc receptor. In some embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments, the inhibitory Fc receptor is inhibitory Fc gamma receptor IIB (FcγIIB).

[0159] In certain embodiments of any of the antibodies provided herein, the antibody has an IgG1 isotype. In some embodiments, the antibody contains a mouse IgG1 constant region. In some embodiments, the antibody contains a human IgG1 constant region. In some embodiments, the human IgG1 constant region comprises an Fc region. In some embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments, the inhibitory Fc receptor is inhibitory Fc gamma receptor IIB (FcγIIB).

[0160] In certain embodiments of any of the antibodies provided herein, the antibody has an IgG4 isotype. In some embodiments, the antibody contains a human IgG4 constant region. In some embodiments, the human IgG4 constant region comprises an Fc region. In some embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments, the inhibitory Fc receptor is inhibitory Fc gamma receptor IIB (FcγIIB).

[0161] In certain embodiments of any of the antibodies provided herein, the antibody has a hybrid IgG2 / 4 isotype. In some embodiments, the antibody comprises an amino acid sequence comprising amino acids 118 to 260 (according to EU numbering) of human IgG2 and amino acids 261 to 447 (according to EU numbering) of human IgG4 (WO1997 / 11971; WO2007 / 106585).

[0162] In some embodiments, the Fc region increases clustering without activating complement compared to a corresponding antibody comprising an Fc region that does not contain the amino acid substitution. In some embodiments, the antibody induces one or more activities of a target to which the antibody specifically binds. In some embodiments, the antibody binds to SIRPA.

[0163] It may also be desirable to modify the anti-SIRPA antibodies of the present disclosure to modify effector function and / or increase the serum half-life of the antibody. For example, Fc receptor binding sites on the constant region may be modified or mutated to eliminate or reduce binding affinity for specific Fc receptors, e.g., FcγRI, FcγRII, and / or FcγRIII, to reduce antibody-dependent cell-mediated cytotoxicity. In some embodiments, effector function is impaired by removing N-glycosylation in the Fc region of the antibody (e.g., within the CH2 domain of IgG). In some embodiments, effector function is impaired by modifying regions such as 233-236, 297, and / or 327-331 of human IgG, as described in WO 99 / 58572 and Armour et al. Molecular Immunology 40:585-593 (2003); Reddy et al. J. Immunology 164:1925-1933 (2000). In other embodiments, it may also be desirable to modify the anti-MerTK antibodies of the present disclosure to modify effector function to increase selectivity for the ITIM-containing FcgRIIb (CD32b) antibody and increase clustering of SIRPA antibodies on neighboring cells without activating humoral responses, including antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis.

[0164] To extend the serum half-life of an antibody, a salvage receptor binding epitope can be incorporated into the antibody (particularly an antibody fragment), as described, for example, in U.S. Patent No. 5,739,277. As used herein, the term "salvage receptor binding epitope" refers to an epitope in the Fc region of an IgG molecule (e.g., IgG1, IgG2, IgG3, or IgG4) that is responsible for increasing the in vivo serum half-life of the IgG molecule. Other amino acid sequence modifications.

[0165] H. Antibody Variants In some embodiments of any of the antibodies provided herein, amino acid sequence variants of the antibody are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody.

[0166] 1. Substitution, insertion, and deletion variants In some embodiments of any of the antibodies provided herein, antibody variants having one or more amino acid substitutions are provided. Amino acid sequence variants of antibodies can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletion of, and / or insertion and / or substitution of, residues within the amino acid sequence of the antibody. [Table 2]

[0167] Substantial modification of antibody biological properties can be achieved by selecting substitutions that significantly differ in their effectiveness in maintaining (a) the conformation of the polypeptide backbone (e.g., sheet or helix) in the region of substitution, (b) the charge or hydrophobicity of the target site molecule, or (c) the bulk of the side chain. Naturally occurring residues are classified into groups based on the following common 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.

[0168] For example, non-conservative substitutions may involve replacing a member of one of these classes with a member of another class. Such substituted residues can be introduced, for example, into regions of the human antibody that are homologous with the non-human antibody, or into the non-homologous regions of the molecule.

[0169] When making modifications to the polypeptides or antibodies described herein, according to certain embodiments, the hydropathic index of amino acids can be considered. Each amino acid is assigned a hydropathic index based on its hydrophobicity and charge characteristics. These include: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine / cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamic acid (-3.5); glutamine (-3.5); aspartic acid (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5).

[0170] ...

Claims

**Claim 1** An isolated antibody that specifically binds to human SIRPA, wherein said antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises a. HVR-H1 comprising an amino acid sequence selected from any one of SEQ ID NOs: 102-122, 318-328, and 346-349, b. HVR-H2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 123-146 and 329-345, and c. HVR-H3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 147-201, 350-360, and 371-386; and / or wherein the light chain variable region (VL) comprises a. HVR-L1 comprising an amino acid sequence selected from any one of SEQ ID NOs: 7-28, b. HVR-L2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 29-40, and c. HVR-L3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 41-101, an antibody. **Claim 2** The antibody according to claim 1, wherein said antibody comprises a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to an amino acid sequence selected from any one of SEQ ID NOs: 202-256, 361-370, and 387-412. **Claim 3** The antibody according to claim 1, wherein said antibody comprises a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to an amino acid sequence selected from any one of SEQ ID NOs: 257-317 and 413. **Claim 4** The antibody according to claim 1, wherein said antibody comprises a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to an amino acid sequence selected from any one of SEQ ID NOs: 202-256, 361-370, and 387-412, and a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to an amino acid sequence selected from any one of SEQ ID NOs: 257-317 and 413. **Claim 5** The antibody according to any one of claims 1-4, wherein the VH comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, insertions, and / or deletions as compared to an amino acid sequence selected from any one of SEQ ID NOs: 202-256, 361-370, and 387-412. **Claim 6** The antibody according to any one of claims 1 to 4, wherein the VL contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, insertions, and / or deletions as compared with the amino acid sequence selected from any one of SEQ ID NOs: 257 to 317 and 413.

7. The antibody according to any one of claims 1 to 4, wherein the antibody contains a VH including an amino acid sequence selected from any one of SEQ ID NOs: 202 to 256, 361 to 370, and 387 to 412.

8. The antibody according to any one of claims 1 to 4, wherein the antibody contains a VL including an amino acid sequence selected from any one of SEQ ID NOs: 257 to 317 and 413.

9. An isolated antibody that specifically binds to human SIRPA, wherein the antibody a. a VH including an HVR-H1 including the amino acid sequence of SEQ ID NO: 102, an HVR-H2 including the amino acid sequence of SEQ ID NO: 123, and an HVR-H3 including the amino acid sequence of SEQ ID NO: 147; and a VL including an HVR-L1 including the amino acid sequence of SEQ ID NO: 7, an HVR-L2 including the amino acid sequence of SEQ ID NO: 29, and an HVR-L3 including the amino acid sequence of SEQ ID NO: 41, b. a VH including an HVR-H1 including the amino acid sequence of SEQ ID NO: 103, an HVR-H2 including the amino acid sequence of SEQ ID NO: 124, and an HVR-H3 including the amino acid sequence of SEQ ID NO: 148; and a VL including an HVR-L1 including the amino acid sequence of SEQ ID NO: 8, an HVR-L2 including the amino acid sequence of SEQ ID NO: 30, and an HVR-L3 including the amino acid sequence of SEQ ID NO: 42, c. a VH including an HVR-H1 including the amino acid sequence of SEQ ID NO: 104, an HVR-H2 including the amino acid sequence of SEQ ID NO: 125, and an HVR-H3 including the amino acid sequence of SEQ ID NO: 149; and a VL including an HVR-L1 including the amino acid sequence of SEQ ID NO: 7, an HVR-L2 including the amino acid sequence of SEQ ID NO: 31, and an HVR-L3 including the amino acid sequence of SEQ ID NO: 43, d. a VH including an HVR-H1 including the amino acid sequence of SEQ ID NO: 105, an HVR-H2 including the amino acid sequence of SEQ ID NO: 125, and an HVR-H3 including the amino acid sequence of SEQ ID NO: 150; and a VL including an HVR-L1 including the amino acid sequence of SEQ ID NO: 7, an HVR-L2 including the amino acid sequence of SEQ ID NO: 31, and an HVR-L3 including the amino acid sequence of SEQ ID NO:

