Methods and compositions for the treatment of myeloproliferative neoplasms

Abstract

Provided herein are methods and compositions useful for treating myeloproliferative neoplasms (MPNs). Provided herein are methods and compositions relating to the use of antibodies or binding fragments thereof to treat myeloproliferative neoplasms (MPNs) by targeting conformational isoforms of cell surface receptor CD110 and thereby targeting diseased cells bearing such conformational isoforms for destruction.

Description

WSGR Docket No.: 68804-705.601METHODS AND COMPOSITIONS FOR THE TREATMENT OF MYELOPROLIFERATIVE NEOPLASMSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 718,331, filed on November 08, 2024, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Myeloproliferative neoplasms (MPNs) are a group of blood disorders which can result in excessive bone marrow production of cells of the myeloid lineage. In some cases, this is due to somatic mutations in bone marrow HSPCs. Among MPNs, three subcategories are associated with mutations in Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia protein (MPL) also known as thrombopoietin receptor or CD110: primary myelofibrosis (PMF), essential thrombocytopenia (ET), and polycythemia vera (PV). The current treatment for PMF includes allogeneic stem cell transplant yet most patients are ineligible due to their progressed state of bone marrow disease. All other treatments to-date offer supportive care to alleviate symptoms but do not eradicate disease.SUMMARY

[0003] Recognized herein is a need for improved therapies for MPNs. The methods and compositions described herein that target CD110 can result in sufficient depletion of diseaseinducing cells to improve the course of disease. Provided herein are methods and compositions relating to the use of antibodies to treat myeloproliferative neoplasms (MPNs) by targeting conformational isoforms of a cell surface receptor and thereby targeting diseased cells bearing such conformational isoforms for destruction. The methods and compositions of the disclosure can be useful, for example, in targeting transformed hematopoietic stem and progenitor cells (HSCs) and more differentiated cells descendant from transformed HSPCs, such as megakaryocytes (MKs), for therapeutic treatment of MPNs such as primary myelofibrosis (PMF), essential thrombocytopenia (ET), and polycythemia vera (PV).

[0004] Provided herein is a method for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, the method comprising: administering a pharmaceutical composition comprising a therapeutic agent targeting CD110 and a pharmaceutically acceptable carrier into the subject, wherein the therapeutic agent preferentially binds to a diseased cell in the subject over a healthy cell. In some embodiments, the diseased cell has a constitutively activated CD110 / JAK2 signaling pathway. In some embodiments, the disease cell comprises a conformational isoform of CD110. In some embodiments, wherein the diseased cellWSGR Docket No.: 68804-705.601 comprises an active CD110 conformation. In some embodiments, the active CD 110 conformation comprises a CD110 dimer. In some embodiments, wherein the therapeutic agent targeting CD110 binds to a membrane proximal domain of CD 110. In some embodiments, wherein the diseased cell is selected from the group consisting of a stem cell, progenitor cell, a blast cell, and a CD110-W515L+ cell. In some embodiments, wherein the therapeutic agent targeting CD110 preferentially binds to an active CD110 conformation compared to an inactive CD110 conformation. In some embodiments, wherein the therapeutic agent targeting CD 110 binds to an active CD110 conformation with a binding affinity that is at least 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 50-fold, 100-fold or more than a binding affinity of the therapeutic agent to the inactive CD110 conformation. In some embodiments, the therapeutic agent targeting CD110 is an antibody or antigen-binding fragment thereof.

[0005] Also provided herein is a method for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, the method comprising: administering a pharmaceutical composition comprising a therapeutic agent targeting CD110 and a pharmaceutically acceptable carrier into the subject, wherein: (i) the subject has not undergone a prior conditioning regimen; (ii) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen does not comprise using a therapeutic agent targeting CD 110; (iii) the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof or (iv) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen comprises using another therapeutic agent targeting CD 110. In some embodiments, the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD110 for treating MPN. In some embodiments, the MPN is associated with a constitutively activated CD110 / JAK2 signaling pathway. In some embodiments, the CD110 is a human CD110. In some embodiments, the MPN is associated with a mutation in a gene or a protein encoded by the gene. In some embodiments, wherein the gene is selected from the group consisting of Janus kinase 2 (JAK2), calreticulin (CALR), CD 110, thrombopoietin (TPO), and any combination thereof. In some embodiments, the gene is JAK2. In some embodiments, a JAK2 protein encoded by the gene comprises one or more point mutations relative to the wild type amino acid sequence set forth in SEQ ID NO: 207. In some embodiments, the one or more point mutations are selected from the group consisting ofWSGR Docket No.: 68804-705.601G335D, F556V, G571S, V617F, V625S, and any combination thereof. In some embodiments, the JAK2 gene comprises a mutation in exon 12. In some embodiments, the gene is CALR, and wherein the CALR gene or a CALR protein encoded by the CALR gene comprises a mutation that results in incorrect trafficking of the CALR protein. In some embodiments, the CALR gene comprises a mutation in exon 9. In some embodiments, the gene comprises a frameshift mutation relative to the wild type CALR gene. In some embodiments, the frameshift mutation is a CALRdel52 or CALRins5 mutation. In some embodiments, the gene is CD 110, and wherein a CD110 protein encoded by the gene comprises one or more point mutations relative to the wild type amino acid sequence set forth in SEQ ID NO: 208, and wherein the one or more point mutations are selected from the group consisting T119I, S204F, S204P, P222S, E230G, Y252H, V285E, R321W, S505N, W515L, W515K, W515A, W515R, Y591D, Y591N, R592Q, and any combination thereof. In some embodiments, the CD110 gene comprises a mutation in exon 10. In some embodiments, the MPN is selected from the group consisting of primary myelofibrosis, essential thrombocytopenia, polycythemia vera, and any combination thereof. In some embodiments, the therapeutic agent is conjugated to a toxin. In some embodiments, the toxin is selected from the group consisting of saporins, saporin derivatives, ricin, abrin, gelonin, momordin, apitoxin, shiga toxins, shiga-like toxins, T-2 mycotoxin, diphtheria toxin, busulfan, pseudomonas exotoxin A, Ricin A chain derivatives, trichosanthin, luffin toxin, maytansine, amatoxin, mechlorethamine, cyclophosphamide, ethylenimine, methylmelamine, methotrexate, fluorouracil, floxuridine, cytarabine, mercaptopurine, azathioprine, thioguanine, fludarabine phosphate, cladribine, and any combination thereof.

[0006] In some embodiments, the method further comprises administering an additional therapeutic agent into the subject prior to, concurrently with, or subsequent to administering the pharmaceutical composition. In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent. In some embodiments, the additional therapeutic agent is a small molecule inhibitor, or an antibody or antigen-binding fragment thereof. In some embodiments, the additional therapeutic agent is an inhibitor of a therapeutic target associated with MPN disease progression. In some embodiments, the therapeutic target is selected from the group consisting of CALR, JAK2, PPM1D, HDM2, MDM2, XPO1, LSD1, BET and any combination thereof and any combination thereof. In some embodiments, the therapeutic target is JAK2, and wherein the inhibitor is an inhibitor ofWSGR Docket No.: 68804-705.601JAK2. In some embodiments, the inhibitor of JAK2 is selected from the group consisting of ruxolitinib, fedratinib, pacritinib, momelotinib, and any combination thereof. In some embodiments, the therapeutic target is PPM1D, and wherein the inhibitor is an inhibitor of PPM1D. In some embodiments, the inhibitor of PPM1D is selected from the group consisting of GSK2830371, BRD4761, BRD5049, BRD6257. In some embodiments, the therapeutic target is HDM2, and wherein the inhibitor is an inhibitor of HDM2. In some embodiments, the inhibitor of HDM2 is selected from the group consisting of NVP-CGM097, an HLI98 family molecule, MK-8242, and MK-4688. In some embodiments, the therapeutic target is MDM2, and wherein the inhibitor is an inhibitor of MDM2. In some embodiments, the inhibitor of MDM2 is navtemadin. In some embodiments, the therapeutic target is XP01, and wherein the inhibitor is an inhibitor of XP01. In some embodiments, the inhibitor of XP01 is selinexor. In some embodiments, the therapeutic target is LSD1, and wherein the inhibitor is an inhibitor of LSD 1. In some embodiments, the inhibitor of LSD 1 is bodemstat. In some embodiments, the therapeutic target is BET, and wherein the inhibitor is an inhibitor of BET. In some embodiments, the inhibitor of BET is pelabresib. In some embodiments, the therapeutic target is CALR or and wherein the additional therapeutic agent is an antibody or antigen-binding fragment thereof targeting CALR, a CALR variant. In some embodiments, the additional therapeutic agent targets a cell surface antigen expressed by a hematopoietic stem cell or a megakaryocyte. In some embodiments, the cell surface antigen is selected from the group consisting of CD150, CD34, CD38, CD43, CD48, CD117, CD27, CD41, CD61, CD135 (FLT3), CD184 (CXCR4), CD123 (IL3R), CD49d, CD29, VLA-4, CD45, CD33, CD 127 and any combination thereof. In some embodiments, the therapeutic agent targeting CD110 acts synergistically or additively with the additional therapeutic agent. In some embodiments, the therapeutic agent targeting CD110 binds to a membrane proximal domain of CDUO.

[0007] In some embodiments, the therapeutic agent targeting CD110 preferentially binds to an active CD110 conformation compared to an inactive CD110 conformation. In some embodiments, the therapeutic agent targeting CD110 binds to an active CD110 conformation with a binding affinity that is at least 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5- fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 50-fold, 100-fold or more than a binding affinity of the therapeutic agent to the inactive CD110 conformation. In some embodiments,, the therapeutic agent targeting CD110 binds to an active CD110 conformation and does notWSGR Docket No.: 68804-705.601 bind to an inactive CD110 conformation. In some embodiments, the active CD110 conformation comprises a CD110 dimer. In some embodiments, the therapeutic agent targeting CD110 binds to a dimer interface of the CD110 dimer. In some embodiments, the CD110 dimer is dissociated when bound by the therapeutic agent targeting CD 110. In some embodiments, the inactive CD110 conformation comprises or consists of a CD110 monomer. In some embodiments, the therapeutic agent targeting CD110 binds to an active CD110 conformation with a dissociation constant (Kd) of at most about 100 nM, at most about 50 nM, at most about 20 nM, at most about 10 nM or less. In some embodiments, a Kd of the therapeutic agent targeting CD110 to an active CD 110 conformation is lower than a Kd of the therapeutic agent targeting CD110 to an inactive CD110 conformation. In some embodiments, the therapeutic agent targeting CD110 is an antibody or antigen-binding fragment thereof. In some embodiments, the therapeutic agent targeting CD110 is selected from the group consisting of an antibody, an Fv fragment, an Fab fragment, an F(ab’)2 fragment, an Fab’ fragment, an scFv (sFV) fragment, an Fd (N-terminal part of the heavy chain) fragment, an Fv fragment (two variable domains), a diabody (Dbs), a dAb fragment, a single domain fragment or single monomeric variable antibody domain, a single-chain diabody (scDbs), an isolated complementary determining region (CDR), and a nanobody. In some embodiments, the therapeutic agent targeting CD110 is conjugated to a nucleic acid. In some embodiments, the nucleic acid regulates expression of a target gene. In some embodiments, the nucleic acid regulates expression of a target gene. In some embodiments, the nucleic acid is selected from the group consisting of an miRNA, an siRNA, an activating RNA, and an antisense oligonucleotide. In some embodiments, the therapeutic agent targeting CD110 is a multi-specific antibody. In some embodiments, the multi-specific antibody is a CrossMab. In some embodiments, the multi-specific antibody is a bi-specific or tri-specific antibody. In some embodiments, the multi-specific antibody comprises an additional binding domain that binds a subunit of a TCR / CD3 complex, an NK cell receptor, a CALR-CD110 complex, a JAK2-CD110 complex, a CALR-CD110-JAK2 complex or any combination thereof. In some embodiments, the therapeutic agent targeting CD110 is an antagonist, a nonagonist, or an agonist. In some embodiments, the therapeutic agent targeting CD 110 is a naked antibody. In some embodiments, the therapeutic agent targeting CD110 is an antibodydrug conjugate. In some embodiments, the therapeutic agent targeting CD110 comprises an Fc domain. In some embodiments, the Fc domain activates an Fc-dependent effector process.WSGR Docket No.: 68804-705.601In some embodiments, the Fc-dependent effector process is selected from the group consisting of antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity. In some embodiments, the Fc-dependent effector process is ADCC.

[0008] In some embodiments, the subject exhibits a reduction in leukocytosis, a reduction in granulocytosis, a reduction in erythrocytopenia, a reduction in extramedullary hematopoiesis, a reduction in deposition of reticulin in a bone marrow tissue, a reduction in blast cells, a reduction in severity of a symptom of MPN, a reduction in lymphocytosis, a reduction in splenomegaly, a reduction in hepatomegaly, an increase in survival, or any combination thereof. In some embodiments, the subject exhibits a reduction in leukocytosis by at least 5%, 10%, 20%, 40%, 60%, 80%, or 100% compared to leukocytosis in the subject prior to receiving the pharmaceutical composition. In some embodiments, the subject exhibits a reduction in granulocytosis by at least 5%, 10%, 20%, 40%, 60%, 80%, or 100% compared to granulocytosis in the subject prior to receiving the pharmaceutical composition. In some embodiments, the subject exhibits a reduction in erythrocytopenia by at least 5%, 10%, 20%, 40%, 60%, 80%, or 100% compared to erythrocytopenia in the subject prior to receiving the pharmaceutical composition. In some embodiments, the subject exhibits a reduction in extramedullary hematopoiesis by at least 5%, 10%, 20%, 40%, 60%, 80%, or 100% compared to extramedullary hematopoiesis in the subject prior to receiving the pharmaceutical composition. In some embodiments, the subject exhibits a reduction in deposition of reticulin in a bone marrow tissue of the subject by at least 5%, 10%, 20%, 40%, 60%, 80%, or 100% compared to deposition of reticulin in a bone marrow tissue of the subject prior to receiving the pharmaceutical composition. In some embodiments, the subject exhibits a reduction in blast cells by at least 5%, 10%, 20%, 40%, 60%, 80%, or 100% compared to a level of blast cells in the subject prior to receiving the pharmaceutical composition. In some embodiments, the blast cells are CD110-W515L+ cells. In some embodiments, the subject exhibits a reduction in severity of a symptom of MPN for at least 1 day, 2 days, 3 days, 4 days, 5 days, one week, two weeks, three weeks, four weeks, six weeks, eight weeks, 10 weeks, 12 weeks, or more. In some embodiments, the subject exhibits a reduction in lymphocytosis by at least 5%, 10%, 20%, 40%, 60%, 80%, or 100% compared to a level of lymphocytosis in the subject prior to receiving the pharmaceutical composition. In some embodiments, the subject exhibits a reduction in splenomegaly by at least 5%, 10%,WSGR Docket No.: 68804-705.60120%, 40%, 60%, 80%, or 100% compared to the subject prior to receiving the pharmaceutical composition. In some embodiments, the subject exhibits a reduction in hepatomegaly by at least 5%, 10%, 20%, 40%, 60%, 80%, or 100% compared to the subject prior to receiving the pharmaceutical composition. In some embodiments, the reduction persists for at least 1 day, 2 days, 3 days, 4 days, 5 days, one week, two weeks, three weeks, four weeks, six weeks, eight weeks, 10 weeks, 12 weeks, or more following administration of the pharmaceutical composition. In some embodiments, the subject exhibits an increase in survival for at least 1 day, 2 days, 3 days, 4 days, 5 days, one week, two weeks, three weeks, four weeks, six weeks, eight weeks, 10 weeks, 12 weeks, or more compared to an otherwise identical subject not receiving the pharmaceutical composition. In some embodiments, the method further comprises performing an additional therapy, prior to, concurrently with, or subsequent to administering the pharmaceutical composition. In some embodiments, the additional therapy comprises performing a bone marrow transplant.

[0009] In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 4. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 3. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 2. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 10. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 9. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 8. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 1. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 7. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 14. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 13. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 12. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a lightWSGR Docket No.: 68804-705.601 chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 20. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 19. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 18. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 11. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 17. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 24. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 23. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 22. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 29. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 28. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 21. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 27. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 34. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 33. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 39. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 31. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 36. In some embodiments, the antibody comprises a heavyWSGR Docket No.: 68804-705.601 chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 42. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 41. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 40. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 43. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 47. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 46. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 45. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 136. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 42. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 41. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 30. In someWSGR Docket No.: 68804-705.601 embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 48. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 43. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 51. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 41. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 50. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 49. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 43. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 56. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 55. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 53. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 58. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarityWSGR Docket No.: 68804-705.601 determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 61. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 60. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 59. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 93. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 44. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 56. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 55. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 65. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 58. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 56. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 68. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 67. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 71. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In someWSGR Docket No.: 68804-705.601 embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 66. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 70. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 56. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 26. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 25. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 72. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 43. In some embodiments,, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 74. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 46. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 50. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 73. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 43. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 51. In some embodiments, the VH comprises a HCDR2WSGR Docket No.: 68804-705.601 comprising a sequence set forth in SEQ ID NO: 76. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 79. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 75. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 78. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 83. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 82. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 81. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 87. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 80. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 86. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 61. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 90. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 89. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 93. In some embodiments, the VH comprises a sequenceWSGR Docket No.: 68804-705.601 with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 88. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 92. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 51. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 76. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 79. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 96. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 94. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 95. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 51. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 98. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 97. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 99. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 103. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 102. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth inWSGR Docket No.: 68804-705.601SEQ ID NO: 101. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 109. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 108. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 107. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 100. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 106. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 111. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 41. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 115. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 114. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 113. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 110. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 112. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 119. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 118. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 117. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 124. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 123. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 122. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 116. In some embodiments, theWSGR Docket No.: 68804-705.601VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 121. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 51. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 76. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 79. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 125. In some embodiments, VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 127. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 51. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 76. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 79. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 128. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 129. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 51. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 76. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a lightWSGR Docket No.: 68804-705.601 chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 79. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 130. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 129. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 51. In some embodiments, the VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 76. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 79. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 131. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 132. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 51. In some embodiments, VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 76. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 79. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 133. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to theWSGR Docket No.: 68804-705.601 sequence set forth in SEQ ID NO: 134. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 215. In some embodiments, VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 214. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 213. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 222. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 221. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 220. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 212. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 219. In some embodiments, the antibody comprises a heavy chain variable region (VH) and wherein the VH comprises a heavy chain complementarity determining region 3 (HCDR3) comprising a sequence set forth in SEQ ID NO: 234. In some embodiments, VH comprises a HCDR2 comprising a sequence set forth in SEQ ID NO: 233. In some embodiments, the VH comprises a HCDR1 comprising a sequence set forth in SEQ ID NO: 232. In some embodiments, the antibody comprises a light chain variable region (VL) and wherein the VL comprises a light chain complementarity determining region 3 (LCDR3) comprising a sequence set forth in SEQ ID NO: 241. In some embodiments, the VL comprises a LCDR2 comprising a sequence set forth in SEQ ID NO: 240. In some embodiments, the VL comprises a LCDR1 comprising a sequence set forth in SEQ ID NO: 239. In some embodiments, the VH comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 231. In some embodiments, the VL comprises a sequence with at least 80% sequence identity to the sequence set forth in SEQ ID NO: 238. In some embodiments, the antibody comprises a heavy chain variable region (VH) comprising a complementarity determining region 3 (HCDR3), wherein the HCDR3 has an amino acid sequence set forth in any one of SEQ ID NOs: 4, 14, 24, 34, 42, 47, 51, 56, 61, 74, 83, 103, 111, 119, 215, and 237. In some embodiments, the VH further comprises a complementarity determining region 2 (HCDR2), wherein the HCDR2 has an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, 13, 16, 23, 26, 33, 35, 41, 46, 55, 60, 63, 68, 76, 82, 85, 90, 91,WSGR Docket No.: 68804-705.60198, 102, 105, 118, 120, 214, and 233. In some embodiments, the VH further comprises a complementarity determining region 1 (HCDR1), wherein the HCDR1 has an amino acid sequence set forth in any one of SEQ ID NOs: 2, 5, 12, 15, 22, 25, 32, 50, 52, 54, 57, 59, 62, 67, 69, 77, 81, 84, 89, 101, 104, 117, 126, 135, 213, and 232. In some embodiments, the VH comprises a sequence having at least 80% sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 1, 11, 21, 31, 40, 44, 45, 48, 49, 53, 65, 66, 72, 73, 75, 80, 88, 94, 97, 100, 110, 116, 125, 128, 130, 131, 133, 212, and 231. In some embodiments, the antibody further comprises a light chain variable region (VL) comprising a light chain complementarity determining region 3 (LCDR3), wherein the LCDR3 has an amino acid sequence set forth in any one of SEQ ID NOs: 10, 20, 30, 39, 71, 79, 109, 115, 124, 222, and 241. In some embodiments, the VL further comprises a LCDR2, wherein the LCDR2 has an amino acid sequence set forth in any one of SEQ ID NOs: 9, 19, 29, 38, 108, 114, 123, 221, and 240. In some embodiments, the VL further comprises a LCDR1, wherein the LCDR1 has an amino acid sequence set forth in any one of SEQ ID NOs: 8, 18, 28, 37, 87, 93, 96, 107, 113, 122, 220, and 239. In some embodiments, the VL comprises a sequence having at least 80% sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 7, 17, 27, 36, 43, 58, 64, 70, 78, 86, 92, 95, 99, 106, 112, 121, 127, 129, 132, 134, 136, 219, and 238.

