Anti-IL1RAP Antibodies and Antibody-Drug Conjugates

Abstract

The present specification discloses interleukin-1 receptor accessory protein (IL1RAP) antibodies and antibody-drug conjugates (ADCs), including compositions and methods using the antibodies and ADCs. In certain aspects, the present invention provides anti-IL1RAP antibodies, antigen-binding portions thereof, and antibody-drug conjugates (ADCs). In certain embodiments of the present invention, the antibody or antigen-binding portion thereof binds to IL1RAP (SEQ ID NO: 286) or the extracellular domain of IL1RAP. In yet other embodiments of the present invention, the anti-IL1RAP antibody-drug conjugates (ADCs) of the present invention (e.g., IL1RAP antibodies of the present invention conjugated to a toxin) are capable of internalization. In another embodiment, the anti-IL1RAP antibody-drug conjugates (ADCs) of the present invention are capable of inducing cell death of cells that endogenously express IL1RAP.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Application No. 62 / 518,069, filed June 12, 2017, the entire contents of which are expressly incorporated herein by reference in their entirety.

[0002] Sequence Listing This application has been submitted electronically in ASCII format and contains a Sequence Listing, which is hereby incorporated by reference in its entirety. The ASCII copy was created on June 12, 2018, has the file name 127913-00820_SL.txt, and is 163,057 bytes in size. [Background technology]

[0003] IL1RAP, also known as "interleukin-1 receptor accessory protein," "IL-1R accessory protein," "IL-1 receptor accessory protein," "interleukin-1 receptor 3," "IL-1RAcP," "C3orf13," "IL-1R3," "IL1R3," "interleukin-1 receptor accessory protein beta," "interleukin-1 receptor accessory protein," and "IL-1R-3" (Wesche, H., J. Biol. Chem. 272: 7727-7731, 1997), is an essential part of the interleukin-1 (IL-1) receptor complex that initiates signaling events that lead to the activation of interleukin-1 responsive genes. In addition to IL1 signaling, IL1RAP is important in mediating the effects of IL33 via the ST2 / IL1RAP complex and IL36 via the IL1Rrp2 / IL1RAP complex (Garlanda et al, Immunity. 2013 Dec 12;39(6):1003-18).

[0004] Two IL-1 receptors have been identified: type I IL-1R and type II IL-1R. Both receptors can interact with all three forms of IL-1 family molecules. IL-1RI mediates IL-1-induced cell activation. However, the IL-1 / IL-1RI complex cannot signal alone and is dependent on its association with IL1RAP (Dinarello, CA, Blood 30 1996, 87(6): 2095-147) (see, e.g., WO2015 / 132602).

[0005] Alternative splicing of IL1RAP results in two transcript variants encoding two distinct isoforms, one membrane-bound and the other soluble. The ratio of the soluble form to the membrane-bound form increases during acute phase induction or stress. IL1RAP is expressed on candidate leukemia stem cells in the majority of AML patients, but not on normal hematopoietic stem cells (Agerstam, et al. PNAS USA (2015) vol. 112:34, 10786-10791).

[0006] Interleukin-1 Interleukin-1 (IL-1) is a potent proinflammatory cytokine that induces the synthesis of acute-phase and proinflammatory proteins during infection, tissue injury, or stress by forming a complex with the interleukin-1 receptor and accessory proteins at the cell membrane. IL-1 can be produced by various cell types, including mononuclear phagocytes, in response to infection and inflammation. The IL-1 family consists of seven agonists, including IL-1α and IL-1β, and three naturally occurring receptor antagonists, including the IL-1 receptor antagonist (IL-25 1Ra) (Dinarello, CA, Blood 1996, 87(6): 2095-147).

[0007] IL-1 can activate several cell types, including leukocytes and endothelial cells. IL-1 induces and amplifies immunological responses by promoting the production and expression of adhesion molecules, cytokines, chemokines, and other inflammatory mediators, such as prostaglandin E2 and nitric oxide (NO). As a result, local inflammation is amplified and sustained. Furthermore, IL-1-induced production of inflammatory mediators leads to fever, headache, hypotension, and weight loss. Furthermore, IL-1 is a hematopoietic growth factor and has been shown to reduce nadir white blood cell and platelet counts in patients during bone marrow transplantation. IL-1 has also been shown to promote angiogenesis by inducing the production of vascular endothelial growth factor, thereby enhancing pannus formation and blood supply in rheumatoid joints. Finally, IL-1 has been shown to promote bone and cartilage degradation in rheumatic diseases.

[0008] IL-1 has been implicated in a wide range of diseases and conditions, ranging from gout to cancer, including diseases of the joints, bones, and muscles such as rheumatoid arthritis and osteoarthritis, inherited systemic autoinflammatory diseases such as familial Mediterranean fever, systemic autoinflammatory diseases such as systemic juvenile idiopathic arthritis and adult-onset Still's disease, general inflammatory diseases such as gout and type 2 diabetes, acute-onset ischemic diseases such as myocardial infarction, and cancer (for reviews, see Dinarello et al., 2012, Nature Reviews 11:633-652 and Dinarello, 2014, Mol. Med. 20 (suppl. 1):S43-S58, the disclosures of which are incorporated herein by reference).