44. e. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 106, HVR-H2 containing the amino acid sequence of SEQ ID NO: 125, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 151; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 9, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 45, f. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 107, HVR-H2 containing the amino acid sequence of SEQ ID NO: 126, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 152; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 7, HVR-L2 containing the amino acid sequence of SEQ ID NO: 29, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 46, g. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 103, HVR-H2 containing the amino acid sequence of SEQ ID NO: 127, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 153; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 10, HVR-L2 containing the amino acid sequence of SEQ ID NO: 30, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 47, h. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 103, HVR-H2 containing the amino acid sequence of SEQ ID NO: 124, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 154; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, i. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 106, HVR-H2 containing the amino acid sequence of SEQ ID NO: 128, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 155; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 12, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 49, j. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 107, HVR-H2 containing the amino acid sequence of SEQ ID NO: 126, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 156; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 13, HVR-L2 containing the amino acid sequence of SEQ ID NO: 34, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 50, k. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 102, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 123, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 157; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 51, l. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 108, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 129, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 158; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 52, m. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 106, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 125, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 53, n. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 130, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 160; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, o. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 110, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 131, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 161; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 55, p. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 111, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 132, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 162; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 56, q. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 110, HVR-H2 containing the amino acid sequence of SEQ ID NO: 133, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 163; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 16, HVR-L2 containing the amino acid sequence of SEQ ID NO: 36, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 57, r. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 112, HVR-H2 containing the amino acid sequence of SEQ ID NO: 134, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 164; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 12, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 58, s. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 103, HVR-H2 containing the amino acid sequence of SEQ ID NO: 124, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 165; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 59, t. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 103, HVR-H2 containing the amino acid sequence of SEQ ID NO: 124, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 154; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, u. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 113, HVR-H2 containing the amino acid sequence of SEQ ID NO: 135, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 166; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 8, HVR-L2 containing the amino acid sequence of SEQ ID NO: 30, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 61, v. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 109, HVR-H2 containing the amino acid sequence of SEQ ID NO: 130, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 167; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 62, w. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 136, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 168; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 37, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 63, x. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 169; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 64, y. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 110, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 138, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 170; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 65, z. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 111, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 132, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 18, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, aa. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 139, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 172; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 67, bb. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 173; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 68, cc. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 173; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 69, dd. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 174; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 70, ee. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 110, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 138, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 170; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 71, ff. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 175; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, gg. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 110, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 133, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 176; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 73, hh. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 118, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74, ii. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 119, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 129, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 178; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 75, jj. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 113, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 135, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 179; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 22, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 76, kk. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 139, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 180; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 23, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 77, ll. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 139, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 180; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, mm. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 129, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 181; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 79, nn. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 119, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 142, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 182; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 80, oo. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 143, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 81 pp. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 143, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 25, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 82 qq. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 139, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 184; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 83 rr. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 144, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 185; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84 ss. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 186; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 85 tt. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 104, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 125, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 187; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 38, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 86 uu. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 119, HVR-H2 containing the amino acid sequence of SEQ ID NO: 129, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 188; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 12, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 87, vv. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 103, HVR-H2 containing the amino acid sequence of SEQ ID NO: 124, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 189; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 10, HVR-L2 containing the amino acid sequence of SEQ ID NO: 30, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 88, ww. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 109, HVR-H2 containing the amino acid sequence of SEQ ID NO: 130, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 190; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 12, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 89, xx. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 109, HVR-H2 containing the amino acid sequence of SEQ ID NO: 144, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 191; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 10, HVR-L2 containing the amino acid sequence of SEQ ID NO: 30, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, yy. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 110, HVR-H2 containing the amino acid sequence of SEQ ID NO: 138, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 192; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 20, HVR-L2 containing the amino acid sequence of SEQ ID NO: 38, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 91, zz. A VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 118, HVR-H2 containing the amino acid sequence of SEQ ID NO: 141, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 193; and a VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 20, HVR-L2 containing the amino acid sequence of SEQ ID NO: 40, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 92, aaa. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 116, HVR-H2 containing the amino acid sequence of SEQ ID NO: 145, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 194; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 93, bbb. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 115, HVR-H2 containing the amino acid sequence of SEQ ID NO: 139, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 195; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 12, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 94, ccc. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 112, HVR-H2 containing the amino acid sequence of SEQ ID NO: 146, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 196; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 27, HVR-L2 containing the amino acid sequence of SEQ ID NO: 35, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 95, ddd. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 109, HVR-H2 containing the amino acid sequence of SEQ ID NO: 130, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 197; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 12, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, eee. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 122, HVR-H2 containing the amino acid sequence of SEQ ID NO: 139, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 198; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 7, HVR-L2 containing the amino acid sequence of SEQ ID NO: 31, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 97, fff. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 122, HVR-H2 containing the amino acid sequence of SEQ ID NO: 139, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 199; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 98, ggg. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 121, HVR-H2 containing the amino acid sequence of SEQ ID NO: 143, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 200; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 99, hhh. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 109, HVR-H2 containing the amino acid sequence of SEQ ID NO: 144, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 201; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 7, HVR-L2 containing the amino acid sequence of SEQ ID NO: 29, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 100, iii. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 119, HVR-H2 containing the amino acid sequence of SEQ ID NO: 129, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 178; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 13, HVR-L2 containing the amino acid sequence of SEQ ID NO: 39, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 75, jjj. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 109, HVR-H2 containing the amino acid sequence of SEQ ID NO: 144, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 201; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 28, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 101, kkk. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 318, HVR-H2 containing the amino acid sequence of SEQ ID NO: 329, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 350; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 9, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 45, lll. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 318, HVR-H2 containing the amino acid sequence of SEQ ID NO: 330, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 351; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 9, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 45, mmm. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 319, HVR-H2 containing the amino acid sequence of SEQ ID NO: 331, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 352; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 9, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 45, nnn. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 318, HVR-H2 containing the amino acid sequence of SEQ ID NO: 125, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 353; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 9, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 45, ooo. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 320, HVR-H2 containing the amino acid sequence of SEQ ID NO: 332, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 371; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, ppp. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 320, HVR-H2 containing the amino acid sequence of SEQ ID NO: 332, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 154; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, qqq. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 103, HVR-H2 containing the amino acid sequence of SEQ ID NO: 333, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 154; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 45, rrr. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 320, HVR-H2 containing the amino acid sequence of SEQ ID NO: 334, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 154; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, sss. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 321, HVR-H2 containing the amino acid sequence of SEQ ID NO: 125, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 372; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 14, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 53, ttt. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 321, HVR-H2 containing the amino acid sequence of SEQ ID NO: 335, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 373; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 14, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 53, uuu. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 322, HVR-H2 containing the amino acid sequence of SEQ ID NO: 125, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 159; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 14, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 53, vvv. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 323, HVR-H2 containing the amino acid sequence of SEQ ID NO: 336, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 354; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 59, www. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 323, HVR-H2 containing the amino acid sequence of SEQ ID NO: 336, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 355; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 59, xxx. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 346, HVR-H2 containing the amino acid sequence of SEQ ID NO: 336, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 356; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 59, yyy. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 103, HVR-H2 containing the amino acid sequence of SEQ ID NO: 337, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 357; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 59, zzz. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 103, HVR-H2 containing the amino acid sequence of SEQ ID NO: 337, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 374; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 59, aaaa. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 347, HVR-H2 containing the amino acid sequence of SEQ ID NO: 338, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 165; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 59, bbbb. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 103, HVR-H2 containing the amino acid sequence of SEQ ID NO: 337, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 375; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 59, cccc. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 103, HVR-H2 containing the amino acid sequence of SEQ ID NO: 339, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 376; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 59, dddd. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 103, HVR-H2 containing the amino acid sequence of SEQ ID NO: 336, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 377; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 59, eeee. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 348, HVR-H2 containing the amino acid sequence of SEQ ID NO: 337, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 378; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 59, ffff. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 323, HVR-H2 containing the amino acid sequence of SEQ ID NO: 336, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 379; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 59, gggg. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 349, HVR-H2 containing the amino acid sequence of SEQ ID NO: 340, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 380; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 59, hhhh. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 103, HVR-H2 containing the amino acid sequence of SEQ ID NO: 337, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 381; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 11, HVR-L2 containing the amino acid sequence of SEQ ID NO: 33, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 59, iiii. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 324, HVR-H2 containing the amino acid sequence of SEQ ID NO: 341, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 197; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 12, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, jjjj. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 325, HVR-H2 containing the amino acid sequence of SEQ ID NO: 342, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 197; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 12, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, kkkk. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 325, HVR-H2 containing the amino acid sequence of SEQ ID NO: 341, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 382; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 12, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, llll. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 325, HVR-H2 containing the amino acid sequence of SEQ ID NO: 343, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 383; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 12, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, mmmm. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 325, HVR-H2 containing the amino acid sequence of SEQ ID NO: 341, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 197; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 12, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, nnnn. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 326, HVR-H2 containing the amino acid sequence of SEQ ID NO: 341, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 197; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 12, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, oooo. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 327, HVR-H2 containing the amino acid sequence of SEQ ID NO: 341, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 384; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 12, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, pppp. VH comprising HVR-H1 containing the amino acid sequence of SEQ ID NO: 325, HVR-H2 containing the amino acid sequence of SEQ ID NO: 341, and HVR-H3 containing the amino acid sequence of SEQ ID NO: 385; and VL comprising HVR-L1 containing the amino acid sequence of SEQ ID NO: 12, HVR-L2 containing the amino acid sequence of SEQ ID NO: 32, and HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, qqqq. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 325, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 341, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 386; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, rrrr. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 325, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 341, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 358; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, ssss. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 327, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 344, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 359; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, or tttt. VH comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 328, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 345, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 360; and VL comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96 An antibody comprising