[0010] Also provided herein is use of a therapeutic agent targeting CD110 for the treatment of a myeloproliferative neoplasm (MPN) in a subject in need thereof, wherein the therapeutic agent is the therapeutic agent of any one of the preceding embodiments, wherein the therapeutic agent preferentially binds to a diseased cell in the subject over a healthy cell.

[0011] Also provided herein is use of a therapeutic agent targeting CD110 for the treatment of a myeloproliferative neoplasm (MPN) in a subject in need thereof, wherein the therapeutic agent is the therapeutic agent of any one of the preceding embodiments, wherein (i) the subject has not undergone a prior conditioning regimen; (ii) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen does not comprise using a therapeutic agent targeting CD 110; (iii) the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof; or (iv) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen comprises using anotherWSGR Docket No.: 68804-705.601 therapeutic agent targeting CD 110. In some embodiments, the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD110 for treating MPN.

[0012] Also provided herein is use of a therapeutic agent targeting CD110 in the manufacture of a medicament for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, wherein the therapeutic agent is the therapeutic agent of any one of the preceding embodiments, wherein the therapeutic agent preferentially binds to a diseased cell in the subject over a healthy cell.

[0013] Also provided herein is use of a therapeutic agent targeting CD110 in the manufacture of a medicament for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, wherein the therapeutic agent is the therapeutic agent of any one of the preceding embodiments, wherein (i) the subject has not undergone a prior conditioning regimen; (ii) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen does not comprise using a therapeutic agent targeting CD110; (iii) the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof; or (iv) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen comprises using another therapeutic agent targeting CD 110. In some embodiments, the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD 110 for treating MPN.

[0014] Also provided herein is a therapeutic agent for use in treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, wherein the therapeutic agent is the therapeutic agent targeting CD110 of any one of the preceding embodiments, wherein the therapeutic agent preferentially binds to a diseased cell in the subject over a healthy cell.

[0015] Also provided herein is a therapeutic agent for use in treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, wherein the therapeutic agent is the therapeutic agent targeting CD110 of any one of the preceding embodiments, wherein (i) the subject has not undergone a prior conditioning regimen; (ii) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen does not comprise using a therapeutic agent targeting CD 110; (iii) the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof; or (iv) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen comprises using anotherWSGR Docket No.: 68804-705.601 therapeutic agent targeting CD 110. In some embodiments, the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD110 for treating MPN.

[0016] Also provided herein is a method for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, the method comprising: (a) providing a subject having an MPN associated with a mutation in a gene, wherein the gene is selected from the group consisting of Janus kinase 2 (JAK2), calreticulin (CALR), CD 110, thrombopoietin (TPO), and any combination thereof; and (b) administering a pharmaceutical composition comprising means for binding to CD110 and a pharmaceutically acceptable carrier into the subject. In some embodiments, (i) the subject has not undergone a prior conditioning regimen; (ii) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen does not comprise using means for binding to CD110; (iii) the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof; or (iv) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen comprises using another therapeutic agent targeting CD 110. In some embodiments, the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD110 for treating MPN.

[0017] Also provided herein is a method for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, the method comprising: (a) providing a subject having an MPN associated with a mutation in a gene, wherein the gene is selected from the group consisting of Janus kinase 2 (JAK2), calreticulin (CALR), CD 110, thrombopoietin (TPO), and any combination thereof; and (b) administering a pharmaceutical composition comprising means for the combination of (A) binding to CD110 and (B) blocking CDllO-mediated signaling, and a pharmaceutically acceptable carrier into the subject. In some embodiments, wherein: (i) the subject has not undergone a prior conditioning regimen; (ii) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen does not comprise using means for binding to CD 110; (iii) the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof or (iv) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen comprises using another therapeutic agent targeting CD 110. In some embodiments, the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD110 for treating MPN.WSGR Docket No.: 68804-705.601

[0018] Also provided herein is a method for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, the method comprising: (a) providing a subject having a MPN associated with a mutation in a gene, wherein the gene is selected from the group consisting of Janus kinase 2 (JAK2), calreticulin (CALR), CD 110, thrombopoietin (TPO), and any combination thereof; and (b) administering a pharmaceutical composition comprising means for preferential binding to an activated CD110 conformation and a pharmaceutically acceptable carrier into the subject. In some embodiments, (i) the subject has not undergone a prior conditioning regimen; (ii) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen does not comprise using means for binding to CD110;(iii) the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof, or(iv) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen comprises using another therapeutic agent targeting CD 110. In some embodiments, the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD110 for treating MPN.INCORPORATION BY REFERENCE

[0019] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The novel features of the disclosure are set forth with particularity in the appended claims. Abetter understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0021] FIGs. 1A-1C depict the murine model of PMF in which hallmarks of human disease develop in the absence of therapeutic intervention. FIG. 1A demonstratesWSGR Docket No.: 68804-705.601 hepatosplenomegaly. FIG. IB depicts lymphocytosis. FIG. 1C depicts bone marrow reticulin fibrosis.

[0022] FIG. 2 depicts the survival of diseased animals in response to various anti-human CD110 antibodies, including isotype control (think black line), 921 (thick black line), and 1125 (grey dashed line).

[0023] FIGs. 3A-3E depict the responses of diseased animals to various treatments, including isotype control (thin black line), ruxolitinib (thin dashed black line), antibody 921 (thick black line) or 921 + ruxolitinib (thick dashed black line). Initiation of treatment is indicated on X axis as dO and extended for 14 days, after which treatments ceased. FIG. 3A depicts animal survival. FIG. 3B depicts peripheral white blood cell count. FIG. 3C depicts liver mass. FIG. 3D depicts spleen mass. FIG. 3E depicts blast burden, represented by GFP+ cells.

[0024] FIGs. 4A-4B depict histology of bone marrow sections stained with H&E and for reticulin. Arrowheads highlight examples of reticulin fibers. FIG. 4A depicts sections obtained from diseased animals at cessation of treatment (day 15) with isotype control, ruxolitinib, antibody 921, or antibody 921 + ruxolitinib, as indicated. FIG. 4B depicts sections obtained from diseased animals treated with antibody 921 or antibody 921 + ruxolitinib, 12 days after cessation of indicated treatment (day 27).

[0025] FIG. 5 depicts the rapid sera clearance of antibody 921 from diseased animals (n=3). Each line represents data from one animal.

[0026] FIGs. 6A-6B demonstrate that antibody 921 is capable of inducing cell killing in vitro. FIG. 6A depicts dose-dependent antibody-dependent cellular cytotoxicity (ADCC) observed in response to 921 and not to isotype control. FIG. 6B depicts Dose-dependent antibody-dependent cellular phagocytosis (ADCP) observed in response to 921 and not to isotype control.

[0027] FIGs. 7A-7C depict the response of diseased animals to various treatments, including isotype control (thin black line), antibody 921 (thick black line) or effector-null 921-N297A (thick grey line). Initiation of treatment is indicated on X axis as dO and extended for 14 days, after which treatments ceased. FIG. 7A depicts animal survival. FIG. 7B depicts blast burden, represented by GFP+ cells. FIG. 7C depicts peripheral white blood cell counts.

[0028] FIGs. 8A-8B demonstrate that the ability of anti-CDUO antibodies to antagonize TPO-induced CD110 signaling. FIG. 8A demonstrates that TPO (black dots) agonizes CD110WSGR Docket No.: 68804-705.601 while none of the indicated antibodies agonize CD 110. FIG. 8B demonstrates that antibody 921 (thick black line) antagonizes signaling induced by TPO treatment of the reporter cells. Istotype control (dotted grey line) does not antagonize CD 110.

[0029] FIG. 9 depicts the loss of binding of anti -human CD110 antibody 921 to CD 110 chimeras when the membrane-proximal D4 domain of human CD110 is replaced by that of murine D4.DETAILED DESCRIPTIONDefinitions

[0030] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear, however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, the use of the term “including”, as well as other forms, such as “includes” and “included”, is not limiting.

[0031] Generally, nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those well- known and commonly used in the art. The methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. Enzymatic reactions and purification techniques are performed according to manufacturer’s specifications, as commonly accomplished in the art or as described herein. The nomenclatures used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.WSGR Docket No.: 68804-705.601

[0032] As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise.

[0033] The terms “about” and “approximately” indicate and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates a range within 20%, within 15%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2%, within 1%, or less of a given value or range. In certain embodiments, the term “about” indicates the designated value ± one standard deviation of that value.

[0034] The term “combinations thereof’ includes every possible combination of elements to which the term refers to.

[0035] The determination of “percent identity” between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be accomplished using a mathematical algorithm. A specific, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin S & Altschul SF (1990) PNAS 87: 2264-2268, modified as in Karlin S & Altschul SF (1993) PNAS 90: 5873-5877, each of which is herein incorporated by reference in its entirety. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul SF et al., (1990) J Mol Biol 215: 403, which is herein incorporated by reference in its entirety. BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecule described herein. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score 50, wordlength=3 to obtain amino acid sequences homologous to a protein molecule described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul SF et al., (1997) Nuc Acids Res 25: 3389-3402, which is herein incorporated by reference in its entirety. Alternatively, PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). Another specific, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4: 11-17, which is herein incorporated by reference in its entirety. Such an algorithm is incorporated in the ALIGNWSGR Docket No.: 68804-705.601 program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.

[0036] The terms “CD110,” “c-MPL” and “MPL” are used interchangeably herein. CD110 is also known by synonyms, including thrombopoietin receptor and myeloproliferative leukemia protein, among others. Unless specified otherwise, the terms include any variants, isoforms and species homologs of human CD110 that are naturally expressed by cells, or that are expressed by cells transfected with a c-MPL gene. CD110 proteins include, for example, human CD110 (NCBI Reference Sequence: NP_005364.1). c-MPL genes include, for example, Homo sapiens MPL proto-oncogene, thrombopoietin receptor (MPL), RefSeqGene (LRG 510) on chromosome 1 (NCBI Reference Sequence: NG 007525.1).

[0037] The term “immunoglobulin” refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In an “intact immunoglobulin,” all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch. 5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically comprises a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region typically comprises three domains, abbreviated CHI, CH2, and CH3. Each light chain typically comprises a light chain variable region (VL) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated CL.

[0038] The term “antibody” describes a type of immunoglobulin molecule and is used herein in its broadest sense. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), and antibody fragments. Antibodies can comprise at least one antigenbinding domain. One example of an antigen-binding domain is an antigen binding domain formed by a VH-VL dimer. An antibody as described herein may be monospecific, bi-specific, or multispecific. Multispecific antibodies may be specific for different epitopes of one target polypeptide or may contain antigen-binding domains specific for more than one target polypeptide. See, e.g., Tutt et al., (1991), J. Immunol. 147:60-69; Kufer et al., (2004), TrendsWSGR Docket No.: 68804-705.601Biotechnol. 22:238-244; and Brinkmann and Kontermann, (2017), MABS, 9(2): 182-212. The anti-CDUO antibodies described herein can be linked to or co-expressed with another functional molecule, e.g., another peptide or protein. For example, an antibody or fragment thereof can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment to produce a bi-specific or a multispecific antibody with a second binding specificity.

[0039] An “antibody fragment” comprises a portion of an intact antibody, such as the antigen binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab’)2 fragments, F(ab’) fragments, scFv (sFv) fragments, scFv- Fc fragments and nanobody fragments.

[0040] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0041] “Fab” fragments comprise, in addition to the heavy and light chain variable domains, the constant domain of the light chain and the first constant domain (CHI) of the heavy chain. Fab fragments may be generated, for example, by recombinant methods or by papain digestion of a full-length antibody.

[0042] “F(ab’)2” fragments contain two Fab’ fragments joined, near the hinge region, by disulfide bonds. F(ab’)2 fragments may be generated, for example, by recombinant methods or by pepsin digestion of an intact antibody. The F(ab’) fragments can be dissociated, for example, by treatment with P-mercaptoethanol.

[0043] “Single-chain Fv” or “sFv” or “scFv” antibody fragments comprise a VH domain and a VL domain in a single polypeptide chain. The VH and VL are generally linked by a peptide linker. See Pliickthun A. (1994).

[0044] “ scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminus of the scFv. The Fc domain may follow the VH or VL, depending on the orientation of the variable domains in the scFv (i.e., VHVL or VLVH). Any suitable Fc domain known in the art or described herein may be used. In some cases, the Fc domain comprises an IgGl Fc domain.

[0045] “Nanobody” fragments comprise only the variable domain of the heavy chain and lack a light chain and heavy chain constant domain. In some cases, the nanobody can be conjugated to other nanobodies and / or proteins to make a multispecific protein.WSGR Docket No.: 68804-705.601

[0046] Antibodies described herein may also comprise additional antibody variants, such as diabodies, diabody-Fc, single-chain diabodies, tandem diabodies (Tandab's), tandem scFv, tandem scFv-scFc, tandem di-scFvs, tandem tri-scFvs, “multivalent antibodies” (e.g., trivalent or tetravalent antibodies), bivalent or bispecific single chain variable fragments, including bispecific IgG and Fab-IgG bispecific. Bis-scFv or di-scFv variants can be engineered by linking two scFv molecules with a linker. Bispecific antibodies may comprise two scFv molecules having different binding specificities ((scFv)2). Ligation can be performed by creating a single peptide chain with two VH and two VL regions, resulting in a tandem scFv (see, eg, Kufer P. et al. (2004) Trends in Biotechnology 22(5):238-244). Diabodies can be generated with scFv molecules having linker peptides that are too short for the two variable regions to fold together (eg, about 5 amino acids), forcing the scFv to dimerize. See, eg, Hollinger, Philipp et al. (July 1993) Proceedings of the National Academy of Sciences of the United States of America 90(14): 6444-8). Successfully purified multitarget affinity agents can be screened using a variety of in vitro and in vivo methods. Binding assays with engineered cell lines overexpressing CD110 can be used to screen for a multitarget affinity agent that favorably bind to cells expressing CD 110. Cells can be incubated with multitarget affinity agents, followed by a fluorescently labelled secondary antibody. Flow cytometry can be used to detect the level of antibody binding to the engineered cells.

[0047] The term “monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s), except for variants that may normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts. A monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further altered, for example, to improve affinity for the target (“affinity maturation”), to humanize the antibody, to improve its production in cell culture, and / or to reduce its immunogenicity in a subject.WSGR Docket No.: 68804-705.601

[0048] The term “chimeric antibody” refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0049] “Humanized” forms of non-human antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. A humanized antibody is generally a human immunoglobulin (recipient antibody) in which residues from one or more CDRs are replaced by residues from one or more CDRs of a non-human antibody (donor antibody). The donor antibody can be any suitable non-human antibody, such as a mouse, rat, rabbit, chicken, or non-human primate antibody having a desired specificity, affinity, or biological effect. In some instances, selected framework region residues of the recipient antibody are replaced by the corresponding framework region residues from the donor antibody. Humanized antibodies may also comprise residues that are not found in either the recipient antibody or the donor antibody. Such modifications may be made to further refine antibody function. For further details, see Jones et al., Nature, 1986, 321 :522-525; Riechmann et al., Nature, 1988, 332:323-329; and Presta, Curr. Op. Struct. BioL, 1992, 2:593-596, each of which is incorporated by reference in its entirety.

[0050] A “human antibody” is one which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.

[0051] An “isolated antibody” is one that has been separated and / or recovered from a component of its natural environment. Components of the natural environment may include enzymes, hormones, and other proteinaceous or nonproteinaceous materials. In some embodiments, an isolated antibody is purified to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence, for example by use of a spinning cup sequenator. In some embodiments, an isolated antibody is purified to homogeneity by gel electrophoresis (e.g., SDS-PAGE) under reducing or nonreducing conditions, with detection by Coomassie blue or silver stain. An isolated antibody includes an antibody in situ within recombinant cells, since at least one component of the antibody’s natural environment is not present. In some aspects, an isolated antibody is prepared by at least one purification step.WSGR Docket No.: 68804-705.601

[0052] In some embodiments, an isolated antibody is purified to at least 80%, 85%, 90%, 95%, or 99% by weight. In some embodiments, an isolated antibody is purified to at least 80%, 85%, 90%, 95%, or 99% by volume. In some embodiments, an isolated antibody is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% by weight. In some embodiments, an isolated antibody is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% by volume.

[0053] “Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity, which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Affinity can be determined, for example, using surface plasmon resonance (SPR) technology, such as a Biacore® instrument. In some embodiments, the affinity is determined at 25°C.