[0009] Several treatments for blocking IL-1 activity have been approved and are in development. Targeting IL-1 began in 1993 with the introduction of anakinra (Kineret™, Amgen), a recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1 Ra), which blocks the activity of both IL-1α and IL-1β. Since then, this therapeutic agent has been used to demonstrate the role of IL-1 in a number of diseases. Neutralizing IL-1 with antibodies or soluble receptors has also proven effective; the soluble decoy receptor rilonacept (Arcalyst™, Regeneron) and the anti-IL-1β (anti-IL-1) (3) neutralizing monoclonal antibody canakinumab (IIaris™, Novartis) are currently approved. Other therapeutic approaches are under investigation, including IL-1α neutralization, therapeutic vaccines targeting IL-1β, and chimeric IL-1Ra. Additionally, orally active small molecule inhibitors of IL-1 production, such as caspase 1 inhibitors, are being developed. Antibody drug conjugates (ADCs) represent a new class of therapeutic agents comprising antibodies conjugated to cytotoxic drugs via chemical linkers. The therapeutic concept of ADCs is to combine the binding capacity of antibodies with drugs, using antibodies to deliver the drugs to tumor cells by binding to target surface antigens. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2015 / 132602 [Non-patent literature]

[0011] [Non-Patent Document 1] Wesche, H., J. Biol. Chem. 272: 7727-7731, 1997 [Non-patent document 2] Garlanda et al, Immunity. 2013 Dec 12;39(6):1003-18 [Non-patent document 3] Dinarello, CA, Blood 30 1996, 87(6): 2095-147 [Non-patent document 4] Agerstam, et al. PNAS USA (2015) vol. 112:34, 10786-10791 [Non-Patent Document 5] Dinarello et al., 2012, Nature Reviews 11 :633-652 [Non-patent document 6] Dinarello, 2014, Mol. Med. 20 (suppl. 1):S43-S58 Summary of the Invention [Means for solving the problem]

[0012] Thus, there remains a need in the art for anti-IL1RAP antibodies and ADCs that can be used therapeutically in the treatment of cancer. In certain aspects, the present invention provides anti-IL1RAP antibodies, antigen-binding portions thereof, and antibody-drug conjugates (ADCs). In certain embodiments of the invention, the antibody or antigen-binding portion thereof binds to IL1RAP (SEQ ID NO: 286) or the extracellular domain of IL1RAP.

[0013] In one embodiment, an antibody or antigen-binding portion thereof of the invention has a K of about 2,000 nM or less, about 1,000 nM or less, about 500 nM or less, about 200 nM or less, about 100 nM or less, about 75 nM or less, about 25 nM or less, about 21 nM or less, about 12 nM or less, about 11 nM or less, about 10 nM or less, about 9 nM or less, about 8 nM or less, about 7 nM or less, about 6 nM or less, about 5 nM or less, about 4 nM or less, about 3 nM or less, about 2 nM or less, about 1 nM or less, about 0.5 nM or less, about 0.3 nM or less, about 0.1 nM or less, or about 0.01 nM or less, or about 0.001 nM or less. d It binds to IL1RAP.

[0014] In yet other embodiments of the invention, the anti-IL1RAP antibody drug conjugates (ADCs) of the invention (e.g., IL1RAP antibodies of the invention conjugated to a toxin) are capable of internalization. In another embodiment, the anti-IL1RAP antibody drug conjugates (ADCs) of the invention are capable of inducing cell death of cells that endogenously express IL1RAP.

[0015] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:4, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:8.

[0016] In some embodiments, the antibody, or antigen-binding portion thereof, further comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 7. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 2, and a light chain variable region comprising a CDR1 having the amino acid sequence of any of SEQ ID NOs: 6.

[0017] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 12, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 16.

[0018] In some embodiments, the antibody, or antigen-binding portion thereof, further comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 11, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 15. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR1 having the amino acid sequence of any of SEQ ID NOs: 14.

[0019] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:20, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:24.

[0020] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 19, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 23. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 18, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 22.

[0021] In yet another aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 28, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 31.

[0022] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 27, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 23. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 30.

[0023] In another aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 35, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 39.

[0024] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 34, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 37.

[0025] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 43, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 47.

[0026] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 42, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 46. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 41, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 45.

[0027] In another aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 51, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 55.

[0028] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 50, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 54. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 49, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 53.

[0029] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:59, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:63.

[0030] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 58, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 57, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 61.

[0031] In another aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 67, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70.

[0032] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 66, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 65, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 69.

[0033] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 67, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70.

[0034] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 72, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 65, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 69.

[0035] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 77, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 81.

[0036] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 76, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 80. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 75, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 79.

[0037] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 12, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 16.

[0038] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 11, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 15. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 14.

[0039] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 86, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 89.

[0040] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 85, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 80. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 88.

[0041] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 92, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 95.

[0042] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 91, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 80. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 94.

[0043] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 92, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 99.

[0044] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 97, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 80. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 79.

[0045] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:20, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:24.

[0046] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 102, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 105. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 101, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 104.

[0047] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 86, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 89.

[0048] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 107, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 80. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 88.

[0049] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 112, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 39.

[0050] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 111, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 110, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 37.

[0051] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 35, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 39.

[0052] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 34, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 115.