10. wherein the antibody is a. comprising the HVR of claim 9.a and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 202, b. comprising the HVR of claim 9.b and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 203, c. comprising the HVR of claim 9.c and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 204, d. comprising the HVR of claim 9.d, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 205 e. comprising the HVR of claim 9.e, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 206 f. comprising the HVR of claim 9.f, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 207 g. comprising the HVR of claim 9.g, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 208 h. comprising the HVR of claim 9.h, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 209 i. comprising the HVR of claim 9.i, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 210 j. comprising the HVR of claim 9.j, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 211 k. comprising the HVR of claim 9.k, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 212 l. comprising the HVR of claim 9.l, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 213 m. comprising the HVR of claim 9.m, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 214 n. comprising the HVR of claim 9.n, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 215 o. comprising the HVR of claim 9.o, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 216 p. comprising the HVR of claim 9.p, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 217 q. comprising the HVR of claim 9.q, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 218 r. comprising the HVR of claim 9.r, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 219 s. comprising the HVR of claim 9.s, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 220 t. comprising the HVR of claim 9.t, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 209 u. comprising the HVR of claim 9.u, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 221 v. comprising the HVR of claim 9.v, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 222 w. comprising the HVR of claim 9.w, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 223 x. comprising the HVR of claim 9.x, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 224 y. comprising the HVR of claim 9.y, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 225 z. comprising the HVR of claim 9.z, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 226 aa. comprising the HVR of claim 9.aa, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 227 bb. comprising the HVR of claim 9.bb, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 228 cc. comprising the HVR of claim 9.cc, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 228 dd. comprising the HVR of claim 9.dd, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 229 ee. comprising the HVR of claim 9.ee, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 225 ff. comprising the HVR of claim 9.ff, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 230 gg. comprising the HVR of claim 9.gg, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 231 hh. comprising the HVR of claim 9.hh, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 232 ii. comprising the HVR of claim 9.ii, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 233 jj. comprising the HVR of claim 9.jj, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 234 kk. Claim 9. It includes the HVR of kk, and further includes a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

235. ll. Claim 9. It includes the HVR of ll, and further includes a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

235. mm. Claim 9. It includes the HVR of mm, and further includes a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

236. nn. Claim 9. It includes the HVR of nn, and further includes a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

237. oo . Claim 9. It includes the HVR of oo, and further includes a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

238. pp . Claim 9. It includes the HVR of pp, and further includes a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

238. qq. Claim 9. It includes the HVR of qq, and further includes a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

239. rr. Claim 9. It includes the HVR of rr, and further includes a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

240. ss. Claim 9. It includes the HVR of ss, and further includes a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

241. tt. Claim 9. It includes the HVR of tt, and further includes a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

242. uu. Claim 9. It includes the HVR of uu, and further includes a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

243. vv. Comprising the HVR of claim 9.vv, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 244 ww. Comprising the HVR of claim 9.ww, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 245 xx. Comprising the HVR of claim 9.xx, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 246 yy. Comprising the HVR of claim 9.yy, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 247 zz. Comprising the HVR of claim 9.zz, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 248 aaa. Comprising the HVR of claim 9.aaa, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 249 bbb. Comprising the HVR of claim 9.bbb, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 250 ccc. Comprising the HVR of claim 9.ccc, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 251 ddd. Comprising the HVR of claim 9.ddd, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 252 eee. Comprising the HVR of claim 9.eee, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 253 fff. Comprising the HVR of claim 9.fff, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 254 ggg. Comprising the HVR of claim 9.ggg, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 255, hhh. Comprising the HVR of claim 9.hhh, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 256, iii. Comprising the HVR of claim 9.iii, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 233, jjj. Comprising the HVR of claim 9.jjj, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 256, kkk. Comprising the HVR of claim 9.kkk, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 361, lll. Comprising the HVR of claim 9.lll, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 362, mmm. Comprising the HVR of claim 9.mmm, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 363, nnn. Comprising the HVR of claim 9.nnn, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 364, ooo. Comprising the HVR of claim 9.ooo, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 365, ppp. Comprising the HVR of claim 9.ppp, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 366, qqq. Comprising the HVR of claim 9.qqq, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 367, rrr. Claim 9. comprising the HVR of rrr, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 368, sss. Claim 9. comprising the HVR of sss, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 369, ttt. Claim 9. comprising the HVR of ttt, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 370, uuu. Claim 9. comprising the HVR of uuu, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 387, vvv. Claim 9. comprising the HVR of vvv, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 388, www. Claim 9. comprising the HVR of www, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 389, xxx. Claim 9. comprising the HVR of xxx, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 390, yyy. Claim 9. comprising the HVR of yyy, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 391, zzz. Claim 9. comprising the HVR of zzz, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 392, aaaa. Claim 9. comprising the HVR of aaaa, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 393, bbbb. Claim 9. comprising the HVR of bbbb, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 394, cccc. Claim 9, comprising the HVR of cccc, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

395. dddd. Claim 9, comprising the HVR of dddd, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

396. eeee. Claim 9, comprising the HVR of eeee, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

398. ffff. Claim 9, comprising the HVR of ffff, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

399. ggg g. Claim 9, comprising the HVR of gggg, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

400. hhhh. Claim 9, comprising the HVR of hhhh, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

401. iiii . Claim 9, comprising the HVR of iiiii, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

402. jjjj. Claim 9, comprising the HVR of jjjj, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

403. kkkk. Claim 9, comprising the HVR of kkkk, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

404. llll. Claim 9, comprising the HVR of llll, and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

405. mmmm. Claim 9. comprising the HVR of mmmm, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 406, nnnn. Claim 9. comprising the HVR of nnnn, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 407, oooo. Claim 9. comprising the HVR of oooo, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 408, pppp. Claim 9. comprising the HVR of pppp, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 409, qqqq. Claim 9. comprising the HVR of qqqq, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 410, rrrr. Claim 9. comprising the HVR of rrrr, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 411, ssss. Claim 9. comprising the HVR of ssss, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 397, or tttt. Claim 9. comprising the HVR of tttt, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 412, The antibody according to claim 9.

11. wherein the antibody is a. Claim 9. comprising the HVR of a, further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 257, b. Claim 9. comprising the HVR of b, further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 258, c. Comprising the HVR of claim 9.c, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 259 d. Comprising the HVR of claim 9.d, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 260 e. Comprising the HVR of claim 9.e, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 261 f. Comprising the HVR of claim 9.f, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 262 g. Comprising the HVR of claim 9.g, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 263 h. Comprising the HVR of claim 9.h, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 264 i. Comprising the HVR of claim 9.i, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 265 j. Comprising the HVR of claim 9.j, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 266 k. Comprising the HVR of claim 9.k, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 267 l. Comprising the HVR of claim 9.l, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 268 m. Comprising the HVR of claim 9.m, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 269 n. Comprising the HVR of claim 9.n, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 270 o. Comprising the HVR of claim 9.o, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 271 p. Comprising the HVR of claim 9.p, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 272 q. Comprising the HVR of claim 9.q, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 273 r. Comprising the HVR of claim 9.r, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 274 s. Comprising the HVR of claim 9.s, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275 t. Comprising the HVR of claim 9.t, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 276 u. Comprising the HVR of claim 9.u, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 277 v. Comprising the HVR of claim 9.v, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 278 w. Comprising the HVR of claim 9.w, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 279 x. Comprising the HVR of claim 9.x, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 280 y. Comprising the HVR of claim 9.y, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 281 z. Comprising the HVR of claim 9.z, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 282 aa. Comprising the HVR of claim 9.ss, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 283 bb. Comprising the HVR of claim 9.bb, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 284 cc. Comprising the HVR of claim 9.cc, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 285 dd. Comprising the HVR of claim 9.dd, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 286 ee. Comprising the HVR of claim 9.ee, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 287 ff. Comprising the HVR of claim 9.ff, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 288 gg. Comprising the HVR of claim 9.gg, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 289 hh. Comprising the HVR of claim 9.hh, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 290 ii. Comprising the HVR of claim 9.ii, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 291 jj. Comprising the HVR of claim 9.jj, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 292 kk. Comprising the HVR of claim 9.kk, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 293 ll. Comprising the HVR of claim 9.ll, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 294 mm. Comprising the HVR of claim 9.mm, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 295 nn. Comprising the HVR of claim 9.nn, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 296 oo . Comprising the HVR of claim 9.oo, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 297 pp. Comprising the HVR of claim 9.pp, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 298 qq. Comprising the HVR of claim 9.qq, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 299 rr. Comprising the HVR of claim 9.rr, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 300 ss. Comprising the HVR of claim 9.ss, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 301 tt. Comprising the HVR of claim 9.tt, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 302 uu. Comprising the HVR of claim 9.uu, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 303 vv. Comprising the HVR of claim 9.vv, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 304 ww. Comprising the HVR of claim 9.ww, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 305 xx. Comprising the HVR of claim 9.xx, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 306 yy. Comprising the HVR of claim 9.yy, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 307 zz. Comprising the HVR of claim 9.zz, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 308 aaa. Comprising the HVR of claim 9.aaa, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 309 bbb. Comprising the HVR of claim 9.bbb, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 310 ccc. Comprising the HVR of claim 9.ccc, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 311 ddd. Comprising the HVR of claim 9.ddd, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312 eee. Comprising the HVR of claim 9.eee, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 313 fff. Claim 9. including the HVR of fff, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 314, ggg. Claim 9. including the HVR of ggg, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 315, hhh. Claim 9. including the HVR of hhh, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 316, iii. Claim 9. including the HVR of iii, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 291, jjj. Claim 9. including the HVR of jjj, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 317, kkk. Claim 9. including the HVR of kkk, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 261, lll. Claim 9. including the HVR of lll, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 261, mmm. Claim 9. including the HVR of mmm, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 261, nnn. Claim 9. including the HVR of nnn, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 261, ooo. Claim 9. including the HVR of ooo, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 264, ppp. Claim 9. including the HVR of ppp, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 264, qqq. Claim 9. It includes the HVR of qqq, and further includes a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

264. rrr. Claim 9. It includes the HVR of rrr, and further includes a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

264. sss. Claim 9. It includes the HVR of sss, and further includes a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

269. ttt. Claim 9. It includes the HVR of ttt, and further includes a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

269. uuu. Claim 9. It includes the HVR of uuu, and further includes a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

269. vvv. Claim 9. It includes the HVR of vvv, and further includes a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

275. www. Claim 9. It includes the HVR of www, and further includes a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