[0054] With regard to the binding of an antibody to a target molecule, the terms “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule. Specific binding can also be determined by competition with a control molecule that mimics the antibody binding site on the target. In that case, specific binding is indicated if the binding of the antibody to the target is competitively inhibited by the control molecule. In some embodiments, “selectively binds” refers to the ability of a selective binding compound, for example an antibody or an antigen binding fragment thereof, to bind to a target protein, such as, for example, CD 110, with greater affinity than it binds to a non-target protein. In certain embodiments, specific binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, 1000 or more times greater than the affinity for a nontarget.

[0055] As used herein, to “functionally disrupt” or a “functional disruption” of signaling between a stem cell surface receptor (e.g., CD110) and its cognate ligand (e.g. thrombopoietin) means that the interaction between the receptor and ligand is decreased suchWSGR Docket No.: 68804-705.601 that the normal biological activity (e.g., hematopoietic stem cell proliferation) otherwise resulting from their interaction is attenuated. In some embodiments, the normal biological activity is eliminated. In some embodiments, functional disruption is effected by an antibody or antigen-binding fragment thereof that binds to the receptor or the ligand and blocks or dampens binding of the ligand to the receptor, and / or antagonizes the function of the ligand or the receptor such that normal signaling between the ligand and receptor cannot be achieved. In other embodiments, the functional disruption is achieved by a mechanism other than direct binding or direct inhibition of the receptor or the ligand. For example, the functional disruption may be achieved by binding and / or inhibiting a cofactor, upstream signaling molecule, or downstream signaling molecule to the receptor or ligand which may, for example, be required for effective signaling between the ligand and receptor. In some embodiments, functional reduction means that binding or signaling between the receptor and its cognate ligand is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% relative to the signaling between the receptor and ligand under physiological conditions. Any method known in the art useful for assessing biological activity resulting from signaling between the receptor and its cognate ligand can be used to assess the functional disruption, including but not limited to, cellular proliferation assays and receptor competition assays. In other embodiments of the methods provided herein, binding of a target protein by antibody or antigen-binding fragment thereof does not functionally disrupt signaling, but instead facilitates immune-mediated depletion of such antibody-bound cells, for example, through ADCC, ADCP, or CDC.

[0056] As used herein, the terms “subject”, “individual” or “patient” refer, interchangeably, to a warm-blooded animal such as a mammal. In particular embodiments, the term refers to a human. A subject may have, be suspected of having, or be predisposed to, a disease or disorder (e.g., a hemoglobinopathy) for which receiving an HSCT may be beneficial. The term also includes livestock, pet animals, or animals kept for study, including horses, cows, sheep, poultry, pigs, cats, dogs, zoo animals, goats, primates (e.g., cynomolgus macaques, or rhesus macaques), and rodents (e.g., mice and rats). A “subject in need thereof’ refers to a subject that has one or more symptoms of, that has received a diagnosis, or that is suspectedWSGR Docket No.: 68804-705.601 of having or being predisposed to a disease or condition which may be treated with, and / or may potentially benefit from HSCT as described herein.

[0057] The term “administering” as used herein refers to a method of giving a dosage of a composition (e.g., an antibody and / or cell therapy composition) to a subject. The method of administration can vary depending on various factors (e.g., the pharmaceutical composition being administered, and the severity of the condition, disease, or disorder being treated).

[0058] The term “treating” or “treatment” refers to any one of the following: ameliorating one or more symptoms of a disease or condition; preventing the manifestation of such symptoms before they occur; slowing down or completely preventing the progression of the disease or condition (as may be evident by longer periods between reoccurrence episodes, slowing down or prevention of the deterioration of symptoms, etc.); enhancing the onset of a remission period; slowing down the irreversible damage caused in the progressive-chronic stage of the disease or condition (both in the primary and secondary stages); delaying the onset of said progressive stage; or any combination thereof.

[0059] An “effective amount” refers to an amount of a compound or composition, as disclosed herein effective to achieve a particular biological, therapeutic, or prophylactic result. Such results include, without limitation, the depletion of hematopoietic stem cells, the engraftment of exogenous hematopoietic stem cells, and the treatment of a disease or condition disclosed herein as determined by any means suitable in the art.

[0060] The term “agonist” refers to a molecule (e.g., an antibody or binding fragment thereof) that, when binding to a target receptor, can induce or increase the biological activity of the target receptor.

[0061] The term “antagonist” refers to a molecule (e.g., an antibody or binding fragment thereof) that, when binding to a target receptor, can reduce or abolish the biological activity of the target receptor. In some embodiments, the antagonist is a “non-competitive antagonist”, which refers to a molecule that binds to a site on the target receptor that is not bound by a natural ligand of the target receptor. In some embodiments, the antagonist is a “competitive antagonist”, which refers to a molecule that binds to a site that is bound by a natural ligand of the target receptor.

[0062] With regard to the binding of an antibody or binding fragment thereof to a target molecule, the terms “preferential binding” or “preferentially binds” describe an antibody or antigen binding fragment thereof that (i) binds to the target molecule with a greater affinityWSGR Docket No.: 68804-705.601 than it binds to a non-target molecule or a different target molecule, or (ii) binds to one conformation of the target molecule with a greater affinity than it binds to another conformation of the target molecule. In some cases, preferential binding refers to selective binding and these two terms can be used interchangeably. In some embodiments, the antibody or antigen binding fragment thereof binds an activated conformation of the target molecule with a greater affinity than it binds to an inactive conformation of the target molecule. In some embodiments, the antibody or antigen binding fragment thereof binds an activated conformation of the target molecule with a binding affinity that is at least 1.1-fold, at least 1.5-fold, at least 2-fold, at least 2.5-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 1,000-fold, at least 10,000-fold or more, higher than it binds to an inactive conformation of the target molecule.Overview

[0063] CD110 can play an important role in maintenance of HSPC quiescence as well as regulating megakaryocytopoiesis and platelet formation in response to its ligand, thrombopoietin (TPO). Upon TPO binding, CD110 can dimerize, which may result in the phosphorylation and activation of JAK2, already physically associated with CD110. This can, in turn, activate signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase (MAPK) signaling pathways, promoting cell growth and differentiation. CALR can be resident in the endoplasmic reticulum (ER) and can act as a molecular chaperone enabling glycoprotein folding.

[0064] In some MPN cases, JAK2 bears a constitutively activating mutation (V617F) that results in STAT and MAPK pathway activation, and cell growth leading to excessive production of blood cells such as platelets, MKs, and / or red blood cells (RBCs); other mutations in JAK2 can be activating. Other commonly detected mutations in MPNs are in CALR, and can result in incorrect trafficking of CALR with CD 110, and in so doing, constitutively activates CD 110. Activating mutations including, but not limited to, W515L / K / A / R, S505N, Y252H in CD110 can also contribute to MPNs. Thus, somatic mutations in MPN can converge on constitutive activation of the CD110 / JAK2 signaling pathway in the absence of TPO. Both mutant CALR and mutant CD110 can activate via CD110 dimerization, and JAK2 activation (whether by phosphorylation or mutation) may induce “inside-out” dimerization of CD110. Thus, CD110 dimers present a conformationalWSGR Docket No.: 68804-705.601 isoform that can be therapeutically targeted for identification and elimination of cells bearing somatic mutations inducing MPN disease, including blasts.

[0065] Lifelong production of hematopoietic cells in an individual can depend on a rare population of hematopoietic stem cells (HSCs) that are capable of cell renewal. Among other cells of the hematopoietic lineage, HSCs and HSPCs can give rise to megakaryocytes, platelets, and red blood cells, all cell types implicated in the MPNs described above. Extramedullary hematopoiesis is one hallmark of PMF, which may result in splenomegaly and hepatomegaly. Other hallmarks include reticulin fibrosis of the bone marrow, which can be initiated by diseased megakaryocytes. Additional signs and symptoms of PMF can include, but are not limited to, atypical megakaryocytes, granulocyte proliferation, decreased erythropoiesis, anemia, leukocytosis, fever, night sweats, bone pain, and fatigue. In some cases, PMF can transform into acute myeloid leukemia.

[0066] In some cases, an allogeneic stem cell transplant can cure PMF, yet most patients are ineligible due to their progressed state of bone marrow disease. All other treatments to-date can offer supportive care to alleviate symptoms but do not eradicate disease. JAK2 inhibitors such as ruxolitinib, fedratinib, pacritinib, and momelotinib can improve symptoms of PMF by reducing spleen volume but have minimal impact on disease progression, including BM fibrosis and long-term survival. Thus, there is a need for therapeutics that can dampen or eliminate disease-inducing hematopoietic blasts and megakaryocytes. While not intending to be bound by any particular theory, the embodiments described herein, by targeting CD 110, can result in sufficient depletion of disease-inducing cells to improve the course of disease, survival, extramedullary hematopoiesis, and bone marrow fibrosis.

[0067] Provided herein are methods and compositions relating to the use of antibodies to treat myeloproliferative neoplasms (MPNs) by targeting conformational isoforms of a cell surface receptor and thereby targeting diseased cells bearing such conformational isoforms for destruction. Accordingly, in one aspect, provided herein is a method by which antibodies recognize and bind activated CD 110 conformations whether so-induced by mutations in CD 110, CALR, or JAK2, and may not recognize or bind monomeric CD110 conformations or recognize / bind the monomeric CD110 conformations with less binding affinity than its binding affinity to the activated CD110 conformation. Such antibodies can bind activated CD110 dimers at the dimer interface. Such antibodies can bind activated dimers outside the dimer interface. Such antibodies can target cells bearing activated CD110 conformations forWSGR Docket No.: 68804-705.601 destruction, whether as a naked antibody, an effector-enhanced antibody, an antibody-drug conjugate, an antibody-oligonucleotide conjugate, a bi- or tri-specific immune cell engager, a bi-, tri- or multi-specific antibody. In another aspect, such antibodies can accelerate CD110 internalization and destruction of CD 110, CALR-CD110, CD110-JAK2, and / or CALR- CD110- JAK2 complexes.

[0068] Accordingly, in another aspect, provided herein is a method by which antibodies recognize and bind activated CD 110 conformations whether so-induced by mutations in CD 110, CALR, or JAK2, and in so doing, disturb the conformation such that signaling is disrupted. Such antibodies can remain bound to the new conformation. Such antibodies can impair maintenance of dimers.

[0069] For example, the methods provided herein can comprise administering a pharmaceutical composition comprising a therapeutic agent targeting CD110 and a pharmaceutically acceptable carrier into a subject. For another example, the methods provided herein can comprise administering a pharmaceutical composition comprising means for binding to CD110 and a pharmaceutically acceptable carrier into a subject. In some embodiments, the methods provided herein can comprise administering a pharmaceutical composition comprising means for binding to CD110. In some embodiments, the methods provided herein can comprise administering a pharmaceutical composition comprising means for blocking CDllO-mediated signaling. In some embodiments, the methods provided herein can comprise administering a pharmaceutical composition comprising means for inducing cell killing via an antibody -mediated effector function. In some embodiments, the methods provided herein can comprise administering a pharmaceutical composition comprising means for inducing cell killing via antibody-mediated recruitment of immune cells (T cell, NK cell engager). For another example, the methods provided herein can comprise administering a pharmaceutical composition comprising means for the combination of (A) binding to CD110 and (B) blocking CDllO-mediated signaling, and a pharmaceutically acceptable carrier into a subject. For another example, the methods provided herein can comprise administering a pharmaceutical composition comprising means for preferential binding to an activated CD110 conformation and a pharmaceutically acceptable carrier into a subject.Methods of Treatment

[0070] Provided herein is a method of treating a myeloproliferative neoplasm (MPN) in a subject in need thereof. In some embodiments, the method comprising: administering aWSGR Docket No.: 68804-705.601 pharmaceutical composition comprising a therapeutic agent targeting CD110 and a pharmaceutically acceptable carrier into the subject. In some embodiments, the therapeutic agent preferentially binds to a diseased cell in the subject over a healthy cell. In some embodiments, the diseased cell has a constitutively activated CD110 / JAK2 signaling pathway. In some embodiments, the disease cell comprises a conformational isoform of CD 110. In some embodiments, the diseased cell comprises an active CD110 conformation. In some embodiments, the active CD110 conformation comprises a CD110 dimer. In some embodiments, the therapeutic agent targeting CD110 binds to a membrane proximal domain of CD110. In some embodiments, the diseased cell is selected from the group consisting of a stem cell, progenitor cell, a blast cell, and a CD110-W515L+ cell. In some embodiments, the diseased cell is selected from the group consisting of a stem cell, progenitor cell, a blast cell and a JAK2-V617F+ cell. In some embodiments, the diseased cell is selected from the group consisting of a stem cell, progenitor cell, a blast cell and a CALR-mutant cell. In some embodiments, the diseased cell is a stem cell. In some embodiments, the diseased cell is an HSC. In some embodiments, the diseased cell is a progenitor cell. In some embodiments, the diseased cell is a blast cell. In some embodiments, the diseased cell is a CD110-W515L+ cell. In some embodiments, the therapeutic agent targeting CD110 binds to an active CD110 conformation with a binding affinity that is at least 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 50-fold, 100-fold or more than a binding affinity of the therapeutic agent to the inactive CD110 conformation. In some embodiments, the therapeutic agent targeting CD110 is an antibody or antigen-binding fragment thereof.

[0071] In some embodiments the diseased cell is selected from the group consisting of a megakaryocyte progenitor cell, diseased megakaryocyte progenitor cell, and diseased megakaryocyte cell. In some embodiments, the diseased cell is a CD110-W515L cell. In some embodiments, the diseased cell is a JAK2-V617F+ cell. In some embodiments, the diseased cell is a CALR-mutant cell.

[0072] Provided herein is a method of treating a myeloproliferative neoplasm (MPN) in a subject in need thereof. In some embodiments, the method comprises administering a pharmaceutical composition comprising a therapeutic agent targeting CD110 and a pharmaceutically acceptable carrier into the subject. In some embodiments, the subject has not undergone a prior conditioning regimen. In some embodiments, the subject hasWSGR Docket No.: 68804-705.601 undergone a prior conditioning regimen and the prior conditioning regimen does not comprise using a therapeutic agent targeting CD110. In some embodiments, the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy. In some embodiments, the subject has undergone a prior conditioning regimen comprising immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy and irradiation. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising irradiation and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy, irradiation, and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen and the prior conditioning regimen comprises another therapeutic agent targeting CD 110. In some embodiments, the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD110 for treating MPN. In some embodiments, the subject may have undergone a prior conditioning regimen. In some embodiments, the subject may not have undergone a prior conditioning regimen. In some embodiments, the methods disclosed herein can be used to treat any patient with MPN.

[0073] In some embodiments, the MPN is associated with a constitutively activated CD110 / JAK2 signaling pathway. In some embodiments, the MPN is associated with a transiently activated CD110 / JAK2 signaling pathway. In some embodiments, the CD110 is a human CD 110. In some embodiments, the MPN is associated with a mutation in a gene or a protein encoded by the gene. In some embodiments, the MPN is associated with a mutation in a gene. In some embodiments, the MPN is associated with a mutation in a protein encoded by a gene. In some embodiments the protein comprises a sequence set forth in Table 1. In some embodiments, the MPN is associated with a gene encoding a protein comprising a sequence set forth in Table 1.Table 1. Wild Type Target Protein SequencesWSGR Docket No.: 68804-705.601WSGR Docket No.: 68804-705.601

[0074] In some embodiments, the gene is selected from the group consisting of Janus kinase 2 (JAK2), calreticulin (CALR), CD 110, thrombopoietin (TPO), and any combination thereof. In some embodiments, the gene is JAK2. In some embodiments, the gene is CALR. In some embodiments, the gene is CD110. In some embodiments, the gene is TPO. In some embodiments, the MPN is associated with a mutation in two or more genes or proteins encoded by the two or more genes. In some embodiments, the two or more genes comprise JAK2 and CALR. In some embodiments, the two or more genes comprise JAK2 and CD110. In some embodiments, the two or more genes comprise JAK2 and CALR. In some embodiments, the two or more genes comprise CALR and CD110. In some embodiments, the two or more genes comprise CALR and TPO. In some embodiments, the two or more genes comprise CD110 and TPO. In some embodiments, the two or more genes comprise JAK2, CALR, and CD110. In some embodiments, the two or more genes comprise JAK2, CALR, and TPO. In some embodiments, the two or more genes comprise JAK2, CD110, and TPO. InWSGR Docket No.: 68804-705.601 some embodiments, the two or more genes comprise CALR, CD110, and TPO. In some embodiments, the two or more genes comprise JAK2, CALR, CD110, and TPO.

[0075] In some embodiments, the gene is JAK2. In some embodiments, the protein encoded by the gene comprises one or more point mutations relative to the wild type amino acid sequence set forth in SEQ ID NO: 207. In some embodiments, the one or more point mutations are selected from the group consisting of G335D, F556V, G571S, V617F, V625S, and any combination thereof. In some embodiments, the one or more point mutations comprise G335D. In some embodiments, the one or more point mutations comprise F556V. In some embodiments, the one or more point mutations comprise G571S. In some embodiments, the one or more point mutations comprise V617F. In some embodiments, the one or more point mutations comprise V625S.

[0076] In some embodiments, the gene is CALR. In some embodiments, the CALR gene or a CALR protein encoded by the gene comprises a mutation that results in incorrect trafficking of the CALR protein. In some embodiments, the CALR gene comprises a mutation in exon 9. In some embodiments, the gene comprises a frameshift mutation relative to the wild type CALR gene. In some embodiments, the frameshift mutation is an indel mutation. In some embodiments, the frameshift mutation is a CALRdel52 mutation. In some embodiments, the frameshift mutation is a CALRins5 mutation.

[0077] In some embodiments, the gene is CD110. In some embodiments, a CD110 protein encoded by the gene comprises one or more point mutations relative to the wild type amino acid sequence set forth in SEQ ID NO: 208. In some embodiments, the gene comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more point mutations relative to the wild type amino acid sequence set forth in SEQ ID NO: 139. In some embodiments, the one or more point mutations are selected from the group consisting of T119I, S204F, S204P, P222S, E230G, Y252H, V285E, R321W, S505N, W515L, W515K, W515A, W515R, Y591D, Y591N, R592Q,and any combination thereof. In some embodiments, the one or more point mutations comprises W515L. In some embodiments, the one or more point mutations comprises W515K. In some embodiments, the one or more point mutations comprises W515A. In some embodiments, the one or more point mutations comprises W515R. In some embodiments, the one or more point mutations comprises S505N. In some embodiments, the one or more point mutations comprises Y252H. In some embodiments, the one or more point mutations comprises T119I. In some embodiments, the one or more point mutations comprises S204F. In someWSGR Docket No.: 68804-705.601 embodiments, the one or more point mutations comprises S204P. In some embodiments, the one or more point mutations comprises P222S. In some embodiments, the one or more point mutations comprises E230G. In some embodiments, the one or more point mutations comprises V285E. In some embodiments, the one or more point mutations comprises R321W. In some embodiments, the one or more point mutations comprises Y591D. In some embodiments, the one or more point mutations comprises Y591N. In some embodiments, the one or more point mutations comprises R592Q. In some embodiments, the CD110 gene comprises a mutation in exon 10.