[0053] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 35, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 39.

[0054] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 34, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 117, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 37.

[0055] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 67, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70.

[0056] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 119, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 69.

[0057] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 67, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70.

[0058] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 66, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 101, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 69.

[0059] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 67, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70.

[0060] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 66, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 69.

[0061] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 67, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 129.

[0062] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 66, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 101, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 69.

[0063] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 133, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70.

[0064] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 132, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 131, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 135.

[0065] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 51, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 55.

[0066] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 50, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 139. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 49, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 138.

[0067] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 142, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 47.

[0068] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 42, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 46. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 141, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 45.

[0069] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 43, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 150.

[0070] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 146, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 149. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 145, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 148.

[0071] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 43, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 157.

[0072] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 153, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 156. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 152, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 155.

[0073] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 43, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 162.

[0074] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 159, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 161. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 145, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 148.

[0075] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 166, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 169.

[0076] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 165, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 168. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 164, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 155.

[0077] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 171, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 169.

[0078] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 165, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 168. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 164, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 155.

[0079] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 176, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 179.

[0080] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 175, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 178. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 174, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 79.

[0081] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 183, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 179.

[0082] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 182, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 80. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 101, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 79.

[0083] In one aspect of the present invention, the disclosure provides an isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 188, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 63.

[0084] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 187, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. In another embodiment, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 186, and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 190.

[0085] In some aspects, the antibody or antigen-binding portion thereof is a human or humanized antibody. In one embodiment, the antibody or antigen-binding portion thereof is an IgG isotype. In some embodiments, the antibody or antigen-binding portion thereof is an IgG1 isotype. In another embodiment, the antibody or antigen-binding portion thereof is an IgG4 isotype. In another embodiment, the antibody or antigen-binding portion thereof is an IgG2 isotype. In another embodiment, the antibody or antigen-binding portion thereof is an IgG3 isotype.

[0086] In one embodiment, the antibody or antigen-binding portion thereof is capable of inducing antibody-dependent cellular cytotoxicity (ADCC). In one embodiment, the antibody or antigen-binding portion thereof is unable to induce ADCC.

[0087] In one embodiment, the antibody or antigen-binding portion thereof is capable of inducing complement-dependent cytotoxicity (CDC). In one embodiment, the antibody or antigen-binding portion thereof is not capable of inducing CDC.

[0088] In one embodiment, the antibody or antigen-binding portion thereof is capable of inducing ADCC and CDC. In one embodiment, the antibody or antigen-binding portion thereof is unable to induce ADCC or CDC.

[0089] In certain embodiments, the anti-IL1RAP antibody, or antigen-binding portion thereof, is a multispecific antibody, eg, a bispecific antibody.

[0090] In some embodiments, the antibody or antigen-binding portion thereof has a K D It has.

[0091] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 3, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 8, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 7, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 6.

[0092] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 12, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 11, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 16, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 14.

[0093] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 19, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 18, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 24, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 22.

[0094] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 28, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 27, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 31, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 30.

[0095] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37.

[0096] In one aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 41, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 47, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 46, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 45.

[0097] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 51, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 50, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 49, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 55, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 54, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 53.

[0098] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 59, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 58, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 57, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 63, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 61.

[0099] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 66, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 65, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69.

[0100] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 72, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 65, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69.

[0101] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 77, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 76, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 75, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 81, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 79.

[0102] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 86, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 85, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 88.

[0103] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 92, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 91, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 95, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 94.

[0104] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 92, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 97, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 99, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 79.

[0105] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 102, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 24, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 105, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 104.

[0106] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 86, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 107, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 88.

[0107] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 112, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 111, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 110, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37.

[0108] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 115.

[0109] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 117, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37.

[0110] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 119, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69.

[0111] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 66, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69.

[0112] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 66, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69.

[0113] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 66, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 129, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69.

[0114] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 133, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 132, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 131, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 135.

[0115] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 51, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 50, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 49, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 55, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 139, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 138.

[0116] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 142, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 141, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 47, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 46, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 45.

[0117] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 146, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 145, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 150, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 149, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 148.

[0118] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 153, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 152, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 157, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 156, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 155.

[0119] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 159, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 145, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 162, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 161, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 148.

[0120] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 166, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 165, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 164, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 169, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 168, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 155.

[0121] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 171, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 165, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 164, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 169, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 168, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 155.

[0122] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 176, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 175, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 174, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 179, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 178, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 79.

[0123] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 183, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 182, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 181, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 179, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 79.

[0124] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 188, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 187, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 186, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 63, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 190.

[0125] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:1, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:5.

[0126] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:1, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:1, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO:5, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:5.

[0127] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:13.

[0128] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 9, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 9, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 13, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 13.

[0129] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:17, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:21.

[0130] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 17, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 17, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 21, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 21.

[0131] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:25, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:29.

[0132] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:25, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:25, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO:29, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:29.

[0133] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:32, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:36.

[0134] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 32, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 32, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 36, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 36.

[0135] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:40, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:44.

[0136] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:40, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:40, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO:44, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:44.

[0137] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:48, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:52.

[0138] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:48, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:48, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO:52, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:52.

[0139] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:60.

[0140] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:56, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:56, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO:60, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:60.