275. xxx. Claim 9. It includes the HVR of xxx, and further includes a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

275. yyy. Claim 9. It includes the HVR of yyy, and further includes a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

275. zzz. Claim 9. It includes the HVR of zzz, and further includes a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

275. aaaa. Claim 9. It includes the HVR of aaaa, and further includes a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

275. bbb. Claim 9. comprising the HVR of bbbb, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275 ccc. Claim 9. comprising the HVR of cccc, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275 ddd. Claim 9. comprising the HVR of dddd, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275 eee. Claim 9. comprising the HVR of eeee, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 264 fff. Claim 9. comprising the HVR of ffff, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275 ggg g. Claim 9. comprising the HVR of gggg, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275 hhh. Claim 9. comprising the HVR of hhhh, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275 iii . Claim 9. comprising the HVR of iii, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 416 jjj. Claim 9. comprising the HVR of jjjj, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312 kkk. Claim 9. comprising the HVR of kkkk, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312 lll Comprising the HVR of claim 9.llll, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312, mmmm. Comprising the HVR of claim 9.mmmm, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312, nnnn. Comprising the HVR of claim 9.nnnn, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312, oooo. Comprising the HVR of claim 9.oooo, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312, pppp. Comprising the HVR of claim 9.pppp, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312, qqqq. Comprising the HVR of claim 9.qqqq, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312, rrrr. Comprising the HVR of claim 9.rrrr, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312, ssss. Comprising the HVR of claim 9.ssss, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312, or tttt. Comprising the HVR of claim 9.tttt, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312, The antibody according to claim 9.

12. The antibody is a. comprising the HVR of claim 9.a., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 202, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 257; b. comprising the HVR of claim 9., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 203, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 258; c. comprising the HVR of claim 9.c., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 204, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 259; d. comprising the HVR of claim 9.d., further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 260; e. comprising the HVR of claim 9.e., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 206, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 261; f. comprising the HVR of claim 9.f., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 207, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 262; g. comprising the HVR of claim 9.g., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 208, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 263; h. comprising the HVR of claim 9.h., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 209, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 264; i. comprising the HVR of claim 9.i., further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 265; j. comprising the HVR of claim 9.j., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 210, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 266; k. comprising the HVR of claim 9.k., further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 267; l. comprising the HVR of claim 9.l., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 212, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 268; m. comprising the HVR of claim 9.m., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 214, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 269; n. comprising the HVR of claim 9.n., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 215, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 270; o. comprising the HVR of claim 9.o., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 216, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 271; p. comprising the HVR of claim 9.p., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 217, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 272; q. comprising the HVR of claim 9.q., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 218, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 273; r. comprising the HVR of claim 9.r., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 219, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 274; s. comprising the HVR of claim 9.s., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 220, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275; t. comprising the HVR of claim 9.t., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 209, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 276; u. comprising the HVR of claim 9.u., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 221, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 277; v. comprising the HVR of claim 9.v., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 222, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 278; w. comprising the HVR of claim 9.w., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 223, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 279; x. comprising the HVR of claim 9.x., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 224, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 280; y. comprising the HVR of claim 9.y., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 225, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 281; z. Comprising the HVR of claim 9.z., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 226, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 282; aa. Comprising the HVR of claim 9.ss., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 227, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 283; bb. Comprising the HVR of claim 9.bb., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 228, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 284; cc. Comprising the HVR of claim 9.cc., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 228, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 285; dd. Comprising the HVR of claim 9.dd., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 229, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 286; ee. Comprising the HVR of claim 9.ee., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 225, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 287; ff. Comprising the HVR of claim 9.ff., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 230, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 288; gg. Comprising the HVR of claim 9.gg., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 231, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 289; hh. Comprising the HVR of claim 9.hh., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 232, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 290; ii. Comprising the HVR of claim 9.ii., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 233, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 291; jj. Comprising the HVR of claim 9.34, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 212, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 292; kk. Comprising the HVR of claim 9.kk., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 235, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 293; ll. Comprising the HVR of claim 9.ll., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 235, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 294; mm. Comprising the HVR of claim 9.mm., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 236, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 295; nn. Comprising the HVR of claim 9.nn., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 237, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 296; oo. Comprising the HVR of claim 9.oo., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 238, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 297; pp. Comprising the HVR of claim 9.pp., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 238, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 298; qq. Comprising the HVR of claim 9.qq., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 239, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 299; rr. comprising the HVR of claim 9.rr., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 240, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 300; ss. comprising the HVR of claim 9.ss., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 241, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 301; tt. comprising the HVR of claim 9.tt., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 242, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 302; uu. comprising the HVR of claim 9.uu., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 243, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 303; vv. comprising the HVR of claim 9.vv., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 244, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 304; ww. comprising the HVR of claim 9.ww., further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 245, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 305; Including the HVR of claim 9. xx., further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 246, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 306; Including the HVR of claim 9. yy., further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 247, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 307; Including the HVR of claim 9. zz., further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 248, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 308; aaa. Including the HVR of claim 9. aaa., further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 249, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 309; bbb. Including the HVR of claim 9. bbb., further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 250, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 310; ccc. Including the HVR of claim 9. ccc., further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 251, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 311; Including the HVR of claim 9, and further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 252, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312; Including the HVR of claim 9, and further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 253, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 313; Including the HVR of claim 9, and further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 254, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 314; Including the HVR of claim 9, and further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 255, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 315; Including the HVR of claim 9, and further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 256, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 316; Including the HVR of claim 9, and further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 233, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 291; jjj. Comprising the HVR of claim 9.jjj., and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 317; kkk. Comprising the HVR of claim 9.kkk., and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 361, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 261; lll. Comprising the HVR of claim 9.lll., and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 362, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 261; mmm. Comprising the HVR of claim 9.mmm., and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 363, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 261; nnn. Comprising the HVR of claim 9.nnn., and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 364, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 261; ooo. Comprising the HVR of claim 9.ooo., and further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 365, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 264; Including the HVR of claim 9, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 366, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 264; Including the HVR of claim 9, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 367, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 264; Including the HVR of claim 9, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 368, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 264; Including the HVR of claim 9, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 369, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 269; Including the HVR of claim 9, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 370, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 269; Including the HVR of claim 9, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 387, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 269; vvv. Claim 9. vvv. comprising an HVR, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 388, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275; www. Claim 9. www. comprising an HVR, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 389, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275; xxx. Claim 9. xxx. comprising an HVR, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 390, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275; yyy. Claim 9. yyy. comprising an HVR, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 391, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275; zzz. Claim 9. zzz. comprising an HVR, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 392, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275; aaaa. Claim 9. aaaa. comprising an HVR, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 393, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275; Including the HVR of claim 9, further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 394, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275; Including the HVR of claim 9, further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 395, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275; Including the HVR of claim 9, further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 396, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275; Including the HVR of claim 9, further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 398, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 264; Including the HVR of claim 9, further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 399, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275; Including the HVR of claim 9, further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 400, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275; Including the HVR of claim 9, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 401, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 275; Including the HVR of claim 9, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 402, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 416; Including the HVR of claim 9, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 403, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312; Including the HVR of claim 9, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 404, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312; Including the HVR of claim 9, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 405, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312; Including the HVR of claim 9, further comprising a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 406, and further comprising a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312; nnnn. Claim 9. including the HVR of nnnn., further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 407, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312; oooo. Claim 9. including the HVR of oooo., further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 408, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312; pppp. Claim 9. including the HVR of pppp., further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 409, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312; qqqq. Claim 9. including the HVR of qqqq., further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 410, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312; rrrr. Claim 9. including the HVR of rrrr., further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 411, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312; Including the HVR of claim 9, further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 397, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 312; or Including the HVR of claim 9, further including a VH that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 412, and further including a VL that is at least 90%, at least 95%, at least 97%, or at least 99% identical to the amino acid sequence of SEQ ID NO:

312. Including The antibody according to claim 9.

13. Wherein the antibody is a. Including the HVR of claim 9.a, further including a VH including the amino acid sequence of SEQ ID NO: 202 b. Including the HVR of claim 9.b, further including a VH including the amino acid sequence of SEQ ID NO: 203 c. Including the HVR of claim 9.c, further including a VH including the amino acid sequence of SEQ ID NO: 204 d. Including the HVR of claim 12.d, further including a VH including the amino acid sequence of SEQ ID NO: 205 e. Including the HVR of claim 9.e, further including a VH including the amino acid sequence of SEQ ID NO: 206 f. Including the HVR of claim 9.f, further including a VH including the amino acid sequence of SEQ ID NO: 207 g. Including the HVR of claim 9.g, further including a VH including the amino acid sequence of SEQ ID NO: 208 h. Including the HVR of claim 9.h, further including a VH including the amino acid sequence of SEQ ID NO: 209 i. Including the HVR of claim 9.i, further including a VH including the amino acid sequence of SEQ ID NO: 210 j. Including the HVR of claim 9.j, further including a VH including the amino acid sequence of SEQ ID NO: 211 k. Including the HVR of claim 9.k, further including a VH including the amino acid sequence of SEQ ID NO: 212 l. Including the HVR of claim 9.l, further including a VH including the amino acid sequence of SEQ ID NO: 213 m. Including the HVR of claim 9.m, further including a VH including the amino acid sequence of SEQ ID NO: 214 n. Including the HVR of claim 9.n, further including a VH including the amino acid sequence of SEQ ID NO: 215 o. Comprising the HVR of claim 9.o, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 216 p. Comprising the HVR of claim 9.p, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 217 q. Comprising the HVR of claim 9.q, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 218 r. Comprising the HVR of claim 9.r, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 219 s. Comprising the HVR of claim 9.s, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 220 t. Comprising the HVR of claim 9.t, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 209 u. Comprising the HVR of claim 9.u, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 221 v. Comprising the HVR of claim 9.v, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 222 w. Comprising the HVR of claim 9.w, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 223 x. Comprising the HVR of claim 9.x, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 224 y. Comprising the HVR of claim 9.y, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 225 z. Comprising the HVR of claim 9.z, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 226 aa. Comprising the HVR of claim 9.aa, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 227 bb. Comprising the HVR of claim 9.bb, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 228 cc. Comprising the HVR of claim 9.cc, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 228 dd. Comprising the HVR of claim 9.dd, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 229 ee. Comprising the HVR of claim 9.ee, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 225 ff. Comprising the HVR of claim 9.ff, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 230 gg. Comprising the HVR of claim 9.gg, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 231 hh. Comprising the HVR of claim 9.hh, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 232 ii. Comprising the HVR of claim 9.ii, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 233 jj. Comprising the HVR of claim 9.jj, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 234 kk. Claim 9. comprising the HVR of kk, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 235, ll. Claim 9. comprising the HVR of ll, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 235, mm. Claim 9. comprising the HVR of mm, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 236, nn. Claim 9. comprising the HVR of nn, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 237, oo . Claim 9. comprising the HVR of oo, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 238, pp. Claim 9. comprising the HVR of pp, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 238, qq. Claim 9. comprising the HVR of qq, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 239, rr. Claim 9. comprising the HVR of rr, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 240, ss. Claim 9. comprising the HVR of ss, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 241, tt. Claim 9. comprising the HVR of tt, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 242, uu. Claim 9. comprising the HVR of uu, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 243, vv. Claim 9. comprising the HVR of vv, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 244, ww. Claim 9. comprising the HVR of ww, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 245, xx. Claim 9. comprising the HVR of xx, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 246, yy. Claim 9. comprising the HVR of yy, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 247, zz. Claim 9. comprising the HVR of zz, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 248, aaa. Claim 9. comprising the HVR of aaa, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 249, bbb. Claim 9. comprising the HVR of bbb, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 250, ccc. Claim 9. comprising the HVR of ccc, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 251, ddd. Claim 9. comprising the HVR of ddd, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 252, eee. Claim 9. comprising the HVR of eee, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 253, fff. Comprising the HVR of claim 9.fff and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 254 ggg. Comprising the HVR of claim 9.ggg and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 255 hhh. Comprising the HVR of claim 9.hhh and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 256 iii. Comprising the HVR of claim 9.iii and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 233 jjj. Comprising the HVR of claim 9.jjj and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 256 kkk. Comprising the HVR of claim 9.kkk and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 361 lll. Comprising the HVR of claim 9.lll and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 362 mmm. Comprising the HVR of claim 9.mmm and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 363 nnn. Comprising the HVR of claim 9.nnn and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 364 ooo. Comprising the HVR of claim 9.ooo and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 365 ppp. Comprising the HVR of claim 9.ppp and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 366 qqq. Comprising the HVR of claim 9.qqq and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 367 rrr. Comprising the HVR of claim 9.rrr and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 368 sss. Comprising the HVR of claim 9.sss and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 369 ttt. Comprising the HVR of claim 9.ttt and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 370 uuu. Comprising the HVR of claim 9.uuu and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 387 vvv. Comprising the HVR of claim 9.vvv and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 388 www. Comprising the HVR of claim 9.www and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 389 xxx. Comprising the HVR of claim 9.xxx and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 390 yyy. Comprising the HVR of claim 9.yyy and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 391 zzz. Comprising the HVR of claim 9.zzz and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 392 aaaa. Comprising the HVR of claim 9. aaaa, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 393 bbbb. Comprising the HVR of claim 9. bbbb, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 394 cccc. Comprising the HVR of claim 9. cccc, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 395 dddd. Comprising the HVR of claim 9. dddd, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 396 eeee. Comprising the HVR of claim 9. eeee, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 398 ffff. Comprising the HVR of claim 9. ffff, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 399 ggg g. Comprising the HVR of claim 9. gggg, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 400 hhhh. Comprising the HVR of claim 9 hhhh, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 401 iiii. Comprising the HVR of claim 9. iiiii, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 402 jjjj. Comprising the HVR of claim 9. jjjj, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 403 kkkk. Comprising the HVR of claim 9. kkkk, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 404 llll. Comprising the HVR of claim 9. llll, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 405 mmmm. Comprising the HVR of claim 9. mmmm, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 406 nnnn. Comprising the HVR of claim 9. nnnn, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 407 oooo. Comprising the HVR of claim 9. oooo, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 408 pppp. Comprising the HVR of claim 9. pppp, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 409 qqqq. Comprising the HVR of claim 9. qqqq, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 410 rrrr. Comprising the HVR of claim 9. rrrr, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 411 ssss. Comprising the HVR of claim 9. ssss, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 397, or tttt. Comprising the HVR of claim 9. tttt, and further comprising a VH comprising the amino acid sequence of SEQ ID NO: 412 The antibody according to any one of claims 9 to 12.

14. wherein the antibody is a. comprising the HVR of claim 9.a and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 257, b. comprising the HVR of claim 9.b and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 258, c. comprising the HVR of claim 9.c and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 259, d. comprising the HVR of claim 9.d and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 260, e. comprising the HVR of claim 9.e and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 261, f. comprising the HVR of claim 9.f and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 262, g. comprising the HVR of claim 9.g and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 263, h. comprising the HVR of claim 9.h and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 264, i. comprising the HVR of claim 9.i and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 265, j. comprising the HVR of claim 9.j and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 266, k. comprising the HVR of claim 9.k and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 267, l. comprising the HVR of claim 9.l and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 268, m. comprising the HVR of claim 9.m and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 269, n. comprising the HVR of claim 9.n and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 270, o. comprising the HVR of claim 9.o and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 271, p. comprising the HVR of claim 9.p and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 272, q. comprising the HVR of claim 9.q and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 273, r. comprising the HVR of claim 9.r and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 274, s. comprising the HVR of claim 9.s and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275, t. comprising the HVR of claim 9.t and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 276, u. comprising the HVR of claim 9.u and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 277, v. comprising the HVR of claim 9.v and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 278, w. Comprising the HVR of claim 9.w, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 279 x. Comprising the HVR of claim 9.x, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 280 y. Comprising the HVR of claim 9.y, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 281 z. Comprising the HVR of claim 9.z, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 282 aa. Comprising the HVR of claim 9.ss, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 283 bb. Comprising the HVR of claim 9.bb, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 284 cc. Comprising the HVR of claim 9.cc, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 285 dd. Comprising the HVR of claim 9.dd, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 286 ee. Comprising the HVR of claim 9.ee, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 287 ff. Comprising the HVR of claim 9.ff, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 288 gg. Comprising the HVR of claim 9.gg, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 289 hh. Comprising the HVR of claim 9.hh, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 290 ii. Comprising the HVR of claim 9.ii, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 291 jj. Comprising the HVR of claim 9.jj, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 292 kk. Comprising the HVR of claim 9.kk, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 293 ll. Comprising the HVR of claim 9.ll, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 294 mm. Comprising the HVR of claim 9.mm, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 295 nn. Comprising the HVR of claim 9.nn, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 296 oo . Comprising the HVR of claim 9.oo, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 297 pp. Comprising the HVR of claim 9.pp, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 298 qq. Comprising the HVR of claim 9.qq, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 299 rr. Comprising the HVR of claim 9.rr, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 300 ss. comprising the HVR of claim 9.ss, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 301 tt. comprising the HVR of claim 9.tt, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 302 uu. comprising the HVR of claim 9.uu, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 303 vv. comprising the HVR of claim 9.vv, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 304 ww. comprising the HVR of claim 9.ww, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 305 xx. comprising the HVR of claim 9.xx, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 306 yy. comprising the HVR of claim 9.yy, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 307 zz. comprising the HVR of claim 9.zz, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 308 aaa. comprising the HVR of claim 9.aaa, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 309 bbb. comprising the HVR of claim 9.bbb, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 310 ccc. comprising the HVR of claim 9.ccc, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 311 ddd. comprising the HVR of claim 9.ddd, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 312 eee. comprising the HVR of claim 9.eee, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 313 fff. comprising the HVR of claim 9.fff, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 314 ggg. comprising the HVR of claim 9.ggg, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 315 hhh. comprising the HVR of claim 9.hhh, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 316 iii. comprising the HVR of claim 9.iii, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 291 jjj. comprising the HVR of claim 9.jjj, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 317 kkk. comprising the HVR of claim 9.kkk, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 261 lll. comprising the HVR of claim 9.lll, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 261 mmm. comprising the HVR of claim 9.mmm, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 261 nnn. Comprising the HVR of claim 9.nnn, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 261 ooo. Comprising the HVR of claim 9.ooo, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 264 ppp. Comprising the HVR of claim 9.ppp, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 264 qqq. Comprising the HVR of claim 9.qqq, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 264 rrr. Comprising the HVR of claim 9.rrr, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 264 sss. Comprising the HVR of claim 9.sss, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 269 ttt. Comprising the HVR of claim 9.ttt, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 269 uuu. Comprising the HVR of claim 9.uuu, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 269 vvv. Comprising the HVR of claim 9.vvv, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275 www. Comprising the HVR of claim 9.www, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275 xxx. Comprising the HVR of claim 9.xxx, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275 yyy. Comprising the HVR of claim 9.yyy, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275 zzz. Comprising the HVR of claim 9.zzz, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275 aaaa. Comprising the HVR of claim 9.aaaa, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275 bbbb. Comprising the HVR of claim 9.bbbb, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275 cccc. Comprising the HVR of claim 9.cccc, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275 dddd. Comprising the HVR of claim 9.dddd, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275 eeee. Comprising the HVR of claim 9.eeee, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 264 ffff. Comprising the HVR of claim 9.ffff, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275 ggg g. Comprising the HVR of claim 9.gggg, and further comprising a VL comprising the amino acid sequence of SEQ ID NO: 275 hhhh. Claim 9. It includes the HVR of hhhh, and further includes a VL containing the amino acid sequence of SEQ ID NO:

275. iiii. Claim 9. It includes the HVR of iiiii, and further includes a VL containing the amino acid sequence of SEQ ID NO:

416. jjjj. Claim 9. It includes the HVR of jjjjj, and further includes a VL containing the amino acid sequence of SEQ ID NO:

312. kkkk. Claim 9. It includes the HVR of kkkkk, and further includes a VL containing the amino acid sequence of SEQ ID NO:

312. llll. Claim 9. It includes the HVR of lllll, and further includes a VL containing the amino acid sequence of SEQ ID NO:

312. mmmm. Claim 9. It includes the HVR of mmmmmm, and further includes a VL containing the amino acid sequence of SEQ ID NO:

312. nnnn. Claim 9. It includes the HVR of nnnnn, and further includes a VL containing the amino acid sequence of SEQ ID NO:

312. oooo. Claim 9. It includes the HVR of ooooo, and further includes a VL containing the amino acid sequence of SEQ ID NO:

312. pppp. Claim 9. It includes the HVR of ppppp, and further includes a VL containing the amino acid sequence of SEQ ID NO:

312. qqqq. Claim 9. It includes the HVR of qqqqq, and further includes a VL containing the amino acid sequence of SEQ ID NO:

312. rrrr. Claim 9. It includes the HVR of rrrrr, and further includes a VL containing the amino acid sequence of SEQ ID NO:

312. ssss. Claim 9. It includes the HVR of sssss, and further includes a VL containing the amino acid sequence of SEQ ID NO: 312, or tttt. Claim 9. It includes the HVR of ttttt, and further includes a VL containing the amino acid sequence of SEQ ID NO:

312. The antibody according to any one of Claims 9 to 12.

15. The antibody is a. VH containing the amino acid sequence of SEQ ID NO: 202 and VL containing the amino acid sequence of SEQ ID NO: 257, b. VH containing the amino acid sequence of SEQ ID NO: 203 and VL containing the amino acid sequence of SEQ ID NO: 258, c. VH containing the amino acid sequence of SEQ ID NO: 204 and VL containing the amino acid sequence of SEQ ID NO: 259, d. VH containing the amino acid sequence of SEQ ID NO: 205 and VL containing the amino acid sequence of SEQ ID NO: 260, e. VH containing the amino acid sequence of SEQ ID NO: 206 and VL containing the amino acid sequence of SEQ ID NO: 261, f. VH containing the amino acid sequence of SEQ ID NO: 207 and VL containing the amino acid sequence of SEQ ID NO: 262, g. VH containing the amino acid sequence of SEQ ID NO: 208 and VL containing the amino acid sequence of SEQ ID NO:

263. h. VH containing the amino acid sequence of SEQ ID NO: 209 and VL containing the amino acid sequence of SEQ ID NO: 264, i. VH containing the amino acid sequence of SEQ ID NO: 210 and VL containing the amino acid sequence of SEQ ID NO: 265, j. VH containing the amino acid sequence of SEQ ID NO: 211 and VL containing the amino acid sequence of SEQ ID NO: 266, k. VH containing the amino acid sequence of SEQ ID NO: 212 and VL containing the amino acid sequence of SEQ ID NO: 267, l. VH containing the amino acid sequence of SEQ ID NO: 213 and VL containing the amino acid sequence of SEQ ID NO: 268, m. VH containing the amino acid sequence of SEQ ID NO: 214 and VL containing the amino acid sequence of SEQ ID NO: 269, n. VH containing the amino acid sequence of SEQ ID NO: 215 and VL containing the amino acid sequence of SEQ ID NO: 270, o. VH containing the amino acid sequence of SEQ ID NO: 216 and VL containing the amino acid sequence of SEQ ID NO: 271, p. VH containing the amino acid sequence of SEQ ID NO: 217 and VL containing the amino acid sequence of SEQ ID NO: 272, q. VH containing the amino acid sequence of SEQ ID NO: 218 and VL containing the amino acid sequence of SEQ ID NO: 273, r. VH containing the amino acid sequence of SEQ ID NO: 219 and VL containing the amino acid sequence of SEQ ID NO: 274, s. VH containing the amino acid sequence of SEQ ID NO: 220 and VL containing the amino acid sequence of SEQ ID NO: 275, t. VH containing the amino acid sequence of SEQ ID NO: 209 and VL containing the amino acid sequence of SEQ ID NO: 276, u. VH containing the amino acid sequence of SEQ ID NO: 221 and VL containing the amino acid sequence of SEQ ID NO: 277, v. VH containing the amino acid sequence of SEQ ID NO: 222 and VL containing the amino acid sequence of SEQ ID NO: 278, w. VH containing the amino acid sequence of SEQ ID NO: 223 and VL containing the amino acid sequence of SEQ ID NO: 279, x. VH containing the amino acid sequence of SEQ ID NO: 224 and VL containing the amino acid sequence of SEQ ID NO: 280, y. VH containing the amino acid sequence of SEQ ID NO: 225 and VL containing the amino acid sequence of SEQ ID NO: 281, z. VH containing the amino acid sequence of SEQ ID NO: 226 and VL containing the amino acid sequence of SEQ ID NO: 282, aa. VH containing the amino acid sequence of SEQ ID NO: 227 and VL containing the amino acid sequence of SEQ ID NO: 283, bb. VH containing the amino acid sequence of SEQ ID NO: 228 and VL containing the amino acid sequence of SEQ ID NO: 284, cc. VH containing the amino acid sequence of SEQ ID NO: 228 and VL containing the amino acid sequence of SEQ ID NO: 285, dd. VH containing the amino acid sequence of SEQ ID NO: 229 and VL containing the amino acid sequence of SEQ ID NO: 286, ee. VH containing the amino acid sequence of SEQ ID NO: 225 and VL containing the amino acid sequence of SEQ ID NO: 287 ff. VH containing the amino acid sequence of SEQ ID NO: 230 and VL containing the amino acid sequence of SEQ ID NO: 288 gg. VH containing the amino acid sequence of SEQ ID NO: 231 and VL containing the amino acid sequence of SEQ ID NO: 289 hh. VH containing the amino acid sequence of SEQ ID NO: 232 and VL containing the amino acid sequence of SEQ ID NO: 290 ii. VH containing the amino acid sequence of SEQ ID NO: 233 and VL containing the amino acid sequence of SEQ ID NO: 291 jj. VH containing the amino acid sequence of SEQ ID NO: 234 and VL containing the amino acid sequence of SEQ ID NO: 292 kk. VH containing the amino acid sequence of SEQ ID NO: 235 and VL containing the amino acid sequence of SEQ ID NO: 293 ll. VH containing the amino acid sequence of SEQ ID NO: 235 and VL containing the amino acid sequence of SEQ ID NO: 294 mm. VH containing the amino acid sequence of SEQ ID NO: 236 and VL containing the amino acid sequence of SEQ ID NO: 295 nn. VH containing the amino acid sequence of SEQ ID NO: 237 and VL containing the amino acid sequence of SEQ ID NO: 296 oo. VH containing the amino acid sequence of SEQ ID NO: 238 and VL containing the amino acid sequence of SEQ ID NO: 297 pp. VH containing the amino acid sequence of SEQ ID NO: 238 and VL containing the amino acid sequence of SEQ ID NO: 298 qq. VH containing the amino acid sequence of SEQ ID NO: 239 and VL containing the amino acid sequence of SEQ ID NO: 299 rr. VH containing the amino acid sequence of SEQ ID NO: 240 and VL containing the amino acid sequence of SEQ ID NO: 300 ss. VH containing the amino acid sequence of SEQ ID NO: 241 and VL containing the amino acid sequence of SEQ ID NO: 301 tt. VH containing the amino acid sequence of SEQ ID NO: 242 and VL containing the amino acid sequence of SEQ ID NO: 302 uu. VH containing the amino acid sequence of SEQ ID NO: 243 and VL containing the amino acid sequence of SEQ ID NO: 303 vv. VH containing the amino acid sequence of SEQ ID NO: 244 and VL containing the amino acid sequence of SEQ ID NO: 304 ww. VH containing the amino acid sequence of SEQ ID NO: 245 and VL containing the amino acid sequence of SEQ ID NO: 305 xx. VH containing the amino acid sequence of SEQ ID NO: 246 and VL containing the amino acid sequence of SEQ ID NO: 306 yy. VH containing the amino acid sequence of SEQ ID NO: 247 and VL containing the amino acid sequence of SEQ ID NO: 307 zz. VH containing the amino acid sequence of SEQ ID NO: 248 and VL containing the amino acid sequence of SEQ ID NO: 308 aaa. VH containing the amino acid sequence of SEQ ID NO: 249 and VL containing the amino acid sequence of SEQ ID NO: 309, bbb. VH containing the amino acid sequence of SEQ ID NO: 250 and VL containing the amino acid sequence of SEQ ID NO: 310, ccc. VH containing the amino acid sequence of SEQ ID NO: 251 and VL containing the amino acid sequence of SEQ ID NO: 311, ddd. VH containing the amino acid sequence of SEQ ID NO: 252 and VL containing the amino acid sequence of SEQ ID NO: 312, eee. VH containing the amino acid sequence of SEQ ID NO: 253 and VL containing the amino acid sequence of SEQ ID NO: 313, fff. VH containing the amino acid sequence of SEQ ID NO: 254 and VL containing the amino acid sequence of SEQ ID NO: 314, ggg. VH containing the amino acid sequence of SEQ ID NO: 255 and VL containing the amino acid sequence of SEQ ID NO: 315, hhh. VH containing the amino acid sequence of SEQ ID NO: 256 and VL containing the amino acid sequence of SEQ ID NO: 316, iii. VH containing the amino acid sequence of SEQ ID NO: 233 and VL containing the amino acid sequence of SEQ ID NO: 291, jjj. VH containing the amino acid sequence of SEQ ID NO: 256 and VL containing the amino acid sequence of SEQ ID NO: 317, kkk. VH containing the amino acid sequence of SEQ ID NO: 361 and VL containing the amino acid sequence of SEQ ID NO: 261, lll. VH containing the amino acid sequence of SEQ ID NO: 362 and VL containing the amino acid sequence of SEQ ID NO: 261, mmm. VH containing the amino acid sequence of SEQ ID NO: 363 and VL containing the amino acid sequence of SEQ ID NO: 261, nnn. VH containing the amino acid sequence of SEQ ID NO: 364 and VL containing the amino acid sequence of SEQ ID NO: 261, ooo. VH containing the amino acid sequence of SEQ ID NO: 365 and VL containing the amino acid sequence of SEQ ID NO: 264, ppp. VH containing the amino acid sequence of SEQ ID NO: 366 and VL containing the amino acid sequence of SEQ ID NO: 264, qqq. VH containing the amino acid sequence of SEQ ID NO: 367 and VL containing the amino acid sequence of SEQ ID NO: 264, rrr. VH containing the amino acid sequence of SEQ ID NO: 368 and VL containing the amino acid sequence of SEQ ID NO: 264, sss. VH containing the amino acid sequence of SEQ ID NO: 369 and VL containing the amino acid sequence of SEQ ID NO: 269, ttt. VH containing the amino acid sequence of SEQ ID NO: 370 and VL containing the amino acid sequence of SEQ ID NO: 269, uuu. VH containing the amino acid sequence of SEQ ID NO: 387 and VL containing the amino acid sequence of SEQ ID NO: 269, vvv. VH containing the amino acid sequence of SEQ ID NO: 388 and VL containing the amino acid sequence of SEQ ID NO: 275, VH containing the amino acid sequence of SEQ ID NO: 389 and VL containing the amino acid sequence of SEQ ID NO: 275 VH containing the amino acid sequence of SEQ ID NO: 390 and VL containing the amino acid sequence of SEQ ID NO: 275 VH containing the amino acid sequence of SEQ ID NO: 391 and VL containing the amino acid sequence of SEQ ID NO: 275 VH containing the amino acid sequence of SEQ ID NO: 392 and VL containing the amino acid sequence of SEQ ID NO: 275 VH containing the amino acid sequence of SEQ ID NO: 393 and VL containing the amino acid sequence of SEQ ID NO: 275 VH containing the amino acid sequence of SEQ ID NO: 394 and VL containing the amino acid sequence of SEQ ID NO: 275 VH containing the amino acid sequence of SEQ ID NO: 395 and VL containing the amino acid sequence of SEQ ID NO: 275 VH containing the amino acid sequence of SEQ ID NO: 396 and VL containing the amino acid sequence of SEQ ID NO: 275 VH containing the amino acid sequence of SEQ ID NO: 398 and VL containing the amino acid sequence of SEQ ID NO: 264 VH containing the amino acid sequence of SEQ ID NO: 399 and VL containing the amino acid sequence of SEQ ID NO: 275 VH containing the amino acid sequence of SEQ ID NO: 400 and VL containing the amino acid sequence of SEQ ID NO: 275 VH containing the amino acid sequence of SEQ ID NO: 401 and VL containing the amino acid sequence of SEQ ID NO: 275 VH containing the amino acid sequence of SEQ ID NO: 402 and VL containing the amino acid sequence of SEQ ID NO: 413 VH containing the amino acid sequence of SEQ ID NO: 403 and VL containing the amino acid sequence of SEQ ID NO: 312 VH containing the amino acid sequence of SEQ ID NO: 404 and VL containing the amino acid sequence of SEQ ID NO: 312 VH containing the amino acid sequence of SEQ ID NO: 405 and VL containing the amino acid sequence of SEQ ID NO: 312 VH containing the amino acid sequence of SEQ ID NO: 406 and VL containing the amino acid sequence of SEQ ID NO: 312 VH containing the amino acid sequence of SEQ ID NO: 407 and VL containing the amino acid sequence of SEQ ID NO: 312 VH containing the amino acid sequence of SEQ ID NO: 408 and VL containing the amino acid sequence of SEQ ID NO: 312 VH containing the amino acid sequence of SEQ ID NO: 409 and VL containing the amino acid sequence of SEQ ID NO: 312 VH containing the amino acid sequence of SEQ ID NO: 410 and VL containing the amino acid sequence of SEQ ID NO: 312 rrr. VH comprising the amino acid sequence of SEQ ID NO: 411 and VL comprising the amino acid sequence of SEQ ID NO: 312, sss. VH comprising the amino acid sequence of SEQ ID NO: 397 and VL comprising the amino acid sequence of SEQ ID NO: 312, ttt. VH comprising the amino acid sequence of SEQ ID NO: 412 and VL comprising the amino acid sequence of SEQ ID NO: 312, The antibody according to any one of claims 9 to 12, comprising:

16. An isolated antibody that specifically binds to human SIRPA, wherein the antibody is a. Comprising VH and VL, wherein the VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-1 (shown in Table 3), and the VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-1 (shown in Table 2), b. Comprising VH and VL, wherein the VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-2 (shown in Table 3), and the VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-2 (shown in Table 2), c. Comprising VH and VL, wherein the VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-3 (shown in Table 3), and the VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-3 (shown in Table 2), d. Comprising VH and VL, wherein the VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-4 (shown in Table 3), and the VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-4 (shown in Table 2), e. Comprising VH and VL, wherein the VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-5 (shown in Table 3), and the VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-5 (shown in Table 2), f. Comprising VH and VL, wherein the VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-6 (shown in Table 3), and the VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-6 (shown in Table 2), g. Comprising VH and VL, wherein the VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-7 (shown in Table 3), and the VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-7 (shown in Table 2), h. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-8 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-8 (shown in Table 2). i. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-9 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-9 (shown in Table 2). j. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-10 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-10 (shown in Table 2). k. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-11 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-11 (shown in Table 2). l. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-12 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-12 (shown in Table 2). m. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-13 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-13 (shown in Table 2). n. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-14 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-14 (shown in Table 2). o. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-15 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-15 (shown in Table 2). p. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-16 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-16 (shown in Table 2). q. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-17 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-17 (shown in Table 2). r. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-18 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-18 (shown in Table 2). s. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19 (shown in Table 2). t. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-20 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-20 (shown in Table 2). u. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-21 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-21 (shown in Table 2). v. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-22 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-22 (shown in Table 2). w. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-23 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-23 (shown in Table 2). x. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-24 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-24 (shown in Table 2). y. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-25 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-25 (shown in Table 2). z. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-26 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-26 (shown in Table 2). aa. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-27 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-27 (shown in Table 2). bb. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-28 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-28 (shown in Table 2). cc. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-29 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-29 (shown in Table 2). dd. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-30 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-30 (shown in Table 2). ee. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-31 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-31 (shown in Table 2). ff. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-32 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-32 (shown in Table 2). gg. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-33 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-33 (shown in Table 2). hh. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-34 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-34 (shown in Table 2). ii. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-35 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-35 (shown in Table 2). jj. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-36 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-36 (shown in Table 2). kk. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-37 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-37 (shown in Table 2). ll. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-38 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-38 (shown in Table 2). mm. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-39 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-39 (shown in Table 2). nn. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-40 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-40 (shown in Table 2). oo. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-41 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-41 (shown in Table 2). pp. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-42 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-42 (shown in Table 2). qq. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-43 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-43 (shown in Table 2). rr. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-44 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-44 (shown in Table 2). ss. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-45 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-45 (shown in Table 2). tt. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-46 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-46 (shown in Table 2). uu. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-47 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-47 (shown in Table 2). vv. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-48 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-48 (shown in Table 2). ww. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-49 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-49 (shown in Table 2). xx. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-50 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-50 (shown in Table 2). yy. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-51 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-51 (shown in Table 2). zz. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-52 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-52 (shown in Table 2). aaa. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-53 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-53 (shown in Table 2). bbb. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-54 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-54 (shown in Table 2). ccc. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-55 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-55 (shown in Table 2). ddd. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56 (shown in Table 2). eee. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-57 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-57 (shown in Table 2). fff. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-58 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-58 (shown in Table 2). ggg. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-59 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-59 (shown in Table 2). hhh. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-60 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-60 (shown in Table 2). iii. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-61 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-61 (shown in Table 2). jjj. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-62 (shown in Table 3), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-62 (shown in Table 2). kkk. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-5-57 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-5-57 (shown in Table 6). lll. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-5-58 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-5-58 (shown in Table 6). mmm. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-5-59 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-5-59 (shown in Table 6). nnn. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-5-61 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-5-61 (shown in Table 6). ooo. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-8-62 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-8-62 (shown in Table 6). ppp. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-8-64 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-8-64 (shown in Table 6). Including VH and VL, wherein the VH includes HVR-H1, HVR-H2, and HVR-H3 of antibody SA-8-66 (shown in Table 7), and the VL includes HVR-L1, HVR-L2, and HVR-L3 of antibody SA-8-66 (shown in Table 6). Including VH and VL, wherein the VH includes HVR-H1, HVR-H2, and HVR-H3 of antibody SA-8-67 (shown in Table 7), and the VL includes HVR-L1, HVR-L2, and HVR-L3 of antibody SA-8-67 (shown in Table 6). Including VH and VL, wherein the VH includes HVR-H1, HVR-H2, and HVR-H3 of antibody SA-13-68 (shown in Table 7), and the VL includes HVR-L1, HVR-L2, and HVR-L3 of antibody SA-13-68 (shown in Table 6). Including VH and VL, wherein the VH includes HVR-H1, HVR-H2, and HVR-H3 of antibody SA-13-69 (shown in Table 7), and the VL includes HVR-L1, HVR-L2, and HVR-L3 of antibody SA-13-69 (shown in Table 6). Including VH and VL, wherein the VH includes HVR-H1, HVR-H2, and HVR-H3 of antibody SA-13-71 (shown in Table 7), and the VL includes HVR-L1, HVR-L2, and HVR-L3 of antibody SA-13-71 (shown in Table 6). Including VH and VL, wherein the VH includes HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-72 (shown in Table 7), and the VL includes HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-72 (shown in Table 6). Including VH and VL, wherein the VH includes HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-73 (shown in Table 7), and the VL includes HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-73 (shown in Table 6). Including VH and VL, wherein the VH includes HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-74 (shown in Table 7), and the VL includes HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-74 (shown in Table 6). Containing VH and VL, wherein said VH contains HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-75 (shown in Table 7), and said VL contains HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-75 (shown in Table 6). Containing VH and VL, wherein said VH contains HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-76 (shown in Table 7), and said VL contains HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-76 (shown in Table 6). Containing VH and VL, wherein said VH contains HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-77 (shown in Table 7), and said VL contains HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-77 (shown in Table 6). Containing VH and VL, wherein said VH contains HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-78 (shown in Table 7), and said VL contains HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-78 (shown in Table 6). Containing VH and VL, wherein said VH contains HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-79 (shown in Table 7), and said VL contains HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-79 (shown in Table 6). Containing VH and VL, wherein said VH contains HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-80 (shown in Table 7), and said VL contains HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-80 (shown in Table 6). Containing VH and VL, wherein said VH contains HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-81 (shown in Table 7), and said VL contains HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-81 (shown in Table 6). Containing VH and VL, wherein said VH contains HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-82 (shown in Table 7), and said VL contains HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-82 (shown in Table 6). Including VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-83 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-83 (shown in Table 6). Including VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-19-84 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-19-84 (shown in Table 6). Including VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-85 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-85 (shown in Table 6). Including VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-86 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-86 (shown in Table 6). Including VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-87 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-87 (shown in Table 6). Including VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-88 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-88 (shown in Table 6). Including VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-89 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-89 (shown in Table 6). Including VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-90 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-90 (shown in Table 6). oooo. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-91 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-91 (shown in Table 6). pppp. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-92 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-92 (shown in Table 6). qqqq. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-93 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-93 (shown in Table 6). rrrr. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-94 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-94 (shown in Table 6). ssss. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-95 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-95 (shown in Table 6), or tttt. Comprising VH and VL, wherein said VH comprises HVR-H1, HVR-H2, and HVR-H3 of antibody SA-56-96 (shown in Table 7), and said VL comprises HVR-L1, HVR-L2, and HVR-L3 of antibody SA-56-96 (shown in Table 6), an antibody.