[0078] In some embodiments, the MPN is selected from the group consisting of primary myelofibrosis, essential thrombocytopenia, polycythemia vera, and any combination thereof. In some embodiments, the MPN comprises primary myelofibrosis. In some embodiments, the MPN comprises essential thrombocytopenia. In some embodiments, the MPN comprises polycythemia vera. In some embodiments, the MPN comprises primary myelofibrosis and essential thrombocytopenia. In some embodiments, the MPN comprises primary myelofibrosis and polycythemia vera. In some embodiments, the MPN comprises essential thrombocytopenia and polycythemia vera. In some embodiments, the MPN comprises primary myelofibrosis, essential thrombocytopenia, and polycythemia vera.

[0079] In some embodiments, the therapeutic agent is conjugated to a toxin. In some embodiments, the toxin is selected from the group consisting of saporins, saporin derivatives, ricin, abrin, gelonin, momordin, apitoxin, shiga toxins, shiga-like toxins, T-2 mycotoxin, diphtheria toxin, busulfan, pseudomonas exotoxin A, Ricin A chain derivatives, trichosanthin, luffin toxin, maytansine, amatoxin, mechlorethamine, cyclophosphamide, ethylenimine, methylmelamine, methotrexate, fluorouracil, floxuridine, cytarabine, mercaptopurine, azathioprine, thioguanine, fludarabine phosphate, cladribine, and any combination thereof. In some embodiments, the toxin comprises saporins. In some embodiments, the toxin comprises saporin derivatives. In some embodiments, the toxin comprises ricin. In some embodiments, the toxin comprises abrin. In some embodiments, the toxin comprises gelonin. In some embodiments, the toxin comprises momordin. In some embodiments, the toxin comprises apitoxin. In some embodiments, the toxin comprises shiga toxins. In some embodiments, the toxin comprises shiga-like toxins. In some embodiments, the toxin comprises T-2 mycotoxin. In some embodiments, the toxin comprises diphtheria toxin. In some embodiments, the toxin comprises busulfan. In some embodiments, the toxin comprises pseudomonas exotoxin A. InWSGR Docket No.: 68804-705.601 some embodiments, the toxin comprises Ricin A chain derivatives. In some embodiments, the toxin comprises trichosanthin. In some embodiments, the toxin comprises luffin toxin. In some embodiments, the toxin comprises maytansine. In some embodiments, the toxin comprises amatoxin. In some embodiments, the toxin comprises mechlorethamine. In some embodiments, the toxin comprises cyclophosphamide. In some embodiments, the toxin comprises ethylenimine. In some embodiments, the toxin comprises methylmelamine. In some embodiments, the toxin comprises methotrexate. In some embodiments, the toxin comprises fluorouracil. In some embodiments, the toxin comprises floxuridine. In some embodiments, the toxin comprises cytarabine. In some embodiments, the toxin comprises mercaptopurine. In some embodiments, the toxin comprises azathioprine. In some embodiments, the toxin comprises thioguanine. In some embodiments, the toxin comprises fludarabine phosphate. In some embodiments, the toxin comprises cladribine.

[0080] In some embodiments, the method further comprises administering an additional therapeutic agent into the subject prior to, concurrently, or subsequent to administering the pharmaceutical composition. In some embodiments, the method further comprises administering an additional therapeutic agent into the subject prior to administering the pharmaceutical composition. In some embodiments, the method further comprises administering an additional therapeutic agent into the subject concurrently with administering the pharmaceutical composition. In some embodiments, the method further comprises administering an additional therapeutic agent into the subject subsequent to administering the pharmaceutical composition.

[0081] In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent. In some embodiments, the additional therapeutic agent is a small molecule inhibitor, or an antibody or antigen-binding fragment thereof. In some embodiments, the additional therapeutic is a small molecule inhibitor. In some embodiments, the additional therapeutic agent is an antibody or antigen-binding fragment thereof. In some embodiments, the additional therapeutic agent is an inhibitor of a therapeutic target associated with MPN disease progression. In some embodiments, the therapeutic target is selected from the group consisting of CALR, JAK2, PPM1D, HDM2, MDM2, BET, LSD1, XPO1, and any combination thereof. In some embodiments, the therapeutic target comprises CALR. In some embodiments, the therapeutic target comprises JAK2. In some embodiments, the therapeutic target comprises PPM1D. In some embodiments, the therapeutic target comprises HDM2. InWSGR Docket No.: 68804-705.601 some embodiments, the therapeutic target comprises MDM2. In some embodiments, the therapeutic target comprises BET. In some embodiments, the therapeutic target comprises LSD1. In some embodiments, the therapeutic target comprises BET.

[0082] In some embodiments, the therapeutic target is JAK2 and the inhibitor is an inhibitor of JAK2. In some embodiments, the inhibitor of JAK2 is selected from the group consisting of ruxolitinib, fedratinib, pacritinib, momelotinib, and any combination thereof. In some embodiments, the inhibitor of JAK2 comprises ruxolitinib. In some embodiments, the inhibitor of JAK2 comprises fedratinib. In some embodiments, the inhibitor of JAK2 comprises pacritinib. In some embodiments, the inhibitor of JAK2 comprises momelotinib.

[0083] In some embodiments, the therapeutic agent targeting CD110 and the additional therapeutic agent (or the pharmaceutical composition comprising both) exhibit a synergistic or additive effect when compared to either the therapeutic agent targeting CD110 alone or the additional therapeutic agent alone. In some embodiments, the additional therapeutic agent is ruxolitinib.

[0084] In some embodiments, the synergistic or additive effect is an increase in survival of a subject. In some embodiments, the synergistic or additive effect is a reduction in a level of blast cells by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to a subject administered the therapeutic agent targeting CD110 or additional therapeutic agent alone. In some embodiments, the blast cells are CD110-W515L+ cells. In some embodiments, the synergistic or additive effect is an increase in survival of blast cells by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to a subject administered the therapeutic agent targeting CD110 or additional therapeutic agent alone. In some embodiments, the synergistic or additive effect is an increase in survival by at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, one week, two weeks, three weeks, one month, two months, four months, six months, one year, five years, or more compared to a subject administered the therapeutic agent targeting CD110 or additional therapeutic agent alone. In some embodiments, the synergistic or additive effect is an decrease in splenomegaly by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to a subject administered the therapeutic agent targeting CD110 or additional therapeutic agent alone. InWSGR Docket No.: 68804-705.601 some embodiments, the synergistic or additive effect is an decrease in hepatomegaly by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to a subject administered the therapeutic agent targeting CD110 or additional therapeutic agent alone. In some embodiments, the synergistic or additive effect is an decrease in deposition of reticulin by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to a subject administered the therapeutic agent targeting CD110 or additional therapeutic agent alone. In some embodiments, the synergistic or additive effect is a reduction in severity of a symptom of MPN for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, one week, two weeks, three weeks, four weeks, six weeks, eight weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, or more compared to a subject administered the therapeutic agent targeting CD110 or additional therapeutic agent alone.

[0085] In some embodiments the therapeutic target is PPM1D and the inhibitor is an inhibitor of PPM1D. In some embodiments, PPM1D comprises a sequence of SEQ ID NO: 211. In some embodiments, the inhibitor of PPM1D is selected from the group consisting of GSK2830371, BRD4761, BRD5049, BRD6257. In some embodiments, the inhibitor of PPM1D comprises GSK2830371. In some embodiments, the inhibitor of PPM1D comprises BRD4761. In some embodiments, the inhibitor of PPM1D comprises BRD5049. In some embodiments, the inhibitor of PPM1D comprises BRD6257.

[0086] In some embodiments, the therapeutic target is HDM2 and the inhibitor is an inhibitor of HDM2. In some embodiments, HDM2 comprises a sequence of SEQ ID NO: 210. In some embodiments, the inhibitor of HDM2 is selected from the group consisting of NVP-CGM097, an HLI98 family molecule, MK-8242, and MK-4688. In some embodiments, the inhibitor of HDM2 comprises NVP-CGM097. In some embodiments, the inhibitor of HDM2 comprises an HLI98 family molecule. In some embodiments, the inhibitor of HDM2 comprises MK- 8242. In some embodiments, the inhibitor of HDM2 comprises MK-4688.

[0087] In some embodiments, the therapeutic target is CALR and the additional therapeutic agent is an antibody or antigen binding fragment thereof targeting CALR. In some embodiments, the therapeutic target is CALR and the additional therapeutic agent is an antibody or antigen binding fragment thereof targeting a CALR variant.WSGR Docket No.: 68804-705.601

[0088] In some embodiments, the therapeutic target is MDM2 and the additional therapeutic agent is an inhibitor of MDM2. In some embodiments, the additional therapeutic agent is navtemadin.

[0089] In some embodiments, the therapeutic target is XPO1 and the additional therapeutic agent is an inhibitor of XPO1. In some embodiments, the inhibitor of XPO1 is selinexor.

[0090] In some embodiments, the therapeutic target is LSD1 and the additional therapeutic agent is an inhibitor of LSD1. In some embodiments, the inhibitor of LSD1 is bodemstat.

[0091] In some embodiments, the therapeutic target is BET and the additional therapeutic agent is an inhibitor of BET. In some embodiments, the inhibitor of BET is pelabresib.

[0092] In some embodiments, the additional therapeutic agent targets a cell surface antigen expressed by a hematopoietic stem cell. In some embodiments, the additional therapeutic agent targets a cell surface antigen expressed by a megakaryocyte. In some embodiments, the cell surface antigen is selected from the group consisting of CD150, CD34, CD38, CD43, CD48, CD117, CD27, CD41, CD61, CD135 (FLT3), CD184 (CXCR4), CD123 (IL3R), CD49d, CD29, VLA-4, CD45, CD33, CD127 and any combination thereof. In some embodiments, the cell surface antigen comprises CD 150. In some embodiments, the cell surface antigen comprises CD34. In some embodiments, the cell surface antigen comprises CD38. In some embodiments, the cell surface antigen comprises CD43. In some embodiments, the cell surface antigen comprises CD48. In some embodiments, the cell surface antigen comprises CD 117. In some embodiments, the cell surface antigen comprises CD27. In some embodiments, the cell surface antigen comprises CD41. In some embodiments, the cell surface antigen comprises CD61. In some embodiments, the cell surface antigen comprises CD135 (FLT3). In some embodiments, the cell surface antigen comprises CD 184 (CXCR4). In some embodiments, the cell surface antigen comprises CD123 (IL3R). In some embodiments, the cell surface antigen comprises CD49d. In some embodiments, the cell surface antigen comprises CD29. In some embodiments, the cell surface antigen comprises VLA-4. In some embodiments, the cell surface antigen comprises CD45. In some embodiments, the cell surface antigen comprises CD33. In some embodiments, the cell surface antigen comprises CD127.

[0093] In some embodiments, the therapeutic agent targeting CD110 acts synergistically or additively with the additional therapeutic agent. In some embodiments, the therapeutic agent targeting CD110 acts synergistically with the additional therapeutic agent. In someWSGR Docket No.: 68804-705.601 embodiments, the therapeutic agent targeting CD110 acts additively with the additional therapeutic agent.

[0094] In some embodiments, the therapeutic agent targeting CD110 binds to the extracellular domain of CD 110. In some embodiment, the therapeutic agent targeting CD110 binds to a membrane proximal domain of CD110.

[0095] In some embodiments, the therapeutic agent targeting CD 110 preferentially binds to an active CD110 conformation compared to an inactive CD110 conformation. In some embodiments, the therapeutic agent targeting CD110 binds to an active CD110 conformation with a binding affinity that is at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, 70-fold, 75-fold, 80-fold, 85- fold, 90-fold, 95-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1000-fold or more than a binding affinity of the therapeutic agent to the inactive CD110 conformation.

[0096] In some embodiments, the therapeutic agent targeting CD110 binds to an active CD110 conformation and does not bind to an inactive CD110 conformation. In some embodiments, the active CD110 conformation comprises a CD110 dimer. In some embodiments, the therapeutic agent targeting CD110 binds to a dimer interface of the CD110 dimer. In some embodiments, the CD 110 dimer is dissociated when bound by the therapeutic agent targeting CD 110. In some embodiments, the inactive CD110 conformation comprises or consists of a CD110 monomer. In some embodiments, the inactive CD110 conformation comprises a CD110 monomer. In some embodiments, the inactive CD110 conformation consists of a CD110 monomer.

[0097] In some embodiments, the therapeutic agent targeting CD110 binds to an active CD110 conformation with a dissociation constant (Kd) of at most about 1000 nM, at most about 500 nM, at most about 100 nM, at most about 50 nM, at most about 40 nM, at most about 30 nM, at most about 20 nM, at most about 10 nM, at most about 5 nM, at most about 1 nM, at most about 0.5 nM, at most about 0.1 nM, at most about 0.05 nM, at most about 0.01 nM or less. In some embodiments, wherein a Kd of the therapeutic agent targeting CD110 to an active CD110 conformation is lower than a Kd of the therapeutic agent targeting CD110 to an inactive CD110 conformation. In some embodiments, the Kd of the therapeutic agent targeting CD110 to an active CD110 conformation is 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold,WSGR Docket No.: 68804-705.6011.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, 70-fold, 75- fold, 80-fold, 85-fold, 90-fold, 95-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600- fold, 700-fold, 800-fold, 900-fold, or 1000-fold lower than a Kd of the therapeutic agent targeting CD110 to an inactive CD110 conformation.

[0098] In some embodiments, the therapeutic agent targeting CD 110 is an antibody or antigen binding fragment thereof. In some embodiments, the antibody. In some embodiments, the therapeutic agent targeting CD110 is selected from the group consisting of an antibody, an Fv fragment, an Fab fragment, an F(ab’)2 fragment, an Fab’ fragment, an scFv (sFV) fragment, an Fd (N-terminal part of the heavy chain) fragment, an Fv fragment (two variable domains), a diabody (Dbs), a dAb fragment, a single domain fragment or single monomeric variable antibody domain, a single-chain diabody (scDbs), an isolated complementary determining region (CDR), and a nanobody. In some embodiments, the therapeutic agent targeting CD110 is an Fv fragment. In some embodiments, the therapeutic agent targeting CD110 is an Fab fragment. In some embodiments, the therapeutic agent targeting CD110 is an F(ab’)2 fragment. In some embodiments, the therapeutic agent targeting CD110 is an Fab’ fragment. In some embodiments, the therapeutic agent targeting CD 110 is an scFv (sFV) fragment. In some embodiments, the therapeutic agent targeting CD110 is an Fd (N-terminal part of the heavy chain) fragment. In some embodiments, the therapeutic agent targeting CD110 is an Fv fragment (two variable domains). In some embodiments, the therapeutic agent targeting CD110 is a diabody (Dbs). In some embodiments, the therapeutic agent targeting CD110 is a dAb fragment. In some embodiments, the therapeutic agent targeting CD110 is a single domain fragment or single monomeric variable antibody domain. In some embodiments, the therapeutic agent targeting CD110 is a single-chain diabody (scDbs). In some embodiments, the therapeutic agent targeting CD110 is an isolated complementary determining region (CDR). In some embodiments, the therapeutic agent targeting CD110 is a nanobody. The therapeutic agent targeting CD110 can be multispecific. For example, the therapeutic agent target CD110 can be a multispecific antibody or antigen binding fragment thereof. The therapeutic agent target CD110 can be a bispecific antibody or antigen binding fragment thereof. In some embodiments, the therapeutic agent targeting CD110 is conjugated to a nucleic acid. In some embodiments, the nucleic acid regulates expression of a target gene. In some embodiments, the target gene is selected from the group consisting of JAK2,WSGR Docket No.: 68804-705.601CD110, and CALR. In some embodiments, the target gene is JAK2. In some embodiments, the target gene is CD 110. In some embodiments, the target gene is CALR. In some embodiments, the nucleic acid is selected from the group consisting of an miRNA, an siRNA, an activating RNA, and an antisense oligonucleotide. In some embodiments, the nucleic acid is an miRNA. In some embodiments, the nucleic acid is an siRNA. In some embodiments, the nucleic acid is an activating RNA. In some embodiments, the nucleic acid is an antisense oligonucleotide.

[0099] In some embodiments, the therapeutic agent targeting CD110 is a multi-specific antibody. In some embodiments, the multi-specific antibody is a CrossMab. In some embodiments, the multi-specific antibody is a bi-specific antibody. In some embodiments, the multi-specific antibody is a tri-specific antibody. In some embodiments, the multi-specific antibody comprises an additional binding domain that binds a subunit of a TCR / CD3 complex, an NK cell receptor, a CALR-CD110 complex, a JAK2-CD110 complex, a CALR- CD110-JAK2 complex or any combination thereof. In some embodiments, the multi-specific antibody comprises an additional binding domain that binds a subunit of TCR / CD3 complex. In some embodiments, the multi-specific antibody comprises an additional binding domain that binds an NK cell receptor. In some embodiments, the multi-specific antibody comprises an additional binding domain that binds a CALR-CD110 complex. In some embodiments, the multi-specific antibody comprises an additional binding domain that binds a JAK2-CD110 complex. In some embodiments, the multi-specific antibody comprises an additional binding domain that binds a CALR-CD110-JAK2 complex.

[0100] In some embodiments, the therapeutic agent targeting CD110 is an antagonist, a nonagonist, or an agonist. In some embodiments, the therapeutic agent targeting CD110 is an antagonist. In some embodiments, the therapeutic agent targeting CD110 is a non-agonist. In some embodiments, the therapeutic agent targeting CD110 is an agonist. In some embodiments, the therapeutic agent targeting CD110 is a naked antibody. In some embodiments, the therapeutic agent targeting CD110 is an antibody-drug conjugate. In some embodiments, the therapeutic agent targeting CD110 comprises an Fc domain. In some embodiments, the Fc domain activates an Fc-dependent effector process. In some embodiments, the Fc-dependent effector process is selected from the group consisting of antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity. In some embodiments, the Fc-dependentWSGR Docket No.: 68804-705.601 effector process is ADCC. In some embodiments, the Fc-dependent effector process is ADCP. In some embodiments, the Fc-dependent effector process is complement-dependent cytotoxicity.

[0101] The administration of the therapeutic agent targeting CD110 in the subject can lead to beneficial therapeutic effects. In some embodiments, the subject exhibits a reduction in leukocytosis, a reduction in granulocytosis, a reduction in erythrocytopenia, a reduction in extramedullary hematopoiesis, a reduction in deposition of reticulin in a bone marrow tissue, a reduction in blast cells, a reduction in severity of a symptom of MPN, a reduction in lymphocytosis, a reduction in splenomegaly, a reduction in hepatomegaly, an increase in survival, or any combination thereof. For example, in some embodiments, the subject exhibits a reduction in leukocytosis. In some embodiments, the subject exhibits a reduction in leukocytosis by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to leukocytosis in the subject prior to receiving the pharmaceutical composition (e.g., containing the therapeutic agent targeting CD110 and / or an additional therapeutic agent).