[0141] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:64, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:68.

[0142] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 64, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 64, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 68, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 68.

[0143] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:71, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:73.

[0144] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 71, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 71, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 73, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 73.

[0145] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:74, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:78.

[0146] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 74, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 74, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 78, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 78.

[0147] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:82.

[0148] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 9, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 9, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 82, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 82.

[0149] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:83, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:87.

[0150] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 83, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 83, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 87, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 87.

[0151] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:90, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:93.

[0152] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:90, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:90, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO:93, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:93.

[0153] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:96, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:98.

[0154] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:96, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:96, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO:98, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:98.

[0155] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 103.

[0156] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 100, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 100, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 103, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 103.

[0157] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:106, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:108.

[0158] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 106, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 106, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 108, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 108.

[0159] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:109, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:113.

[0160] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 109, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 109, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 113, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 113.

[0161] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 32, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 114.

[0162] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 32, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 32, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 114, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 114.

[0163] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:116, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:36.

[0164] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 116, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 116, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 36, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 36.

[0165] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:118, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:120.

[0166] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 118, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 118, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 120, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 120.

[0167] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:121, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:122.

[0168] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 121, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 121, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 122, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 122.

[0169] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 123, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 124.

[0170] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 123, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 123, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 124, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 124.

[0171] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 125, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126.

[0172] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 125, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 125, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 126, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 126.

[0173] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 127, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 128.

[0174] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 127, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 127, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 128, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 128.

[0175] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 130, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 134.

[0176] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 130, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 130, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 134, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 134.

[0177] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 136, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 137.

[0178] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 136, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 136, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 137, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 137.

[0179] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 140, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 143.

[0180] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 140, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 140, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 143, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 143.

[0181] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 144, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 147.

[0182] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 144, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 144, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 147, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 147.

[0183] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 151, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 154.

[0184] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 151, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 151, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 154, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 154.

[0185] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 158, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 160.

[0186] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 158, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 158, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 160, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 160.

[0187] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 163, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 167.

[0188] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 163, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 163, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 167, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 167.

[0189] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 170, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 172.

[0190] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 170, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 170, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 172, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 172.

[0191] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 173, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 177.

[0192] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 173, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 173, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 177, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 177.

[0193] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 180, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 184.

[0194] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 180, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 180, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 184, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 184.

[0195] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 185, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 189.

[0196] In another aspect of the present invention, the disclosure provides an anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 185, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 185, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 189, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 189.

[0197] In another aspect of the present invention, the present disclosure provides antibodies, or antigen-binding portions thereof, that bind to the same epitope as an antibody, or antigen-binding portion thereof, as described herein.

[0198] In another aspect of the present invention, the disclosure provides an isolated nucleic acid encoding an antibody or antigen-binding portion thereof as described herein.

[0199] In another aspect of the present invention, the present disclosure provides a pharmaceutical composition comprising an antibody or antigen-binding portion thereof as described herein and a pharmaceutically acceptable carrier.

[0200] In another aspect of the present invention, the present disclosure provides an antibody, or antigen-binding portion thereof, as described herein, conjugated to at least one drug.

[0201] In some embodiments, the at least one drug is selected from the group consisting of a DNA damaging agent, an anti-apoptotic agent, a mitotic inhibitor, an antitumor antibiotic, an immunomodulatory agent, a nucleic acid for gene therapy, an anti-angiogenic agent, an antimetabolite, a boron-containing agent, a chemoprotective agent, a hormonal agent, an anti-hormonal agent, a corticosteroid, a photoactive therapeutic agent, an oligonucleotide, a radionuclide agent, a radiosensitizer, a topoisomerase inhibitor, and a tyrosine kinase inhibitor. In one embodiment, the drug is a DNA damaging agent. In one embodiment, the DNA damaging agent is a PBD.

[0202] In other embodiments, at least one drug is conjugated to the antibody or its antigen-binding portion via a linker. In another embodiment, the linker is a cleavable linker. In yet other embodiments, the linker is a non-cleavable linker.

[0203] In another aspect of the present invention, the present disclosure provides a drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 3, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 8, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 7, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 6.

[0204] In another aspect of the present invention, the present disclosure provides a drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 12, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 11, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 16, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 14.

[0205] In another aspect of the present invention, the present disclosure provides a drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 19, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 18, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 24, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 22.

[0206] In another aspect of the present invention, the present disclosure provides a drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 28, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 27, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 31, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 30.

[0207] In another aspect of the present invention, the present disclosure provides a drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37.

[0208] In another aspect of the present invention, the present disclosure provides an antibody drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 41, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 47, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 46, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 45.

[0209] In another aspect of the present invention, the present disclosure provides a drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 51, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 50, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 49, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 55, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 54, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 53.

[0210] In another aspect of the present invention, the present disclosure provides an antibody drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 59, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 58, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 57, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 63, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 61.

[0211] In another aspect of the present invention, the present disclosure provides an antibody drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 66, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 65, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69.

[0212] In another aspect of the present invention, the present disclosure provides an antibody drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 72, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 65, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69.

[0213] In another aspect of the present invention, the present disclosure provides an antibody drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 77, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 76, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 75, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 81, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 79.