17. The antibody has the following properties: a. The antibody increases SIRPA activity, SIRPA signal transduction, CD47-induced SIRPA signal transduction, or any combination thereof in macrophages, dendritic cells, and / or microglial cells. b. The antibody decreases phagocytic activity by phagocytes, decreases cytokine release from dendritic cells (e.g., release of TNF alpha), suppresses synapse loss in microglia-neuron co-cultures, suppresses synapse loss in a mouse model, or any combination thereof. c. The antibody has an affinity (K Ｄ ) for human SIRPA that is less than 1 μM, less than 100 nM, less than 10 nM, less than 1 nM, less than 0.1 nM, less than 0.01 nM, or less than 0.001 nM d. The antibody has an affinity (K Ｄ ) for human SIRPAv1 (SEQ ID NO: 1) of 1 nM to 50 nM, 0.3 nM to 2 nM, or 2 nM to 24 nM e. The antibody has an affinity for human SIRPA that is higher than its affinity for mouse SIRPA. f. The antibody does not bind to mouse SIRPA. g. The antibody has an affinity for human SIRPA that is higher than its affinity for human SIRPB. h. The antibody does not bind to human SIRPB. i. The antibody binds to one or more amino acids of human SIRPAv1 (SEQ ID NO: 1) selected from D40, R54, and W68. j. The antibody has a reduced binding affinity for human SIRPAv1 (SEQ ID NO: 1) compared to wild-type SIRPAv1 consisting of SEQ ID NO: 1 by including one or more of the following substitutions: D40A, R54A, W68A. The antibody according to any one of claims 1 to 3, 9 to 12, or 16, having one or more of the above.

18. The antibody according to any one of claims 1 to 3, 9 to 12, or 16, wherein the antibody is a monoclonal antibody.

19. The antibody according to any one of claims 1 to 3, 9 to 12, or 16, wherein the antibody is a humanized antibody.

20. The antibody is an antigen-binding fragment, for example, Fab, Fab', Fab'-SH, F(ab') ２ , Fv, or scFv fragment, and the antibody according to any one of claims 1 to 3, 9 to 12, or 16.

21. The antibody according to any one of claims 1 to 3, 9 to 12, or 16, wherein the antibody is a bispecific antibody or a multispecific antibody.

22. The antibody according to any one of claims 1 to 3, 9 to 12, or 16, wherein the antibody is of the IgG class, IgM class, or IgA class.

23. The antibody according to claim 22, wherein the antibody is of the IgG class and is of the human IgG1, IgG2, IgG3, or IgG4 isotype, or of the mouse IgG1 or IgG2 isotype.

24. The antibody according to any one of claims 1 to 3, 9 to 12, or 16, wherein the antibody binds to an inhibitory Fc receptor.

25. The antibody according to claim 24, wherein the inhibitory Fc receptor is inhibitory Fc gamma receptor IIB (FcγRIIB).

26. The antibody according to claim 25, wherein the antibody reduces the cellular level of FcγRIIB. **Claim 27** An antibody, wherein the anti-SIRPA antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions at amino acid residues in the Fc region selected from the group consisting of N297A, D265A, D270A, L234A, L235A, G237A, P238D, L328E, E233D, G237D, H268D, P271G, A330R, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E, N297Q, P238S, P238A, A327Q, A327G, P329A, K322A, N325S, L328F, T394D, and any combination thereof, and the numbering of the residues follows EU numbering or includes an amino acid deletion at a position corresponding to glycine 236 of the Fc region; the antibody according to any one of claims 1-3, 9-12 or 16. **Claim 28** The antibody according to any one of claims 1-3, 9-12 or 16, wherein the antibody comprises one or more amino acid substitutions at residue positions in the Fc region selected from the group consisting of C127S, L234A, L234F, L235A, L235E, S267E, K322A, N325S, L328F, A330S, P331S, E345R, E430G, S440Y, and any combination thereof, and the numbering of the amino acid residues follows EU or Kabat numbering. **Claim 29** A pharmaceutical composition comprising the anti-SIRPA antibody according to any one of claims 1-3 and a pharmaceutically acceptable carrier. **Claim 30** An isolated nucleic acid comprising a nucleic acid sequence encoding the anti-SIRPA antibody according to any one of claims 1-3. **Claim 31** An isolated vector comprising the nucleic acid according to claim 30. **Claim 32** An isolated host cell comprising the nucleic acid according to claim 30 or the vector according to claim. **Claim 33** A method for producing an antibody that binds to human SIRPA, the method comprising culturing the cell according to claim 32 such that the antibody is produced. **Claim 34** The method according to claim 33, further comprising recovering the antibody produced by the cell. **Claim 35** The anti-SIRPA antibody according to any one of claims 1 to 3, 9 to 12 or 16 for use in the treatment of a disease or disorder associated with inflammation, transplant rejection, autoimmunity, or cognitive impairment.

36. The anti-SIRPA antibody for use according to claim 35, wherein the disease or disorder is selected from inflammation, enteritis, enteritis associated with colitis, rheumatoid arthritis, organ / graft transplant rejection, multiple sclerosis, synaptic pruning in neurons, synaptic loss in neurons, synaptic pruning by microglia, and cognitive impairment.

37. A method for detecting the presence of SIRPA in a sample or a sample obtained from an individual, the method comprising the anti-SIRPA antibody according to any one of claims 1 to 3, 9 to 12 or 16.

38. The method according to claim 37, further comprising quantification of the antigen-binding anti-SIRPA antibody.

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