[0102] In some embodiments, the subject exhibits a reduction in granulocytosis. In some embodiments, the subject exhibits a reduction in granulocytosis by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to granulocytosis in the subject prior to receiving the pharmaceutical composition. In some embodiments, the subject exhibits a reduction in granulocytosis by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to granulocytosis in an otherwise identical subject not receiving the pharmaceutical composition. In some embodiments, the reduction is at least 1.1-fold, 1.2- fold, 1.5-fold, 2-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold 100-fold or more.

[0103] In some embodiments, the subject exhibits a reduction in erythrocytopenia. In some embodiments, the subject exhibits a reduction in erythrocytopenia by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to erythrocytopenia in the subject prior to receiving the pharmaceutical composition. In some embodiments, the subject exhibits a reduction in erythrocytopenia by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%,WSGR Docket No.: 68804-705.60120%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to erythrocytopenia in an otherwise identical subject not receiving the pharmaceutical composition. In some embodiments, the reduction is at least 1.1-fold, 1.2- fold, 1.5-fold, 2-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold 100-fold or more.

[0104] In some embodiments, the subject exhibits a reduction in extramedullary hematopoiesis. In some embodiments, the subject exhibits a reduction in extramedullary hematopoiesis by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to extramedullary hematopoiesis in the subject prior to receiving the pharmaceutical composition. In some embodiments, the subject exhibits a reduction in extramedullary hematopoiesis by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to extramedullary hematopoiesis in an otherwise identical subject not receiving the pharmaceutical composition. In some embodiments, the reduction is at least 1.1-fold, 1.2-fold, 1.5-fold, 2-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold 100-fold or more.

[0105] In some embodiments, the subject exhibits a reduction in deposition of reticulin in a bone marrow tissue of the subject. In some embodiments, the subject exhibits a reduction in deposition of reticulin in a bone marrow tissue of the subject by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to deposition of reticulin in a bone marrow tissue of the subject prior to receiving the pharmaceutical composition. In some embodiments, the subject exhibits a reduction in deposition of reticulin in a bone marrow tissue of the subject by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to deposition of reticulin in a bone marrow tissue of an otherwise identical subject not receiving the pharmaceutical composition. In some embodiments, the reduction is at least 1.1-fold, 1.2-fold, 1.5-fold, 2-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold 100-fold or more. In some embodiments, the subject exhibits no further increase in deposition of reticulin in a bone marrow tissue of the subject upon receiving the pharmaceutical composition.

[0106] In some embodiments, the subject exhibits a reduction in blast cells. In some embodiments, the subject exhibits a reduction in blast cells by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,WSGR Docket No.: 68804-705.60175%, 80%, 85%, 90%, 95%, or 100% compared to a level of blast cells in the subject prior to receiving the pharmaceutical composition. In some embodiments, the subject exhibits a reduction in blast cells by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to a level of blast cells in an otherwise identical subject not receiving the pharmaceutical composition. In some embodiments, the reduction is at least 1.1-fold, 1.2- fold, 1.5-fold, 2-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold 100-fold or more. In some embodiments, the blast cells are CD110-W515L+ cells.

[0107] In some embodiments, the therapeutic agent increases the survival of the subject. In some embodiments, survival is increased by at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, one week, two weeks, three weeks, one month, six months, one year, five years, or more compared to an otherwise identical subject not receiving the pharmaceutical composition. In some embodiments, the reduction is at least 1.1-fold, 1.2-fold, 1.5-fold, 2- fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold 100-fold or more.

[0108] In some embodiments, the subject exhibits a reduction in severity of a symptom of MPN. In some embodiments, the subject exhibits a reduction in severity of a symptom of MPN for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, one week, two weeks, three weeks, four weeks, six weeks, eight weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, or more. In some embodiments, the reduction is at least 1.1-fold, 1.2-fold, 1.5-fold, 2-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50- fold 100-fold or more.

[0109] In some embodiments, the subject exhibits a reduction in a level of lymphocytosis. In some embodiments, the subject exhibits a reduction in lymphocytosis by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to a level of lymphocytosis of the subject prior to receiving the pharmaceutical composition. In some embodiments, the subject exhibits a reduction in a level of lymphopoiesis by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to a level of blast cells in an otherwise identical subject not receiving the pharmaceutical composition. In some embodiments, the reduction is at least 1.1-fold, 1.2-fold, 1.5-fold, 2-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold 100-fold or more.WSGR Docket No.: 68804-705.601

[0110] In some embodiments, the subject exhibits a reduction in hepatomegaly. In some embodiments, the subject exhibits a reduction in hepatomegaly by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to a level of hepatomegaly of the subject prior to receiving the pharmaceutical composition. In some embodiments, the subject exhibits a reduction in hepatomegaly by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to a level of hepatomegaly in an otherwise identical subject not receiving the pharmaceutical composition. In some embodiments, the reduction is at least 1.1-fold, 1.2- fold, 1.5-fold, 2-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold 100-fold or more.[OHl] In some embodiments, the subject exhibits a reduction in splenomegaly. In some embodiments, the subject exhibits a reduction in splenomegaly by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to a level of splenomegaly of the subject prior to receiving the pharmaceutical composition. In some embodiments, the subject exhibits a reduction in splenomegaly by at least 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to a level of splenomegaly in an otherwise identical subject not receiving the pharmaceutical composition. In some embodiments, the reduction is at least 1.1-fold, 1.2- fold, 1.5-fold, 2-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold 100-fold or more.

[0112] In some embodiments, the therapeutic agent prolongs suppression of lymphocytosis in the subject. For example, the therapeutic agent can prolong suppression of lymphocytosis for at least 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 20 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days or more post-treatment. In some embodiments, the reduction is at least 1.1-fold, 1.2-fold, 1.5-fold, 2-fold, 4-fold, 5-fold, 10- fold, 20-fold, 50-fold 100-fold or more.

[0113] In some embodiments, the method further comprises performing an additional therapy prior to, concurrently with, or subsequent to administering the pharmaceutical composition. In some embodiments, the method further comprises performing an additional therapy prior to administering the pharmaceutical composition. In some embodiments, the method further comprises performing an additional therapy concurrently with administering the pharmaceutical composition. In some embodiments, the method further comprisesWSGR Docket No.: 68804-705.601 performing an additional therapy subsequent to administering the pharmaceutical composition. In some embodiments, the additional therapy comprises performing a bone marrow transplant.

[0114] In some embodiments, the therapeutic agent targeting CD 110 is an antibody. In some embodiments, the antibody comprises one or more of the sequences provided in Tables 2-7. In some embodiments, the antibody comprises a heavy chain complementarity determining region 3 (HCDR3) comprising any one of the HCDR3 sequences provided in Tables 2-7. In some embodiments, the antibody comprises a HCDR2 comprising any one of the HCDR2 sequences provided in Tables 2-7. In some embodiments, the antibody comprises a HCDR1 comprising any one of the HCDR1 sequences provided in Tables 2-7. In some embodiments, the antibody comprises a light chain complementarity determining region 3 (LCDR3) comprising any one of the LCDR3 sequences provided in Tables 2-7. In some embodiments, the antibody comprises a LCDR2 comprising any one of the LCDR2 sequences provided in Tables 2-7. In some embodiments, the antibody comprises a LCDR1 comprising any one of the LCDR1 sequences provided in Tables 2-7. In some embodiments, CDR regions may be identified by any known CDR numbering system. In some embodiments, CDR regions may be identified by a Kabat numbering system. In some embodiments, CDR regions may be identified by a Chothia numbering system. In some embodiments, CDR regions may be identified by an IGMT numbering system.

[0115] In some embodiments, the therapeutic agent targeting CD110 is an antagonist antibody. In some embodiments, the antagonist antibody comprises one or more of the sequences set forth in Table 2.Table 2. Exemplary Anti-CDllO AntibodiesWSGR Docket No.: 68804-705.601WSGR Docket No.: 68804-705.601WSGR Docket No.: 68804-705.601WSGR Docket No.: 68804-705.601WSGR Docket No.: 68804-705.601WSGR Docket No.: 68804-705.601WSGR Docket No.: 68804-705.601WSGR Docket No.: 68804-705.601WSGR Docket No.: 68804-705.601WSGR Docket No.: 68804-705.601

[0116] In some embodiments, the therapeutic agent targeting CD110 comprises a thrombopoietin (TPO) mimetic peptide sequence. In some embodiments, these TPO mimetic peptides can be substituted for one or more complementarity determining regions 1-3 (CDRs 1-3) of an antibody light chain variable region and / or heavy chain variable region. Any antibody or fragment thereof could be used as a framework and have one or more CDRs 1-3 replaced with a peptide provided in Table 3. In some embodiments, the TPO mimetic peptide comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in any one of SEQ ID NOs: 137-152.Table 3. Exemplary TPO Mimetic Peptides

[0117] In some embodiments, the therapeutic agent targeting CD110 comprises an antibody. In some embodiments, the antibody comprises one or more CDR regions provided in Table 4. In some embodiments, the antibody comprises a heavy chain variable region comprising a HCDR1 sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in any one of SEQ ID NOs: 153, 159, 165, 170, or 173. In some embodiments, the antibody comprises a heavy chain variable region comprising a HCDR2 sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in any one of SEQ ID NOs: 154, 160, 166, 168, 171, or 174. In some embodiments, the antibody comprises a heavy chain variable region comprising a HCDR3 sequence with atWSGR Docket No.: 68804-705.601 least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or100% identity to the sequence set forth in any one of SEQ ID NOs: 155, 161, 167, 169, 172, or 175. In some embodiments, the antibody comprises a light chain variable region comprising a LCDR1 sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in any one of SEQ ID NOs: 156, 162, or 176. In some embodiments, the antibody comprises a light chain variable region comprising a LCDR2 sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in any one of SEQ ID NOs: 157, 163, or 177. In some embodiments, the antibody comprises a light chain variable region comprising a LCDR3 sequence with at least 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in any one of SEQ ID NOs: 158, 164, or 178.Table 4. Exemplary Anti-CDllO CDR SequencesWSGR Docket No.: 68804-705.601

[0118] In some embodiments, the therapeutic agent targeting CD110 comprises an antibody. In some embodiments, the antibody comprises one or more sequences provided in Table 5. In some embodiments, the antibody comprises a heavy chain variable region comprising a HCDR1 sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 180 or 183. In some embodiments, the antibody comprises a heavy chain variable region comprising a HCDR2 sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 181 or 184. In some embodiments, the antibody comprises a heavy chain variable region comprising a HCDR3 sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 182. In some embodiments, the antibody comprises a light chain variable region comprising a LCDR1 sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 186. In some embodiments, the antibody comprises a light chain variable region comprising a LCDR2 sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 187. In some embodiments, the antibody comprises a light chain variable region comprising a LCDR3 sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 188. In some embodiments, the antibody comprises a heavy chain variable region comprising a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 179. In some embodiments, the antibody comprises a light chain variable region comprising a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 185.Table 5. Exemplary Anti-CDllO AntibodyWSGR Docket No.: 68804-705.601

[0119] In some embodiments, the therapeutic agent targeting CD110 comprises an antibody. In some embodiments, the antibody comprises one or more sequences provided in Table 6. In some embodiments, the antibody comprises a heavy chain variable region comprising a HCDR1 sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in any one of SEQ ID NOs: 190, 192, 198, 54, 202, or 32. In some embodiments, the antibody comprises a heavy chain variable region comprising a HCDR2 sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in any one of SEQ ID NOs: 6, 193, 26, 199, 26, or 203. In some embodiments, the antibody comprises a heavy chain variable region comprising a HCDR3 sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in any one of SEQ ID NOs: 191, 191, or 24. In some embodiments, the antibody comprises a light chain variable region comprising a LCDR1 sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%,WSGR Docket No.: 68804-705.60198%, 99%, or 100% identity to the sequence set forth in any one of SEQ ID NOs: 195, 37, or 205. In some embodiments, the antibody comprises a light chain variable region comprising a LCDR2 sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 9 or 38. In some embodiments, the antibody comprises a light chain variable region comprising a LCDR3 sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 196 or 30. In some embodiments, the antibody comprises a heavy chain variable region comprising a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in any one of SEQ ID NOs: 189, 197, or 201. In some embodiments, the antibody comprises a light chain variable region comprising a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in any one of SEQ ID NOs: 194, 200 or 204.Table 6. Exemplary Anti-CDllO AntibodiesWSGR Docket No.: 68804-705.601

[0120] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 4. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 3. In some embodiments, the VH comprises aWSGR Docket No.: 68804-705.601HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 2. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 10. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 9. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 8. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 1. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 7.

[0121] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 14. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 13. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 12. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 20. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 19. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 18. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 11. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 17.

[0122] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO:WSGR Docket No.: 68804-705.60124. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 23. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 22. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 29. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 28. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 21. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 27.

[0123] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 34. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 33. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 39. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 31. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 36.WSGR Docket No.: 68804-705.601

[0124] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 42. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 41. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 40. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 43.

[0125] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 47. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 46. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 45. In some embodiments, the VL comprises a sequenceWSGR Docket No.: 68804-705.601 with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 136.

[0126] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 42. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 41. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 48. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 43.

[0127] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 51. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 41. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 50. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%,WSGR Docket No.: 68804-705.60165%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 49. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 43.

[0128] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 56. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 55. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 53. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 58.

[0129] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 61. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 60. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 59. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprisesWSGR Docket No.: 68804-705.601 an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 93. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 44. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 64.

[0130] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 56. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 55. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 65. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 58.

[0131] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 56. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 68. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 67. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO:WSGR Docket No.: 68804-705.60171. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 66. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 70.

[0132] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 56. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 26. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 25. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 72. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 43.

[0133] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 74. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 46. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 50. In some embodiments, the antibody comprises a light chain variable region (VL). In someWSGR Docket No.: 68804-705.601 embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 72. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 43.

[0134] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 74. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 46. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO:50. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 73. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 43.

[0135] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO:51. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 76. In some embodiments, the VH comprisesWSGR Docket No.: 68804-705.601 a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 79. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 75. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 78.

[0136] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 83. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 82. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 81. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 87. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 80. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 86.

[0137] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO:WSGR Docket No.: 68804-705.60161. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 90. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 89. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 93. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 88. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 92.

[0138] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 51. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 76. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 79. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 96. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 94. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 95.WSGR Docket No.: 68804-705.601

[0139] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 51. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 98. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 30. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 97. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 99.

[0140] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 103. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 102. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 101. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 109. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 108. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 107. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 100. In some embodiments, the VL comprises aWSGR Docket No.: 68804-705.601 sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 106.

[0141] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 111. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 41. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 115. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 114. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 113. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 110. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 112.

[0142] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 119. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 118. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 117. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 124. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 123. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 122. In some embodiments, the VH comprises a sequence with at least 50%,WSGR Docket No.: 68804-705.60155%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 116. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 121.

[0143] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 51. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 76. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 79. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 125. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 127.

[0144] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 51. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 76. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 79. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprisesWSGR Docket No.: 68804-705.601 an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 128. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 129.

[0145] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 51. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 76. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 79. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 130. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 129.

[0146] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 51. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 76. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO:WSGR Docket No.: 68804-705.60179. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 131. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 132.

[0147] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 51. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 76. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 54. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 79. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 38. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 37. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 133. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 134.

[0148] In some embodiments, the antibody comprises a heavy chain variable region (VH) comprising a complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 has an amino acid sequence set forth in any one of SEQ ID NOs: 4, 14, 24, 34, 42, 47, 51, 56, 61, 74, 83, 103, 111, 119, 215, and 237. In some embodiments, the HCDR3 has an amino acid sequence set forth in SEQ ID NO:4. In some embodiments, the HCDR3 has an amino acid sequence set forth in SEQ ID NO: 14. In some embodiments, the HCDR3 has an amino acid sequence set forth in SEQ ID NO: 24. In some embodiments, the HCDR3 has anWSGR Docket No.: 68804-705.601 amino acid sequence set forth in SEQ ID NO: 34. In some embodiments, the HCDR3 has an amino acid sequence set forth in SEQ ID NO: 42. In some embodiments, the HCDR3 has an amino acid sequence set forth in SEQ ID NO: 47. In some embodiments, the HCDR3 has an amino acid sequence set forth in SEQ ID NO: 51. In some embodiments, the HCDR3 has an amino acid sequence set forth in SEQ ID NO: 56. In some embodiments, the HCDR3 has an amino acid sequence set forth in SEQ ID NO: 61. In some embodiments, the HCDR3 has an amino acid sequence set forth in SEQ ID NO: 74. In some embodiments, the HCDR3 has an amino acid sequence set forth in SEQ ID NO: 83. In some embodiments, the HCDR3 has an amino acid sequence set forth in SEQ ID NO: 103. In some embodiments, the HCDR3 has an amino acid sequence set forth in SEQ ID NO: 111. In some embodiments, the HCDR3 has an amino acid sequence set forth in SEQ ID NO: 119. In some embodiments, the HCDR3 has an amino acid sequence set forth in SEQ ID NO: 215. In some embodiments, the HCDR3 has an amino acid sequence set forth in SEQ ID NO: 237.

[0149] In some embodiments, the VH further comprises a complementarity determining region 2 (HCDR2). In some embodiments, the HCDR2 has an amino acid sequence set forth in any one of SEQ ID NOs: 3, 6, 13, 16, 23, 26, 33, 35, 41, 46, 55, 60, 63, 68, 76, 82, 85, 90, 91, 98, 102, 105, 118, 120, 214, and 233. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 3. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 6. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 23. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 26. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 33. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 35. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 41. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 46. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 55. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 60. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 63. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 68. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 76. In some embodiments, the HCDR2 has an aminoWSGR Docket No.: 68804-705.601 acid sequence set forth in SEQ ID NO: 82. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 85. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 90. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 91. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 98. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 102. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 105. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 118. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 120. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 214. In some embodiments, the HCDR2 has an amino acid sequence set forth in SEQ ID NO: 233.

[0150] In some embodiments, the VH further comprises a complementarity determining region 1 (HCDR1). In some embodiments, the HCDR2 has an amino acid sequence set forth in any one of SEQ ID NOs: 2, 5, 12, 15, 22, 25, 32, 50, 52, 54, 57, 59, 62, 67, 69, 77, 81, 84, 89, 101, 104, 117, 126, 135, 213, and 232. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 2. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 5. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 15. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 22. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 50. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 52. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 54. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 57. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 59. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 62. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 67. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 69. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 77. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 81. In some embodiments, the HCDR1 has an aminoWSGR Docket No.: 68804-705.601 acid sequence set forth in SEQ ID NO: 84. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 89. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 101. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 104. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 117. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 126. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 135. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 213. In some embodiments, the HCDR1 has an amino acid sequence set forth in SEQ ID NO: 232.

[0151] In some embodiments the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in any one of SEQ ID NOs: 1, 11, 21, 31, 40, 44, 45, 48, 49, 53, 65, 66, 72, 73, 75, 80, 88, 94, 97, 100, 110, 116, 125, 128, 130, 131, 133, 212, and 231. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 1. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 31. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 40. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 44. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 45. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%,WSGR Docket No.: 68804-705.60199%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 48. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 49. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 53. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 65. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 66. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 72. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 73. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 75. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 80. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 88. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 94. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 97. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 100. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%,WSGR Docket No.: 68804-705.60175%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 110. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 116. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 125. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 128. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 130. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 131. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 133. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 212. In some embodiments, the VH comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 231.