[0214] In another aspect of the present invention, the present disclosure provides an antibody drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 86, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 85, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 88.

[0215] In another aspect of the present invention, the present disclosure provides an antibody drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 92, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 91, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 95, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 94.

[0216] In another aspect of the present invention, the present disclosure provides an antibody drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 92, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 97, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 99, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 79.

[0217] In another aspect of the present invention, the present disclosure provides an antibody drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 102, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 24, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 105, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 104.

[0218] In another aspect of the present invention, the present disclosure provides an antibody drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 86, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 107, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 88.

[0219] In another aspect of the present invention, the present disclosure provides an antibody drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 112, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 111, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 110, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37.

[0220] In another aspect of the present invention, the present disclosure provides an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 115.

[0221] In another aspect of the present invention, the present disclosure provides an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 117, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37.

[0222] In another aspect of the present invention, the present disclosure provides an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 119, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69.

[0223] In another aspect of the present invention, the present disclosure provides an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 66, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69.

[0224] In another aspect of the present invention, the present disclosure provides an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 66, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69.

[0225] In another aspect of the present invention, the present disclosure provides an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 66, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 129, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69.

[0226] In another aspect of the present invention, the present disclosure provides an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 133, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 132, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 131, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 135.

[0227] In another aspect of the present invention, the present disclosure provides an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 51, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 50, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 49, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 55, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 139, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 138.

[0228] In another aspect of the present invention, the present disclosure provides an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 142, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 141, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 47, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 46, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 45.

[0229] In another aspect of the present invention, the present disclosure provides an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 146, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 145, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 150, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 149, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 148.

[0230] In another aspect of the present invention, the present disclosure provides an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 153, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 152, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 157, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 156, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 155.

[0231] In another aspect of the present invention, the present disclosure provides an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 159, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 145, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 162, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 161, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 148.

[0232] In another aspect of the present invention, the present disclosure provides an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 166, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 165, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 164, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 169, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 168, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 155.

[0233] In another aspect of the present invention, the present disclosure provides an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 171, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 165, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 164, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 169, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 168, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 155.

[0234] In another aspect of the present invention, the present disclosure provides an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 176, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 175, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 174, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 179, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 178, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 79.

[0235] In another aspect of the present invention, the present disclosure provides an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 183, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 182, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 181, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 179, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 79.

[0236] In another aspect of the present invention, the present disclosure provides an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 188, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 187, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 186, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 63, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 190.

[0237] In another aspect of the present invention, the present disclosure provides an antibody, or antigen-binding portion thereof, as described herein, conjugated to at least one drug.

[0238] In some embodiments, at least one drug is selected from the group consisting of DNA damaging agents, anti-apoptotic agents, mitotic inhibitors, antitumor antibiotics, immunomodulators, nucleic acids for gene therapy, anti-angiogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, hormones, antihormones, corticosteroids, photoactive therapeutic agents, oligonucleotides, radionuclides, radiosensitizers, topoisomerase inhibitors, and tyrosine kinase inhibitors.In one embodiment, the drug is a DNA damaging agent.In one embodiment, the DNA damaging agent is a PBD.

[0239] In other embodiments, at least one drug is conjugated to the antibody or its antigen-binding portion via a linker. In yet another embodiment, the linker is a cleavable linker. In another embodiment, the linker is a non-cleavable linker.

[0240] In some embodiments, the antibody or antigen-binding portion thereof is an IgG1 isotype. In another embodiment, the antibody or antigen-binding portion thereof is an IgG4 isotype. In another embodiment, the antibody or antigen-binding portion thereof is an IgG2 isotype. In another embodiment, the antibody or antigen-binding portion thereof is an IgG3 isotype.

[0241] In another aspect of the present invention, the disclosure provides a pharmaceutical composition comprising an ADC mixture comprising a plurality of ADCs as described herein and a pharmaceutically acceptable carrier.

[0242] In some embodiments, the ADC mixture has an average drug-antibody ratio (DAR) of 0-8.

[0243] In another aspect of the invention, the present disclosure provides a method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen-binding portion thereof as described herein, or an ADC as described herein.

[0244] In some embodiments, the cancer is acute myeloid leukemia (AML). In other embodiments, the cancer is myelodysplastic syndrome (MDS). In other embodiments, the cancer is NSCLC. In other embodiments, the cancer is ovarian cancer.

[0245] In some embodiments, the present disclosure provides a method for inhibiting or reducing solid tumor growth in a subject having a solid tumor, the method comprising administering to the subject having the solid tumor an effective amount of an antibody or antigen-binding portion thereof as described herein, or an ADC as described herein, to inhibit or reduce solid tumor growth.