[0152] In some embodiments, the antibody comprises a light chain variable region (VL) comprising a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 has an amino acid sequence set forth in any one of SEQ ID NOs: 10, 20, 30, 39, 71, 79, 109, 115, 124, 222, and 241. In some embodiments, the LCDR3 has an amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the LCDR3 has an amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the LCDR3 has an amino acid sequence set forth in SEQ ID NO: 30. In some embodiments, the LCDR3 has an amino acid sequence set forth in SEQ ID NO: 39. In some embodiments, the LCDR3 has an amino acid sequence set forth in SEQ ID NO: 71. In some embodiments, the LCDR3 has an amino acid sequence set forth in SEQ ID NO: 79. In some embodiments, the LCDR3 has anWSGR Docket No.: 68804-705.601 amino acid sequence set forth in SEQ ID NO: 109. In some embodiments, the LCDR3 has an amino acid sequence set forth in SEQ ID NO: 115. In some embodiments, the LCDR3 has an amino acid sequence set forth in SEQ ID NO: 124. In some embodiments, the LCDR3 has an amino acid sequence set forth in SEQ ID NO: 222. In some embodiments, the LCDR3 has an amino acid sequence set forth in SEQ ID NO: 241.

[0153] In some embodiments, the VL further comprise a LCDR2. In some embodiments, the LCDR2 has an amino acid sequence set forth in any one of SEQ ID NOs: 9, 19, 29, 38, 108, 114, 123, 221, and 240. In some embodiments, the LCDR2 has an amino acid sequence set forth in SEQ ID NO:9. In some embodiments, the LCDR2 has an amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the LCDR2 has an amino acid sequence set forth in SEQ ID NO: 29. In some embodiments, the LCDR2 has an amino acid sequence set forth in SEQ ID NO: 38. In some embodiments, the LCDR2 has an amino acid sequence set forth in SEQ ID NO: 108. In some embodiments, the LCDR2 has an amino acid sequence set forth in SEQ ID NO: 114. In some embodiments, the LCDR2 has an amino acid sequence set forth in SEQ ID NO: 123. In some embodiments, the LCDR2 has an amino acid sequence set forth in SEQ ID NO: 221. In some embodiments, the LCDR2 has an amino acid sequence set forth in SEQ ID NO: 240.

[0154] In some embodiments, the VL further comprise a LCDR1. In some embodiments, the LCDR1 has an amino acid sequence set forth in any one of SEQ ID NOs: 8, 18, 28, 37, 87, 93, 96, 107, 113, 122, 220 and 239. In some embodiments, the LCDR1 has an amino acid sequence set forth in SEQ ID NO:8. In some embodiments, the LCDR1 has an amino acid sequence set forth in SEQ ID NO: 18. In some embodiments, the LCDR1 has an amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the LCDR1 has an amino acid sequence set forth in SEQ ID NO: 37. In some embodiments, the LCDR1 has an amino acid sequence set forth in SEQ ID NO: 87. In some embodiments, the LCDR1 has an amino acid sequence set forth in SEQ ID NO: 93. In some embodiments, the LCDR1 has an amino acid sequence set forth in SEQ ID NO: 96. In some embodiments, the LCDR1 has an amino acid sequence set forth in SEQ ID NO: 107. In some embodiments, the LCDR1 has an amino acid sequence set forth in SEQ ID NO: 113. In some embodiments, the LCDR1 has an amino acid sequence set forth in SEQ ID NO: 122. In some embodiments, the LCDR1 has an amino acid sequence set forth in SEQ ID NO: 220. In some embodiments, the LCDR1 has an amino acid sequence set forth in SEQ ID NO: 239.WSGR Docket No.: 68804-705.601

[0155] In some embodiments the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in any one of SEQ ID NOs: 7, 17, 27, 36, 43, 58, 64, 70, 78, 86, 92, 95, 99, 106, 112, 121, 127, 129, 132, 134, 136, 219, and 238. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO:7. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 17. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 58. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 64. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 70. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 78. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 86. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 92. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%,WSGR Docket No.: 68804-705.60199%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 95. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 99. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 106. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 112. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 121. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 127. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 129. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 132. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 134. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 136. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 219. In some embodiments, the VL comprises a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence set forth in SEQ ID NO: 238.

[0156] In some embodiments, the therapeutic agent targeting CD110 comprises an antibody. In some embodiments, the antibody comprises one or more sequences provided in Table 7. In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3WSGR Docket No.: 68804-705.601(HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 215. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 214. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 213. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 222. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 221. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 220. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 212. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 219.

[0157] In some embodiments, the antibody comprises a heavy chain variable region (VH). In some embodiments, the VH comprises a heavy chain complementarity determining region 3 (HCDR3). In some embodiments, the HCDR3 comprises a sequence set forth in SEQ ID NO: 234. In some embodiments, the VH comprises an HCDR2. In some embodiments, the HCDR2 comprises a sequence set forth in SEQ ID NO: 233. In some embodiments, the VH comprises a HCDR1. In some embodiments, the HCDR1 comprises a sequence set forth in SEQ ID NO: 232. In some embodiments, the antibody comprises a light chain variable region (VL). In some embodiments, the VL comprises a light chain complementarity determining region 3 (LCDR3). In some embodiments, the LCDR3 comprises a sequence set forth in SEQ ID NO: 241. In some embodiments, the VL comprises an LCDR2. In some embodiments, the LCDR2 comprises a sequence set forth in SEQ ID NO: 240. In some embodiments, the VL comprises an LCDR1. In some embodiments, the LCDR1 comprises a sequence set forth in SEQ ID NO: 239. In some embodiments, the VH comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 231. In some embodiments, the VL comprises a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the sequence set forth in SEQ ID NO: 238.WSGR Docket No.: 68804-705.601

[0158] Also provided herein is use of a therapeutic agent targeting CD110 for the treatment of a myeloproliferative neoplasm (MPN) in a subject in need thereof. In some embodiments, the therapeutic agent is any one of the therapeutic agents disclosed herein. In some embodiments, the therapeutic agent preferentially binds to a diseased cell in the subject over a healthy cell

[0159] Also provided herein is use of a therapeutic agent targeting CD110 for the treatment of a myeloproliferative neoplasm (MPN) in a subject in need thereof. In some embodiments, the therapeutic agent is the therapeutic agent of any of the embodiments described herein. In some embodiments, the subject has not undergone a prior conditioning regimen. In some embodiments the subject has undergone a prior conditioning regimen that does not comprise using a therapeutic agent targeting CD 110. In some embodiments, the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy. In some embodiments, the subject has undergone a prior conditioning regimen comprising immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy and irradiation. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising irradiation and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy, irradiation, and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen and the prior conditioning regimen comprises another therapeutic agent targeting CD 110. In some embodiments, the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD110 for treating MPN.

[0160] Also provided herein is use of a therapeutic agent targeting CD110 in the manufacture of a medicament for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof. In some embodiments, the therapeutic agent is any one of the therapeutic agents disclosed herein. In some embodiments, the therapeutic agent preferentially binds to a diseased cell in the subject over a healthy cell.

[0161] Also provided herein is use of a therapeutic agent targeting CD110 in the manufacture of a medicament for treating a myeloproliferative neoplasm (MPN) in a subject in needWSGR Docket No.: 68804-705.601 thereof. In some embodiments, the therapeutic agent is the therapeutic agent of any of the embodiments described herein. In some embodiments, the subject has not undergone a prior conditioning regimen. In some embodiments the subject has undergone a prior conditioning regimen that does not comprise using a therapeutic agent targeting CD 110. In some embodiments, the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy. In some embodiments, the subject has undergone a prior conditioning regimen comprising immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy and irradiation. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising irradiation and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy, irradiation, and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen and the prior conditioning regimen comprises another therapeutic agent targeting CD 110. In some embodiments, the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD 110 for treating MPN.

[0162] Also provided herein is a therapeutic agent for use in treating a myeloproliferative neoplasm (MPN) in a subject in need thereof. In some embodiments, the therapeutic agent is the therapeutic agent targeting CD110 of any one therapeutic agent targeting CD110 disclosed herein. In some embodiments, the subject has not undergone a prior conditioning regimen. In some embodiments, the subject has undergone a prior conditioning regimen. In some embodiments, the prior conditioning regimen does not comprise using a therapeutic agent targeting CD 110. In some embodiments, the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof. In some embodiments, the subject has undergone a prior conditioning regimen and the prior conditioning regimen comprises another therapeutic agent targeting CD 110. In some embodiments, the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD 110 for treating MPN.WSGR Docket No.: 68804-705.601

[0163] Also provided herein is a therapeutic agent for use in treating a myeloproliferative neoplasm (MPN) in a subject in need thereof. In some embodiments, the therapeutic agent is any one of the therapeutic agents disclosed herein. In some embodiments, the therapeutic agent preferentially binds to a diseased cell in the subject over a healthy cell.

[0164] Also provided herein is therapeutic agent for use in treating a myeloproliferative neoplasm (MPN) in a subject in need thereof. In some embodiments, the therapeutic agent is any one of the therapeutic agents disclosed herein. In some embodiments, the subject has not undergone a prior conditioning regimen. In some embodiments, the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen does not comprise using a therapeutic agent targeting CD 110. In some embodiments, the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof. In some embodiments, the subject has undergone a prior conditioning regimen and the prior conditioning regimen comprises another therapeutic agent targeting CD 110. In some embodiments, the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD 110 for treating MPN.

[0165] Also provided herein is a method for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof. In some embodiments, the method comprises providing a subject having an MPN. In some embodiments, the MPN is associated with a mutation in a gene. In some embodiments, the gene is selected from the group consisting of Janus kinase 2 (JAK2), calreticulin (CALR), CD 110, thrombopoietin (TPO), and any combination thereof. In some embodiments, the gene is JAK2. In some embodiments, the gene is CALR. In some embodiments, the gene is CD110. In some embodiments, the gene is TPO. In some embodiments, the MPN is associated with a mutation in two or more genes or proteins encoded by the two or more genes. In some embodiments, the two or more genes comprise JAK2 and CALR. In some embodiments, the two or more genes comprise JAK2 and CD110. In some embodiments, the two or more genes comprise JAK2 and TPO. In some embodiments, the two or more genes comprise CALR and CD110. In some embodiments, the two or more genes comprise CALR and TPO. In some embodiments, the two or more genes comprise CD110 and TPO. In some embodiments, the two or more genes comprise JAK2, CALR, and CD110. In some embodiments, the two or more genes comprise JAK2, CALR, and TPO. In some embodiments, the two or more genes comprise JAK2, CD110, and TPO. InWSGR Docket No.: 68804-705.601 some embodiments, the two or more genes comprise CALR, CD110, and TPO. In some embodiments, the two or more genes comprise JAK2, CALR, CD110, and TPO. In some embodiments, the method comprises administering a pharmaceutical composition comprising means for binding to CD110 and a pharmaceutically acceptable carrier to the subject. In some embodiments, the means for binding to CD110 comprises any of the antibodies from Tables 2-7. In some embodiments, the subject has not undergone a prior conditioning regimen. In some embodiments, the subject has undergone a prior conditioning regimen and the prior conditioning regimen does not comprise using a therapeutic agent targeting CD 110. In some embodiments, the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy. In some embodiments, the subject has undergone a prior conditioning regimen comprising immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy and irradiation. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising irradiation and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy, irradiation, and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen and the prior conditioning regimen comprises another therapeutic agent targeting CD 110. In some embodiments, the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD 110 for treating MPN.

[0166] Also provided herein is a method for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof. In some embodiments, the method comprises providing a subject having an MPN. In some embodiments, the MPN is associated with a mutation in a gene. In some embodiments, the gene is selected from the group consisting of Janus kinase 2 (JAK2), calreticulin (CALR), CD 110, thrombopoietin (TPO), and any combination thereof. In some embodiments, the gene is JAK2. In some embodiments, the gene is CALR. In some embodiments, the gene is CD110. In some embodiments, the gene is TPO. In some embodiments, the MPN is associated with a mutation in two or more genes or proteins encoded by the two or more genes. In some embodiments, the two or more genes compriseWSGR Docket No.: 68804-705.601JAK2 and CALR. In some embodiments, the two or more genes comprise JAK2 and CD110. In some embodiments, the two or more genes comprise JAK2 and TPO. In some embodiments, the two or more genes comprise CALR and CD110. In some embodiments, the two or more genes comprise CALR and TPO. In some embodiments, the two or more genes comprise CD110 and TPO. In some embodiments, the two or more genes comprise JAK2, CALR, and CD110. In some embodiments, the two or more genes comprise JAK2, CALR, and TPO. In some embodiments, the two or more genes comprise JAK2, CD110, and TPO. In some embodiments, the two or more genes comprise CALR, CD110, and TPO. In some embodiments, the two or more genes comprise JAK2, CALR, CD110, and TPO. In some embodiments, the method comprises administering a pharmaceutical composition comprising means for the combination of (A) binding to CD 110 and (B) blocking CDllO-mediated signaling and a pharmaceutically acceptable carrier to the subject. The means for the combination of (A) binding to CD110 and (B) blocking CDllO-mediated signaling described herein can comprise any of the antibodies disclosed in Table 2. In some embodiments, the subject has not undergone a prior conditioning regimen. In some embodiments, the subject has undergone a prior conditioning regimen and the prior conditioning regimen does not comprise using a therapeutic agent targeting CD110. In some embodiments, the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy. In some embodiments, the subject has undergone a prior conditioning regimen comprising immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy and irradiation. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising irradiation and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy, irradiation, and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen and the prior conditioning regimen comprises another therapeutic agent targeting CD 110. In some embodiments, the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD110 for treating MPN.WSGR Docket No.: 68804-705.601

[0167] Also provided herein is a method for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof. In some embodiments, the method comprises providing a subject having an MPN. In some embodiments, the MPN is associated with a mutation in a gene. In some embodiments, the gene is selected from the group consisting of Janus kinase 2 (JAK2), calreticulin (CALR), CD 110, thrombopoietin (TPO), and any combination thereof. In some embodiments, the gene is JAK2. In some embodiments, the gene is CALR. In some embodiments, the gene is CD110. In some embodiments, the gene is TPO. In some embodiments, the MPN is associated with a mutation in two or more genes or proteins encoded by the two or more genes. In some embodiments, the two or more genes comprise JAK2 and CALR. In some embodiments, the two or more genes comprise JAK2 and CD110. In some embodiments, the two or more genes comprise JAK2 and TPO. In some embodiments, the two or more genes comprise CALR and CD110. In some embodiments, the two or more genes comprise CALR and TPO. In some embodiments, the two or more genes comprise CD110 and TPO. In some embodiments, the two or more genes comprise JAK2, CALR, and CD110. In some embodiments, the two or more genes comprise JAK2, CALR, and TPO. In some embodiments, the two or more genes comprise JAK2, CD110, and TPO. In some embodiments, the two or more genes comprise CALR, CD110, and TPO. In some embodiments, the two or more genes comprise JAK2, CALR, CD110, and TPO. In some embodiments, the method comprises administering a pharmaceutical composition comprising means for preferential binding to a diseased cell. In some embodiments, the method comprises administering a pharmaceutical composition comprising means for preferential binding to an activated CD110 conformation (e.g., CD110 dimer) and a pharmaceutically acceptable carrier to the subject. In some embodiments, the means for preferential binding to a diseased cell comprises any of the antibodies from Tables 2-7. In some embodiments, the means comprises an antibody or binding fragment thereof. In some embodiments, the subject has not undergone a prior conditioning regimen. In some embodiments, the subject has undergone a prior conditioning regimen and the prior conditioning regimen does not comprise using a therapeutic agent targeting CD110. In some embodiments, the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy. In some embodiments, the subject has undergone a prior conditioning regimen comprisingWSGR Docket No.: 68804-705.601 immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy and irradiation. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising irradiation and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen comprising chemotherapy, irradiation, and immunosuppression. In some embodiments, the subject has undergone a prior conditioning regimen and the prior conditioning regimen comprises another therapeutic agent targeting CD 110. In some embodiments, the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD110 for treating MPN.Pharmaceutical Compositions

[0168] The methods of the present disclosure can be used to treat MPNs in a subject in need thereof. In some embodiments, the methods disclosed herein comprise administering a pharmaceutical composition comprising a therapeutic agent targeting CD110 and a pharmaceutically acceptable carrier into a subject.

[0169] Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active agents into preparations which can be used pharmaceutically. Proper formulation can be dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients can be used as suitable and as understood in the art.

[0170] Pharmaceutical compositions can include, in addition to active ingredient, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration.

[0171] Acceptable carriers, excipients, or stabilizers are those that are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins,WSGR Docket No.: 68804-705.601 such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn- protein complexes); and / or non-ionic surfactants such as TWEEN®, PLURONICS® or polyethylene glycol (PEG).

[0172] Acceptable carriers are physiologically acceptable to the administered patient and retain the therapeutic properties of the compounds with / in which it is administered. Acceptable carriers and their formulations are generally described in, for example, Remington’ pharmaceutical Sciences (18thed. A. Gennaro, Mack Publishing Co., Easton, PA 1990). One example of carrier is physiological saline. A pharmaceutically acceptable carrier is a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject compounds from the administration site of one organ, or portion of the body, to another organ, or portion of the body, or in an in vitro assay system. Acceptable carriers are compatible with the other ingredients of the formulation and not injurious to a subject to whom it is administered.

[0173] In one aspect, provided herein are pharmaceutically acceptable or physiologically acceptable compositions including solvents (aqueous or non-aqueous), solutions, emulsions, dispersion media, coatings, isotonic and absorption promoting or delaying agents, compatible with pharmaceutical administration. Pharmaceutical compositions or pharmaceutical formulations therefore refer to a composition suitable for pharmaceutical use in a subject. Compositions can be formulated to be compatible with a particular route of administration (i.e., systemic or local). Thus, compositions include carriers, diluents, or excipients suitable for administration by various routes.

[0174] The pharmaceutical compositions described above may be administered by any delivery route, systemic delivery or local delivery, which results in a therapeutically effective outcome. These include, but are not limited to, enteral, gastroenteral, epidural, oral, transdermal, intracerebral, intracerebroventricular, epicutaneous, intradermal, subcutaneous, nasal, intravenous, intra-arterial, intramuscular, intracardiac, intraosseous, intrathecal, intraparenchymal, intraperitoneal, intravesical, intravitreal, intracavernous), interstitial, intra-WSGR Docket No.: 68804-705.601 abdominal, intralymphatic, intramedullary, intrapulmonary, intraspinal, intrasynovial, intrathecal, intratubular, parenteral, percutaneous, periarticular, peridural, perineural, periodontal, rectal, soft tissue, and topical. In particular embodiments, the cells are administered intravenously. The pharmaceutical compositions may be administered to a subject using any amount and any route of administration effective for preventing, treating, or managing a disease described herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular composition, its mode of administration, its mode of activity, and the like.

[0175] The pharmaceutical composition can be administered, for example, by injection. Compositions for injection include aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, or phosphate buffered saline (PBS). The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Antibacterial and antifungal agents include, for example, parabens, chlorobutanol, phenol, ascorbic acid and thimerosal. Isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride can be included in the composition. The resulting solutions can be packaged for use as is, or lyophilized; the lyophilized preparation can later be combined with a sterile solution prior to administration. For intravenous, injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer’s Injection, Lactated Ringer’s Injection. Preservatives, stabilizers, buffers, antioxidants and / or other additives can be included, as needed. Sterile injectable solutions can be prepared by incorporating an active ingredient in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active ingredient into aWSGR Docket No.: 68804-705.601 sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation can be vacuum drying and freeze drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0176] Compositions can be conventionally administered intravenously, such as by injection of a unit dose, for example. For injection, an active ingredient can be in the form of a parenterally acceptable aqueous solution which is substantially pyrogen-free and has suitable pH, isotonicity and stability. One can prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer’s Injection, Lactated Ringer’s Injection. Preservatives, stabilizers, buffers, antioxidants and / or other additives can be included, as required. Additionally, compositions can be administered via aerosolization.

[0177] When the compositions are considered for use in medicaments or any of the methods provided herein, it is contemplated that the composition can be substantially free of pyrogens such that the composition will not cause an inflammatory reaction or an unsafe allergic reaction when administered to a human patient. Testing compositions for pyrogens and preparing compositions substantially free of pyrogens are well understood to one or ordinary skill of the art and can be accomplished using commercially available kits.

[0178] Acceptable carriers can contain a compound that acts as a stabilizing agent, increases or delays absorption, or increases or delays clearance. Such compounds include, for example, carbohydrates, such as glucose, sucrose, or dextrans; low molecular weight proteins; compositions that reduce the clearance or hydrolysis of peptides; or excipients or other stabilizers and / or buffers. Agents that delay absorption include, for example, aluminum monostearate and gelatin. Detergents can also be used to stabilize or to increase or decrease the absorption of the pharmaceutical composition, including liposomal carriers. To protect from digestion the compound can be complexed with a composition to render it resistant to acidic and enzymatic hydrolysis, or the compound can be complexed in an appropriately resistant carrier such as a liposome. Means of protecting compounds from digestion are known in the art (e.g., Fix (1996) Pharm Res. 13: 1760 1764; Samanen (1996) J. Pharm. Pharmacol. 48:119 135; and U.S. Pat. No. 5,391,377).

[0179] In some embodiments, a pharmaceutical composition described herein for therapeutic treatment can be formulated for parenteral, topical, nasal, oral or local administration. InWSGR Docket No.: 68804-705.601 some embodiments, the pharmaceutical compositions described herein are administered parenterally, e.g., intravenously, subcutaneously, intradermally, or intramuscularly. In some embodiments, described herein are compositions for parenteral administration which comprise a solution of the therapeutic agent dissolved or suspended in an acceptable carrier, for example, an aqueous carrier. A variety of aqueous carriers can be used, e.g., water, buffered water, 0.9% saline, 0.3% glycine, hyaluronic acid and the like. These compositions can be sterilized by conventional, well known sterilization techniques, or can be sterile filtered. The resulting aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile solution prior to administration. The compositions can contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc.EXAMPLES

[0180] The present disclosure will be more specifically illustrated by the following Examples. However, it should be understood that the present disclosure is not limited by these examples in any manner.Example 1: Methods to Establish PMF Disease and Assess Anti-CDHO Antibodies In VivoAntibodies

[0181] In order to generate anti-CDUO antibodies, Wild type mice were immunized with either WT human CD110 extracellular domain recombinant protein or with cDNA expressing human CD110-W515L. Following immunization, reactive clones were recovered either using hybridoma-based methods, single B cell cloning, or construction and panning of immune repertoires recovered from immunized animals. This led to the isolation of anti-CDUO antibodies 921 and 1125. The sequences of these antibodies are provided in Table 7.Table 7. Isolated Anti-CDUO AntibodiesWSGR Docket No.: 68804-705.601WSGR Docket No.: 68804-705.601WSGR Docket No.: 68804-705.601

[0182] Anti-hCDllO antibodies were generated as various murine versions of the antibody by fusing the variable domains with murine heavy and light chain constant regions. For example, effector competent versions were generated using murine IgG2a constant regions. For example, effector-incompetent antibodies were generated by using murine IgGl constant regions wherein mutagenesis of Asn in the murine Fc that is cognate to the human Fc Asn at position 297, to Ala (N297A).Small molecules

[0183] 5 fluorouracil (5FU) (Sigma, CAT# 102638755) were reconstituted in PBS and sterilized via filtration. Aliquots of 5FU and Ruxolitinib (MedChem Express, CAT# HY- 50856) were stored frozen and new aliquots thawed for each study.Retrovirus

[0184] Murine stem cell viruses (MSCV) were constructed to co-express human CD110 and GFP via an internal ribosome entry site (IRES) such that GFP is placed after the IRES. Human CD110 amino acid sequence was based on Uniprot entry P40238 and were either wild type or W515L. Custom vector construction and generation of virus was done commercially.Donor cell isolation.

[0185] In brief, donor mice were administered with 5-fluorourafil (5FU) to generate proliferating HSPCs for transduction with virus encoding human CD110. 8-10 week old HSC donor C57BL / 6 or Balb / C mice were dosed with 150 mg / kg 5FU i.p. Six to ten days later, mice were euthanized, and femur, tibia, humerus, and spines were collected. Bones were crushed to isolate bone marrow, followed by filtration and red blood cell (RBC) lysis using Gibco ACK Lysing buffer, and finally centrifugation to collect bone marrow cells. Lineagenegative cells were then isolated using EasySep kit (CAT #19856) and cultured overnight in RPMI supplemented with 10% fetal bovine serum (FBS), 10 ng / ml IL-3, 10 ng / ml IL-6, andWSGR Docket No.: 68804-705.60120 ng / ml SCF. Next day, lineage-negative cells from C57BL / 6 45.1 or Balb / C mice were washed and filtered, then transduced with MSCV encoding WT or W515L hCDUO coexpressing GFP via double spin-fection. In brief, retrovirus was supplemented with 8 ug / ml final polybrene and added to plated lineage-negative cells and centrifuged for 1.5 h followed by a 2 h rest, upon which a second bolus of retrovirus was added, and cells centrifuged again for 1.5 h. After the second spin-fection, cells were washed and analyzed for cell count to inform same-day transplantation; a small fraction of cells were also cultured overnight to assess GFP expression 24 post transduction. In parallel, lineage negative cells isolated from C57BL / 6 45.2 or Balb / C animals were collected to serve as unmodified supportive HSCs that were mixed with transduced cells to create the transplant.Irradiation and transplantation.

[0186] In brief, mice were transplanted with transduced donor HSCs to induce primary myelofibrosis (PMF) disease. 12+ week old transplant recipient C57BL / 6 CD45.2 or Balb / C mice were irradiated via a split dose 4-5 hours apart for a total of 8-9 Gy. 3-4 hours postsecond irradiation dose, animals were transplanted with 0.25xl06-lxl06lineage-depleted, freshly transduced HSCs. Transplants consisted of 100% MSCV- transduced donor cells or a 1 :2 - 1 : 10 mix of MSCV-transduced cells to untransduced 5FU treated lineage' cells to moderate otherwise accelerated disease progression.Monitoring of disease progression

[0187] At various days post-transplant, mice were bled via tail vein for complete blood count (CBC) measurements and via FACS analysis to ascertain the expression of human CD110 and / or GFP in peripheral blood cells. Mice were also measured for body weight and palpable hepatosplenomegaly.

[0188] Mice were monitored throughout for health and survival. Untreated mice harboring CD110-W515L started to appear hunched between 7- and 21-days post-transplant.Compassionate euthanasia was performed based on symptoms including but not limited to lethargy, hunching, >20% weight loss, dyspnea, etc. All animals including healthy controls were ultimately sacrificed by termination of indicated study design. In some cases, animals were euthanized mid-study to enable analysis of organs and tissues. Spleen and liver ere ultimately isolated from all animals and measured for physical size, color, and mass. Such organs were also dis-aggregated into single cell suspensions for FACS analysis. In addition, murine femurs were collected, fixed in 10% neutral buffered formalin overnight, rinsed 3XWSGR Docket No.: 68804-705.601 phosphate buffered saline (PBS), and stored in 70% ethanol. Fixed femurs were processed, sectioned, and reticulin stained via immunohistochemistry.

[0189] FIGs. 1A-1C demonstrates that mice expressing human CD110 W515L develop splenomegaly and hepatomegaly (FIG. 1A), leukocytosis (FIG. IB), and bone marrow reticulin fibrosis preceding animal death, compared to control mice (FIG. 1C).Administration of antibodies and / or JAK inhibitors

[0190] For antibody monotherapy, starting at various times post-transplant mice were intravenously (i.v.) injected with 10 mg / kg of indicated antibody or isotype control twice per week for 2 weeks. Diphenhydramine was administered prior to antibody treatment by intraperitoneal (i.p.) injections. For JAK2 inhibitor monotherapy, starting at various times post-transplant mice were treated twice daily with 90mg / kg ruxolitinib via oral gavage for 2 weeks. For combination therapy, antibodies were administered i.v. up to 10 mg / kg twice per week and twice daily with 90 mg / kg ruxolitinib via oral gavage for 2 weeks. Cohorts for all treatment groups consisted of at least 5 mice.Example 2. Administration of anti-hCDUO antibody to animals modeling PMF disease can affect disease progression and animal survival.

[0191] In order to determine how the isolated anti-CDUO antibodies affect disease progression, mice were treated as described in Example 1 to model myeloproliferative disease. Antibody treatment led to improved survival or accelerated death (FIG. 2). Diseased mice treated with isotype control died 11 days after initiation of antibody administration.Diseased mice treated with anti-hCDUO antibody 1125 were either found dead between days 4 and 6 after initiation of treatment or were humanely euthanized due to being moribund (scruffy coats, lethargic, distended abdomens). In sharp contrast, diseased animals treated with anti-hCDUO antibody 921 survived for 30-70 days after initiation of treatment.Example 3. Administration of anti-hCDUO antibody 921 to diseased mice ameliorates all symptoms of PMF with persistence of amelioration even after antibody treatment is withdrawn.

[0192] To further elucidate how antibody 921 increased animal survival, diseased animals were either treated with the JAK2 inhibitor ruxolitinib or antibody 921 for 2 weeks, after which treatment ceased, and various hallmarks of disease were monitored over time (FIGs.WSGR Docket No.: 68804-705.6013A-3E). Ruxolitinib manages extramedullary hematopoiesis pre-clinically and clinically. Diseased animals treated with isotype control died between days 9 and 19 while animals treated with 921 survived from day 40-56 of study (FIG. 3A). Increased survival of 921- treated animals correlated with prolonged suppression of lymphocytosis (FIG. 3B), hepatomegaly (FIG. 3C), and splenomegaly (FIG. 3D) when compared to animals compared to isotype control. Animals treated with the JAK2 inhibitor ruxolitinib survived while on treatment and this correlated with suppression of lymphocytosis and hepatomegaly. Upon cessation of treatment with ruxolitinib, lymphocytosis immediately rebounded and animals were either found dead or were humanely euthanized within 6 days. Analysis of GFP expression enabled assessment of expansion of CD110-W515L+ cells when animals were treated with isotype control or ruxolitinib (FIG. 3E). In contrast, animals treated with antibody 921 demonstrated suppression of GFP+ cell growth while on treatment, indicating that the antibody treatment was suppressing growth of the blast burden (CD110-W515L+ cells). Similarly, reticulin deposition in the bone marrow was observed in animals treated with isotype control or ruxolitinib despite 14 days on treatment (FIG. 4A). In contrast, no reticulin deposition was observed in bone marrow of animals treated with antibody 921. As demonstrated in FIG. 3A-3E, ruxolitinib treatment can ameliorate some of the symptoms of myelofibrosis in diseased mice while they are on treatment, but upon cessation of treatment, disease symptoms immediately rebounded and animals did not survive longer than a week. In contrast, upon cessation of treatment with 921, symptoms rebound was delayed.Hepatosplenomegaly rebounded to that of isotype control -treated animals 12 days later (FIGs. 3C-3D) and bone marrow reticulin was also observable (FIG. 4B). Lymphocytosis and GFP+ cellular rebound took ~20 days, to match that of control animals. Analysis of blood sera in diseased animals revealed that antibody levels were cleared by 11 days post administration (FIG. 5). Thus, the delayed rebound of PMF symptoms in diseased mice after treatment with 921 may have been due to its slower elimination kinetics.Example 4: Co-treatment of diseased mice with anti-CDUO antibody and a JAK2 inhibitor prolongs symptom relief and animal survival beyond either treatment alone.

[0193] To determine whether an antibody targeting CD 110+ cells and a JAK2i could together further improve animal survival and disease progression, mice were co-administered 921 and ruxolitinib. As can be seen in FIG. 3A, survival of animals treated with the combination wasWSGR Docket No.: 68804-705.601 extended compared to either treatment alone. This correlated with a more potent inhibition of lymphocytosis (FIG. 3B) than 921 treatment alone as well as a slight delay in lymphocytosis rebound upon cessation of treatment, compared to 921 treatment alone. The combination also suppressed hepatomegaly (FIG. 3C) and splenomegaly (FIG. 3D) compared to either treatment alone, with suppression still observable at day 27 post initiation of treatment. Most notably, deposition of reticulin fibers in animals treated with the combination was limited to perivascular regions and was not extensive by day 27, by comparison to the animals treated with 921 alone (FIG. 4B). These data suggest that the anti-CDUO antibody and JAK2 inhibitor have distinct and additive impacts on extramedullary hematopoiesis and bone marrow fibrosis in this PMF model. The addition of ruxolitinib to 921 treatment did not extend nor amplify the suppression of GFP+ cell expansion (FIG. 3E), suggesting that inhibition of allelic expansion by the anti-CDUO antibody is not enhanced by inhibition of JAK2.Example 5: Antibody 921 is capable of performing antibody-dependent cell cytotoxicity and phagocytosis in vitro.

[0194] To determine whether anti -human CD110 antibodies are capable of inducing the killing human cells via antibody dependent cellular cytotoxicity (ADCC) or antibody dependent cellular phagocytosis (ADCP), antibodies were produced as an effector-competent human G1 isotype antibodies. ADCC was measured by co-incubating primary human natural killer (NK) cells isolated from healthy volunteer peripheral blood with Raji cells engineered to express human CD110 (ADCC target cells), in the absence or presence of antibodies. Cell killing was evaluated using flow cytometry for measuring viable target cells labeled with cell trace violet and calculating the percentage of killed cells as: (% of living cells in target only control-% of living cells in sample well) / % of living cells in target only control x 100. ADCP was measured by co-incubating primary monocyte-derived macrophages isolated from healthy volunteer peripheral blood with cell trace violet labeled K562 cells engineered to express human CD110 (ADCP target cells), in the absence or presence of antibodies. In brief, phagocytosis was measured by flow cytometry to quantify CD14+ primary macrophages that are positive for the cell trace dye indicating phagocytosis of labeled target cells. FIG. 6A demonstrates that 921-hIgGl induces ADCC of target cells expressing human CD110 whileWSGR Docket No.: 68804-705.601 isotype control does not. FIG. 6B demonstrates that 921-hIgGl induces ADCP of target cells expressing human CD110 while isotype control does not.Example 6: Role of Antibody effector function in the ability of antibody 921 to increase animal survival and reduce blast burden.

[0195] Antibody effector functions such as ADCC, ADCP, and complement dependent cytotoxicity (CDC), could be mechanisms by which anti-CDUO antibody 921 was found to ameliorate disease progression in the murine model of PMF, since its Fc is the effector- competent murine G2a isotype and in vitro it is capable of inducing ADCC and ADCP (FIG. 6A-6B). Antibody 921 was rendered effector incompetent by expressing it with murine G1 isotype and N297A mutation. Diseased animals treated with 921-N297A had shortened survival compared to animals treated with 921 (FIG. 7A), suggesting that effector function is contributing to the ability of the antibody to impact disease progression. This correlated with diminished ability of 921-N297Ato reduce blast burden as evidenced by suppressed expansion of GFP+ cells (FIG. 7B). However, animals treated with 921-N297A did survive longer than untreated animals, and some suppression of lymphocytosis was observable in response to 921-N297A (FIG. 7C) though it was neither as potent nor as durable as effector- competent 921. This could be due to incomplete abrogation of antibody effector function through the N297A mutation or due to other characteristics of antibody 921 such as antigen engagement.Example 7: Binding activity of antibody 921.

[0196] To explore whether prolonged animal survival in the murine PMF model in response to 921 could be due to receptor antagonism, a human CD110 reporter cell line that is responsive to human TPO was employed, per manufacturer’s protocol (InvivoGen, CAT#hkb-tpo). Antibody 921 did not agonize CD 110 (FIG. 8A) and was found to be an antagonist of TPO-induced CD110 signaling (FIG. 8B).Example 8: Antibody 921 binds the membrane-proximal domain of CD110.

[0197] Given the ability of antibody 921 to affect disease progression in the murine PMF model, its binding site was interrogated through human-murine CD110 receptor chimeras. The extracellular domain (ECD) of CD110 is composed of 4 globular domains, D1-D4, withWSGR Docket No.: 68804-705.601DI the most membrane-distal and D4 the most membrane-proximal. Human-murine CD110 ECD chimeras were generated by swapping each individual human D domain with that of the murine D domain, and the full-length chimeric receptors were expressed in CHO cells. Binding by 921 was lost when the human D4 domain was swapped with that of mouse D4 (FIG. 9). Control antibody 1.61 was able to bind the D4 chimera.

[0198] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the invention be limited by the specific examples provided within the specification. While the invention has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it shall be understood that all aspects of the invention are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WSGR Docket No.: 68804-705.601CLAIMSWHAT IS CLAIMED IS:

1. A method for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, the method comprising: administering a pharmaceutical composition comprising a therapeutic agent targeting CD110 and a pharmaceutically acceptable carrier into the subject, wherein the therapeutic agent preferentially binds to a diseased cell in the subject over a healthy cell.

2. The method of claim 1, wherein the diseased cell has a constitutively activated CD110 / JAK2 signaling pathway.

3. The method of claim 1 or 2, wherein the disease cell comprises a conformational isoform of CD 110.

4. The method of any one of claims 1-3, wherein the diseased cell comprises an active CD 110 conformation.

5. The method of claim 4, wherein the active CD110 conformation comprises a CD110 dimer.

6. The method of any one of claims 1-5, wherein the therapeutic agent targeting CD110 binds to a membrane proximal domain of CD110.

7. The method of any one of claims 1-6, wherein the diseased cell is selected from the group consisting of a stem cell, a progenitor cell, a blast cell, a megakaryocyte, and any combination thereof.

8. The method of any one of claims 1-7, wherein the therapeutic agent targeting CD110 preferentially binds to an active CD110 conformation compared to an inactive CD110 conformation.

9. The method of any one of claims 1-8, wherein the therapeutic agent targeting CD110 binds to an active CD110 conformation with a binding affinity that is at least 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25- fold, 50-fold, 100-fold or more than a binding affinity of the therapeutic agent to the inactive CD110 conformation.

10. The method of any one of claims 1-9, wherein the therapeutic agent targeting CD110 is an antibody or antigen-binding fragment thereof.

11. A method for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, the method comprising: administering a pharmaceutical compositionWSGR Docket No.: 68804-705.601 comprising a therapeutic agent targeting CD110 and a pharmaceutically acceptable carrier into the subject, wherein:(i) the subject has not undergone a prior conditioning regimen;(ii) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen does not comprise using a therapeutic agent targeting CD110; or(iii) the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof; or(iv) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen does comprise using another therapeutic agent targeting CD110.

12. The method of claim 11, wherein the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD110 for treating MPN.

13. The method of any one of claims 1-12, wherein the MPN is associated with a constitutively activated CD110 / JAK2 signaling pathway.

14. The method of any one of claims 1-13, wherein the CD110 is a human CD110.

15. The method of any one of claims 1-14, wherein the MPN is associated with a mutation in a gene or a protein encoded by the gene.

16. The method of claim 15, wherein the gene is selected from the group consisting of Janus kinase 2 (JAK2), calreticulin (CALR), CD 110, thrombopoietin (TPO), and any combination thereof.

17. The method of claim 16, wherein the gene is JAK2.

18. The method of claim 17, wherein a JAK2 protein encoded by the gene comprises one or more point mutations relative to the wild type amino acid sequence set forth in SEQ ID NO: 207, and wherein the one or more point mutations are selected from the group consisting of G335D, F556V, G571S, V617F, V625S, and any combination thereof.

19. The method of claim 18, wherein the JAK2 gene comprises a mutation in exon 12.

20. The method of any one of claims 16-19, wherein the gene is CALR.WSGR Docket No.: 68804-705.60121. The method of claim 20, wherein the CALR gene or a CALR protein encoded by the CALR gene comprises a mutation that results in incorrect trafficking of the CALR protein.

22. The method of claim 20 or 21, wherein the CALR gene comprises a mutation in exon 9.

23. The method of claim 20, wherein the gene comprises a frameshift mutation relative to the wild type CALR gene.

24. The method of claim 23, wherein the frameshift mutation is a CALRdel52 or CALRins5 mutation.

25. The method of any one of claims 16-24, wherein the gene is CD 110.

26. The method of claim 25, wherein a CD110 protein encoded by the gene comprises one or more point mutations relative to the wild type amino acid sequence set forth in SEQ ID NO: 208, and wherein the one or more point mutations are selected from the group consisting of T119I, S204F, S204P, P222S, E230G, Y252H, V285E, R321W, S505N, W515L, W515K, W515A, W515R, Y591D, Y591N, R592Q, and any combination thereof.

27. The method of claim 25, wherein the CD110 gene comprises a mutation in exon 10.

28. The method of any one of claims 1-27, wherein the MPN is selected from the group consisting of primary myelofibrosis, essential thrombocytopenia, polycythemia vera, and any combination thereof.

29. The method of any one of claims 1-28, wherein the therapeutic agent is conjugated to a toxin.

30. The method of claim 29, wherein the toxin is selected from the group consisting of saporins, saporin derivatives, ricin, abrin, gelonin, momordin, apitoxin, shiga toxins, shiga-like toxins, T-2 mycotoxin, diphtheria toxin, busulfan, pseudomonas exotoxin A, Ricin A chain derivatives, trichosanthin, luffin toxin, maytansine, amatoxin, mechlorethamine, cyclophosphamide, ethylenimine, methylmelamine, methotrexate, fluorouracil, floxuridine, cytarabine, mercaptopurine, azathioprine, thioguanine, fludarabine phosphate, cladribine, and any combination thereof.

31. The method of any one of claims 1-30, further comprising administering an additional therapeutic agent into the subject prior to, concurrently with, or subsequent to administering the pharmaceutical composition.WSGR Docket No.: 68804-705.60132. The method of any one of claims 1-30, wherein the pharmaceutical composition further comprises an additional therapeutic agent.

33. The method of claim 31 or 32, wherein the additional therapeutic agent is a small molecule inhibitor, or an antibody or antigen-binding fragment thereof.

34. The method of claim 33, wherein the additional therapeutic agent is an inhibitor of a therapeutic target associated with MPN disease progression.

35. The method of claim 34, wherein the therapeutic target is selected from the group consisting of CALR, JAK2, PPM1D, HDM2, MDM2, XPO1, LSD1, BET and any combination thereof.

36. The method of claim 34 or 35, wherein the therapeutic target is JAK2, and wherein the inhibitor is an inhibitor of JAK2.

37. The method of claim 36, wherein the inhibitor of JAK2 is selected from the group consisting of ruxolitinib, fedratinib, pacritinib, momelotinib, and any combination thereof.

38. The method of claim 34 or 35, wherein the therapeutic target is PPM1D, and wherein the inhibitor is an inhibitor of PPM1D.

39. The method of claim 38, wherein the inhibitor of PPM1D is selected from the group consisting of GSK2830371, BRD4761, BRD5049, and BRD6257.

40. The method of claim 34 or 35, wherein the therapeutic target is HDM2, and wherein the inhibitor is an inhibitor of HDM2.

41. The method of claim 40, wherein the inhibitor of HDM2 is selected from the group consisting of NVP-CGM097, an HLI98 family molecule, MK-8242, and MK-4688.

42. The method of claim 34 or 35, wherein the therapeutic target is MDM2, and wherein the inhibitor is an inhibitor of MDM2.

43. The method of claim 42, wherein the inhibitor of MDM2 is navtemadin.

44. The method of claim 34 or 35, wherein the therapeutic target is XPO1, and wherein the inhibitor is an inhibitor of XPO1.

45. The method of claim 44, wherein the inhibitor of XPO1 is selinexor.

46. The method of claim 34 or 35, wherein the therapeutic target is LSD1, and wherein the inhibitor is an inhibitor of LSD 1.

47. The method of claim 46, wherein the inhibitor of LSD 1 is bodemstat.WSGR Docket No.: 68804-705.60148. The method of claim 34 or 35, wherein the therapeutic target is BET, and wherein the inhibitor is an inhibitor of BET.

49. The method of claim 48, wherein the inhibitor of BET is pelabresib.

50. The method of any one of claims 35-49, wherein the therapeutic target is CALR and wherein the additional therapeutic agent is an antibody or antigen-binding fragment thereof targeting CALR or a CALR variant.

51. The method of claim 31 or 32, wherein the additional therapeutic agent targets a cell surface antigen expressed by a hematopoietic stem cell or a megakaryocyte.

52. The method of claim 51, wherein the cell surface antigen is selected from the group consisting of CD150, CD34, CD38, CD43, CD48, CD117, CD27, CD41, CD61, CD135 (FLT3), CD184 (CXCR4), CD123 (IL3R), CD49d, CD29, VLA-4, CD45, CD33, CD 127 and any combination thereof.

53. The method of any one of claims 31-52, wherein the therapeutic agent targeting CD110 acts synergistically or additively with the additional therapeutic agent.

54. The method of any one of claims 11-53, wherein the therapeutic agent targeting CD110 binds to a membrane proximal domain of CD 110.

55. The method of any one of claims 11-54, wherein the therapeutic agent targeting CD110 preferentially binds to an active CD110 conformation compared to an inactive CD 110 conformation.

56. The method of any one of claims 11-55, wherein the therapeutic agent targeting CD110 binds to an active CD110 conformation with a binding affinity that is at least 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 50-fold, 100-fold or more than a binding affinity of the therapeutic agent to the inactive CD110 conformation.

57. The method of any one of claims 1-56, wherein the therapeutic agent targeting CD110 binds to an active CD110 conformation and does not bind to an inactive CD110 conformation.

58. The method of any one of claims 55-57, wherein the active CD110 conformation comprises a CD110 dimer.

59. The method of claim 58, wherein the therapeutic agent targeting CD110 binds to a dimer interface of the CD110 dimer.WSGR Docket No.: 68804-705.60160. The method of claim 58 or 59, wherein the CD110 dimer is dissociated when bound by the therapeutic agent targeting CD 110.

61. The method of any one of claims 55-60, wherein the inactive CD110 conformation comprises or consists of a CD110 monomer.

62. The method of any one of claims 1-61, wherein the therapeutic agent targeting CD110 binds to an active CD110 conformation with a dissociation constant (Kd) of at most about 100 nM, at most about 50 nM, at most about 20 nM, at most about 10 nM or less.

63. The method of any one of claims 1-62, wherein a Kd of the therapeutic agent targeting CD110 to an active CD110 conformation is lower than a Kd of the therapeutic agent targeting CD110 to an inactive CD110 conformation.

64. The method of any one of claims 11-63, wherein the therapeutic agent targeting CD110 is an antibody or antigen-binding fragment thereof.

65. The method of any one of claims 1-64, wherein the therapeutic agent targeting CD110 is selected from the group consisting of an antibody, an Fv fragment, an Fab fragment, an F(ab’)2 fragment, an Fab’ fragment, an scFv (sFV) fragment, an Fd (N-terminal part of the heavy chain) fragment, an Fv fragment (two variable domains), a diabody (Dbs), a dAb fragment, a single domain fragment or single monomeric variable antibody domain, a single-chain diabody (scDbs), an isolated complementary determining region (CDR), and a nanobody.

66. The method of any one of claims 1-65, wherein the therapeutic agent targeting CD110 is conjugated to a nucleic acid.

67. The method of claim 66, wherein the nucleic acid regulates expression of a target gene.

68. The method of claim 66 or 67, wherein the nucleic acid is selected from the group consisting of an miRNA, an siRNA, an activating RNA, and an antisense oligonucleotide.

69. The method of any one of claims 1-68, wherein the therapeutic agent targeting CD110 is a multi-specific antibody.

70. The method of claim 69, wherein the multi-specific antibody is a CrossMab.

71. The method of claim 69, wherein the multi-specific antibody is a bi-specific or tri- specific antibody.WSGR Docket No.: 68804-705.60172. The method of any one of claims claim 69-71, wherein the multi-specific antibody comprises an additional binding domain that binds a subunit of a TCR / CD3 complex, an NK cell receptor, a CALR-CD110 complex, a JAK2-CD110 complex, a CALR- CD110-JAK2 complex or any combination thereof.

73. The method of any one of claims 1-72, wherein the therapeutic agent targeting CD110 is an antagonist, a non-agonist, or an agonist.

74. The method of any one of claims 1-73, wherein the therapeutic agent targeting CD110 is a naked antibody.

75. The method of any one of claims 1-73, wherein the therapeutic agent targeting CD110 is an antibody-drug conjugate.

76. The method of any one of claims 1-75, wherein the therapeutic agent targeting CD110 comprises an Fc domain.

77. The method of claim 76, wherein the Fc domain activates an Fc-dependent effector process.

78. The method of claim 77, wherein the Fc-dependent effector process is selected from the group consisting of antibody-dependent cellular cytotoxicity (ADCC), antibodydependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC).

79. The method of claim 77 or 78, wherein the Fc-dependent effector process is ADCC.

80. The method of any one of claims 1-79, wherein the subject exhibits a reduction in leukocytosis, a reduction in granulocytosis, a reduction in erythrocytopenia, a reduction in extramedullary hematopoiesis, a reduction in deposition of reticulin in a bone marrow tissue, a reduction in blast cells, a reduction in severity of a symptom of MPN, a reduction in lymphocytosis, a reduction in splenomegaly, a reduction in hepatomegaly, an increase in survival, or any combination thereof.

81. The method of claim 1-80, wherein the subject exhibits a reduction in leukocytosis by at least 5%, 10%, 20%, 40%, 60%, 80%, or 100% compared to leukocytosis in the subject prior to receiving the pharmaceutical composition.

82. The method of any one of claims 1-81, wherein the subject exhibits a reduction in granulocytosis by at least 5%, 10%, 20%, 40%, 60%, 80%, or 100% compared to granulocytosis in the subject prior to receiving the pharmaceutical composition.WSGR Docket No.: 68804-705.60183. The method of any one of claims 1-82, wherein the subject exhibits a reduction in erythrocytopenia by at least 5%, 10%, 20%, 40%, 60%, 80%, or 100% compared to erythrocytopenia in the subject prior to receiving the pharmaceutical composition.

84. The method of any one of claims 1-83, wherein the subject exhibits a reduction in extramedullary hematopoiesis by at least 5%, 10%, 20%, 40%, 60%, 80%, or 100% compared to extramedullary hematopoiesis in the subject prior to receiving the pharmaceutical composition.

85. The method of any one of claims 1-84, wherein the subject exhibits a reduction in deposition of reticulin in a bone marrow tissue of the subject by at least 5%, 10%, 20%, 40%, 60%, 80%, or 100% compared to deposition of reticulin in a bone marrow tissue of the subject prior to receiving the pharmaceutical composition.

86. The method of any one of claims 1-85, wherein the subject exhibits a reduction in blast cells by at least 5%, 10%, 20%, 40%, 60%, 80%, or 100% compared to a level of blast cells in the subject prior to receiving the pharmaceutical composition.

87. The method of claim 86, wherein the blast cells are CD110-W515L+ cells.

88. The method of any one of claims 1-87, wherein the subject exhibits a reduction in severity of a symptom of MPN for at least 1 day, 2 days, 3 days, 4 days, 5 days, one week, two weeks, three weeks, four weeks, six weeks, eight weeks, 10 weeks, 12 weeks, or more.

89. The method of any one of claims 1-88, wherein the subject exhibits a reduction in lymphocytosis by at least 5%, 10%, 20%, 40%, 60%, 80%, or 100% compared to a level of lymphocytosis in the subject prior to receiving the pharmaceutical composition.

90. The method of any one of claims 1-89, wherein the subject exhibits a reduction in splenomegaly by at least 5%, 10%, 20%, 40%, 60%, 80%, or 100% compared to the subject prior to receiving the pharmaceutical composition.

91. The method of any one of claims 1-90, wherein the subject exhibits a reduction in hepatomegaly by at least 5%, 10%, 20%, 40%, 60%, 80%, or 100% compared to the subject prior to receiving the pharmaceutical composition.

92. The method of any one of claims 80-91, wherein the reduction persists for at least 1 day, 2 days, 3 days, 4 days, 5 days, one week, two weeks, three weeks, four weeks, sixWSGR Docket No.: 68804-705.601 weeks, eight weeks, 10 weeks, 12 weeks, or more following administration of the pharmaceutical composition.

93. The method of any one of claims 1-92, wherein the subject exhibits an increase in survival for at least 1 day, 2 days, 3 days, 4 days, 5 days, one week, two weeks, three weeks, four weeks, six weeks, eight weeks, 10 weeks, 12 weeks, or more compared to an otherwise identical subject not receiving the pharmaceutical composition.

94. The method of any one of claims 1-93, further comprising performing an additional therapy, prior to, concurrently with, or subsequent to administering the pharmaceutical composition.

95. The method of claim 94, wherein the additional therapy comprises performing a bone marrow transplant.

96. Use of a therapeutic agent targeting CD110 for the treatment of a myeloproliferative neoplasm (MPN) in a subject in need thereof, wherein the therapeutic agent is the therapeutic agent of any one of claims 1-95, wherein the therapeutic agent preferentially binds to a diseased cell in the subject over a healthy cell.

97. Use of a therapeutic agent targeting CD110 for the treatment of a myeloproliferative neoplasm (MPN) in a subject in need thereof, wherein the therapeutic agent is the therapeutic agent of any one of claims 1-95, wherein (i) the subject has not undergone a prior conditioning regimen; (ii) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen does not comprise using a therapeutic agent targeting CD 110; (iii) the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof; (iv) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen does comprise using another therapeutic agent targeting CD 110.

98. Use of a therapeutic agent targeting CD110 in the manufacture of a medicament for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, wherein the therapeutic agent is the therapeutic agent of any one of claims 1-95, wherein the therapeutic agent preferentially binds to a diseased cell in the subject over a healthy cell.

99. Use of a therapeutic agent targeting CD110 in the manufacture of a medicament for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, whereinWSGR Docket No.: 68804-705.601 the therapeutic agent is the therapeutic agent of any one of claims 1-95, wherein (i) the subject has not undergone a prior conditioning regimen; (ii) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen does not comprise using a therapeutic agent targeting CD 110; (iii) the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof; or (iv) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen does comprise using another therapeutic agent targeting CD 110.

100. The use of claim 97 or 99, wherein the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD110 for treating MPN.

101. A therapeutic agent for use in treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, wherein the therapeutic agent is the therapeutic agent targeting CD110 of any one of claims 1-95, wherein the therapeutic agent preferentially binds to a diseased cell in the subject over a healthy cell.

102. A therapeutic agent for use in treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, wherein the therapeutic agent is the therapeutic agent targeting CD110 of any one of claims 1-95, wherein (i) the subject has not undergone a prior conditioning regimen; (ii) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen does not comprise using a therapeutic agent targeting CD 110; (iii) the subject has undergone a prior conditioning regimen selected from the group consisting of chemotherapy, irradiation, immunosuppression, and any combination thereof; or (iv) the subject has undergone a prior conditioning regimen, and wherein the prior conditioning regimen comprises using another therapeutic agent targeting CD 110.

103. The therapeutic agent of claim 102, wherein the another therapeutic agent targeting CD110 is different from the therapeutic agent targeting CD 110 for treating MPN.

104. A method for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, the method comprising:(a) providing a subject having an MPN associated with a mutation in a gene, wherein the gene is selected from the group consisting of Janus kinase 2 (JAK2), calreticulin (CALR), CD 110, thrombopoietin (TPO), and any combination thereof; andWSGR Docket No.: 68804-705.601(b) administering a pharmaceutical composition comprising means for binding to CD110 and a pharmaceutically acceptable carrier into the subject.

105. A method for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, the method comprising:(a) providing a subject having an MPN associated with a mutation in a gene, wherein the gene is selected from the group consisting of Janus kinase 2 (JAK2), calreticulin (CALR), CD 110, thrombopoietin (TPO), and any combination thereof; and(b) administering a pharmaceutical composition comprising means for the combination of (A) binding to CD 110 and (B) blocking CDllO-mediated signaling, and a pharmaceutically acceptable carrier into the subject.

106. A method for treating a myeloproliferative neoplasm (MPN) in a subject in need thereof, the method comprising:(a) providing a subject having a MPN associated with a mutation in a gene, wherein the gene is selected from the group consisting of Janus kinase 2 (JAK2), calreticulin (CALR), CD 110, thrombopoietin (TPO), and any combination thereof; and(b) administering a pharmaceutical composition comprising means for preferential binding to an activated CD110 conformation and a pharmaceutically acceptable carrier into the subject.

Images