[0246] In some embodiments, the antibody or antigen-binding portion thereof, or ADC is administered in combination with an additional agent or therapy. In another embodiment, the additional agent is an immune checkpoint inhibitor. In yet another embodiment, the immune checkpoint inhibitor is an antibody. In another embodiment, the antibody is selected from the group consisting of an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody. In another embodiment, the additional therapy is radiation. In yet another embodiment, the additional agent is a chemotherapeutic agent. In some embodiments, the cancer or tumor is characterized as having IL1RAP expression or overexpression. In an embodiment of the present invention, for example, the following items are provided: (Item 1) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 4, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 8. (Item 2) 2. The antibody or antigen-binding portion thereof according to item 1, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 7. (Item 3) 3. The antibody or antigen-binding portion thereof of item 1 or 2, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6. (Item 4) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 12, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 16. (Item 5) 5. The antibody or antigen-binding portion thereof according to item 4, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 11, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 15. (Item 6) 6. The antibody or antigen-binding portion thereof of item 4 or 5, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 14. (Item 7) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 20, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 24. (Item 8) 8. The antibody or antigen-binding portion thereof according to item 7, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 19, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 23. (Item 9) 9. The antibody or antigen-binding portion thereof according to item 7 or 8, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 18, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 22. (Item 10) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 28, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 31. (Item 11) 11. The antibody or antigen-binding portion thereof of item 10, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 23. (Item 12) 12. The antibody or antigen-binding portion thereof of item 10 or 11, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 30. (Item 13) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 35, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 39. (Item 14) 14. The antibody or antigen-binding portion thereof of item 13, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 34 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38. (Item 15) 15. The antibody or antigen-binding portion thereof of item 13 or 14, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 37. (Item 16) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 43, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 47. (Item 17) 17. The antibody or antigen-binding portion thereof of item 16, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 42, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 46. (Item 18) 18. The antibody or antigen-binding portion thereof of item 16 or 17, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 41, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 45. (Item 19) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 51, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 55. (Item 20) 20. The antibody or antigen-binding portion thereof of item 19, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 50, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 54. (Item 21) 21. The antibody or antigen-binding portion thereof of item 19 or 20, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 49, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 53. (Item 22) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 59, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 63. (Item 23) 23. The antibody or antigen-binding portion thereof of claim 22, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 58 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. (Item 24) 24. The antibody or antigen-binding portion thereof of item 22 or 23, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 57, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 61. (Item 25) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 67, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70. (Item 26) 26. The antibody or antigen-binding portion thereof of item 25, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 66, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. (Item 27) 27. The antibody or antigen-binding portion thereof of item 25 or 26, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 65, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 69. (Item 28) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 67, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70. (Item 29) 29. The antibody or antigen-binding portion thereof of item 28, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 72 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. (Item 30) 30. The antibody or antigen-binding portion thereof of item 28 or 29, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 65, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 69. (Item 31) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 77, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 81. (Item 32) 32. The antibody or antigen-binding portion thereof of claim 31, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 76, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 80. (Item 33) 33. The antibody or antigen-binding portion thereof of item 31 or 32, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 75, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 79. (Item 34) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 12, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 16. (Item 35) 35. The antibody or antigen-binding portion thereof of item 34, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 11, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 15. (Item 36) 36. The antibody or antigen-binding portion thereof of item 34 or 35, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 14. (Item 37) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 86, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 89. (Item 38) 38. The antibody or antigen-binding portion thereof of item 37, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 85, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 80. (Item 39) 39. The antibody or antigen-binding portion thereof of item 37 or 38, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 88. (Item 40) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 92, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 95. (Item 41) 41. The antibody or antigen-binding portion thereof of item 40, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 91, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 80. (Item 42) 42. The antibody or antigen-binding portion thereof of item 40 or 41, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 94. (Item 43) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 92, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 99. (Item 44) 44. The antibody or antigen-binding portion thereof of item 43, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 97, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 80. (Item 45) 45. The antibody or antigen-binding portion thereof of claim 43 or 44, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 79. (Item 46) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 20, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 24. (Item 47) 47. The antibody or antigen-binding portion thereof of item 46, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 102, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 105. (Item 48) 48. The antibody or antigen-binding portion thereof of item 46 or 47, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 101, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 104. (Item 49) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 86, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 89. (Item 50) 50. The antibody or antigen-binding portion thereof of item 49, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 107, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 80. (Item 51) 51. The antibody or antigen-binding portion thereof of item 49 or 50, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 88. (Item 52) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 112, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 39. (Item 53) 53. The antibody or antigen-binding portion thereof of item 52, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 111, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38. (Item 54) 54. The antibody or antigen-binding portion thereof of Item 52 or 53, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 110, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 37. (Item 55) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 35, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 39. (Item 56) 56. The antibody or antigen-binding portion thereof of item 55, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 34, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38. (Item 57) 57. The antibody or antigen-binding portion thereof of item 55 or 56, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 115. (Item 58) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 35, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 39. (Item 59) 59. The antibody or antigen-binding portion thereof of claim 58, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 34, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38. (Item 60) 60. The antibody or antigen-binding portion thereof of item 58 or 59, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 117, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 37. (Item 61) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 67, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70. (Item 62) 62. The antibody or antigen-binding portion thereof of claim 61, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 119, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. (Item 63) 63. The antibody or antigen-binding portion thereof of Item 61 or 62, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 69. (Item 64) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 67, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70. (Item 65) 65. The antibody or antigen-binding portion thereof of item 64, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 66, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. (Item 66) 66. The antibody or antigen-binding portion thereof of item 64 or 65, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 101, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 69. (Item 67) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 67, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70. (Item 68) 68. The antibody or antigen-binding portion thereof of Item 67, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 66, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. (Item 69) 69. The antibody or antigen-binding portion thereof of Item 67 or 68, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 69. (Item 70) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 67, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 129. (Item 71) 71. The antibody or antigen-binding portion thereof of claim 70, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 66, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. (Item 72) 72. The antibody or antigen-binding portion thereof of item 70 or 71, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 101, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 69. (Item 73) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 133, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70. (Item 74) 74. The antibody or antigen-binding portion thereof of Item 73, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 132, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. (Item 75) 75. The antibody or antigen-binding portion thereof of item 73 or 74, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 131, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 135. (Item 76) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 51, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 55. (Item 77) 77. The antibody or antigen-binding portion thereof of item 76, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 50, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 139. (Item 78) 78. The antibody or antigen-binding portion thereof of item 76 or 77, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 49, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 138. (Item 79) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 142, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 47. (Item 80) 80. The antibody or antigen-binding portion thereof of Item 79, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 42, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 46. (Item 81) 81. The antibody or antigen-binding portion thereof of item 79 or 80, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 141, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 45. (Item 82) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 43, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 150. (Item 83) 83. The antibody or antigen-binding portion thereof of claim 82, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 146, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 149. (Item 84) 84. The antibody or antigen-binding portion thereof of Item 82 or 83, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 145, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 148. (Item 85) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 43, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 157. (Item 86) 86. The antibody or antigen-binding portion thereof of item 85, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 153, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 156. (Item 87) 87. The antibody or antigen-binding portion thereof of item 85 or 86, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 152, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 155. (Item 88) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 43, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 162. (Item 89) 89. The antibody or antigen-binding portion thereof of Item 88, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 159, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 161. (Item 90) 90. The antibody or antigen-binding portion thereof of claim 88 or 89, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 145, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 148. (Item 91) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 166, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 169. (Item 92) 92. The antibody or antigen-binding portion thereof of Item 91, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 165, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 168. (Item 93) 93. The antibody or antigen-binding portion thereof of Item 91 or 92, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 164, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 155. (Item 94) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 171, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 169. (Item 95) 95. The antibody or antigen-binding portion thereof of Item 94, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 165, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 168. (Item 96) 96. The antibody or antigen-binding portion thereof of item 94 or 95, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 164, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 155. (Item 97) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 176, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 179. (Item 98) 98. The antibody or antigen-binding portion thereof of Item 97, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 175, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 178. (Item 99) 99. The antibody or antigen-binding portion thereof of Item 97 or 98, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 174, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 79. (Item 100) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 183, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 179. (Item 101) 101. The antibody or antigen-binding portion thereof of item 100, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 182, and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 80. (Item 102) 102. The antibody or antigen-binding portion thereof of item 100 or 101, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 101, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 79. (Item 103) An isolated antibody or antigen-binding portion thereof that binds to human IL1RAP, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 188, and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 63. (Item 104) the antibody or antigen-binding portion thereof, wherein the CDR has the amino acid sequence of SEQ ID NO: 187 104. The antibody or antigen-binding portion thereof of Item 103, comprising a heavy chain variable region comprising CDR2 having the amino acid sequence of SEQ ID NO: 62, and a light chain variable region comprising CDR2 having the amino acid sequence of SEQ ID NO: 62. (Item 105) 105. The antibody or antigen-binding portion thereof of claim 103 or 104, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 186, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 190. (Item 106) The antibody or antigen-binding portion thereof of any one of the preceding items, wherein the antibody or antigen-binding portion thereof is an IgG isotype. (Item 107) the antibody or antigen-binding portion thereof has a K D The antibody or antigen-binding portion thereof according to any one of the preceding items, (Item 108) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 4, a CDR2 domain having the amino acid sequence of SEQ ID NO: 3, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 2, and a light chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 8, a CDR2 domain having the amino acid sequence of SEQ ID NO: 7, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 6. (Item 109) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 12, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 11, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 16, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 14. (Item 110) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 19, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 18, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 24, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 22. (Item 111) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 28, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 27, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 31, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 30. (Item 112) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37. (Item 113) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 43, a CDR2 domain having the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 41; and a light chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 47, a CDR2 domain having the amino acid sequence of SEQ ID NO: 46, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 45. (Item 114) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 51, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 50, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 49; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 55, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 54, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 53. (Item 115) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 59, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 58, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 57; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 63, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 61. (Item 116) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 66, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 65; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69. (Item 117) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 72, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 65; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69. (Item 118) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 77, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 76, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 75; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 81, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 79. (Item 119) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 86, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 85, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 84; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 88. (Item 120) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 92, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 91, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 84; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 95, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 94. (Item 121) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 92, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 97, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 84; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 99, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 79. (Item 122) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 20, a CDR2 domain having the amino acid sequence of SEQ ID NO: 102, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 101; and a light chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 24, a CDR2 domain having the amino acid sequence of SEQ ID NO: 105, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 104. (Item 123) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 86, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 107, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 84; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 88. (Item 124) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 112, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 111, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 110; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37. (Item 125) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 115. (Item 126) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 117; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37. (Item 127) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 119, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69. (Item 128) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 66, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69. (Item 129) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 66, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69. (Item 130) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 67, a CDR2 domain having the amino acid sequence of SEQ ID NO: 66, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 101; and a light chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 129, a CDR2 domain having the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 69. (Item 131) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 133, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 132, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 131; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 135. (Item 132) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 51, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 50, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 49; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 55, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 139, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 138. (Item 133) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 142, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 141; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 47, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 46, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 45. (Item 134) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 146, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 145; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 150, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 149, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 148. (Item 135) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 153, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 152; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 157, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 156, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 155. (Item 136) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 159, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 145; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 162, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 161, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 148. (Item 137) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 166, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 165, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 164; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 169, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 168, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 155. (Item 138) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 171, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 165, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 164; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 169, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 168, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 155. (Item 139) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 176, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 175, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 174; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 179, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 178, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 79. (Item 140) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 183, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 182, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 181; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 179, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 79. (Item 141) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 188, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 187, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 186; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 63, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 190. (Item 142) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 1, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 5. (Item 143) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1 or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 1, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 5 or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 5. (Item 144) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:13. (Item 145) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 9, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 9, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 13, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13. (Item 146) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 17, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 21. (Item 147) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 17, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 21, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 21. (Item 148) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 25, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 29. (Item 149) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 25, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 25, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 29, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29. (Item 150) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 32, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36. (Item 151) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 32, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 32, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 36, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 36. (Item 152) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 40, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 44. (Item 153) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 40, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 40, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 44, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 44. (Item 154) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 48, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 52. (Item 155) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 48, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 48, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 52, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 52. (Item 156) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 60. (Item 157) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 56, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 56, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 60, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 60. (Item 158) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 64, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 68. (Item 159) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 64, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 64, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 68, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 68. (Item 160) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 71, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 73. (Item 161) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 71, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 71, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 73, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 73. (Item 162) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 74, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 78. (Item 163) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 74, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 74, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 78, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 78. (Item 164) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 82. (Item 165) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 9, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 9, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 82, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 82. (Item 166) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 83, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 87. (Item 167) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 83, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 83, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 87, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 87. (Item 168) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 90, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 93. (Item 169) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 90, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 90, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 93, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 93. (Item 170) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 96, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 98. (Item 171) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 96, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 96, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 98, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 98. (Item 172) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 103. (Item 173) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 100, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 100, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 103, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 103. (Item 174) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 106, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 108. (Item 175) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 106, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 106, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 108, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 108. (Item 176) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 109, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 113. (Item 177) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 109, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 109, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 113, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 113. (Item 178) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 32, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 114. (Item 179) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 32, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 32, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 114, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 114. (Item 180) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 116, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36. (Item 181) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 116, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 116, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 36, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 36. (Item 182) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 118, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 120. (Item 183) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 118, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 120, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 120. (Item 184) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 121, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 122. (Item 185) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 121, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 121, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 122, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 122. (Item 186) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 123, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 124. (Item 187) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 123, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 123, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 124, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 124. (Item 188) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 125, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 126. (Item 189) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 125, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 125, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 126, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 126. (Item 190) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 127, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 128. (Item 191) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 127, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 127, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 128, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 128. (Item 192) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 130, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 134. (Item 193) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 130, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 130, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 134, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 134. (Item 194) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 136, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 137. (Item 195) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 136, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 136, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 137, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 137. (Item 196) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 140, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 143. (Item 197) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 140, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 140, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 143, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 143. (Item 198) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 144, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 147. (Item 199) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 144, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 144, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 147, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 147. (Item 200) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 151, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 154. (Item 201) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 151, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 151, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 154, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 154. (Item 202) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 158, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 160. (Item 203) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 158, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 158, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 160, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 160. (Item 204) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 163, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 167. (Item 205) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 163, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 163, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 167, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 167. (Item 206) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 170, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 172. (Item 207) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 170, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 170, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 172, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 172. (Item 208) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 173, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 177. (Item 209) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 173, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 173, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 177, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 177. (Item 210) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 180, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 184. (Item 211) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 180, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 180, and / or the amino acid sequence set forth in SEQ ID NO: 184, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 184; An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a light chain comprising a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity. (Item 212) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 185, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 189. (Item 213) An anti-IL1RAP antibody or antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 185, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 185, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 189, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 189. (Item 214) An antibody or antigen-binding portion thereof that binds to the same epitope as the antibody or antigen-binding portion thereof described in any one of the preceding items. (Item 215) An isolated nucleic acid encoding the antibody or antigen-binding portion thereof described in any one of the preceding items. (Item 216) A pharmaceutical composition comprising the antibody or antigen-binding portion thereof described in any one of the preceding items and a pharmaceutically acceptable carrier. (Item 217) The antibody or antigen-binding portion thereof of any one of the preceding items, conjugated to at least one drug. (Item 218) 218. The antibody or antigen-binding portion thereof of item 217, wherein the at least one drug is selected from the group consisting of a DNA damaging agent, an anti-apoptotic agent, a mitotic inhibitor, an antitumor antibiotic, an immunomodulatory agent, a nucleic acid for gene therapy, an anti-angiogenic agent, an antimetabolite, a boron-containing agent, a chemoprotective agent, a hormonal agent, an anti-hormonal agent, a corticosteroid, a photoactive therapeutic agent, an oligonucleotide, a radionuclide agent, a radiosensitizer, a topoisomerase inhibitor, and a tyrosine kinase inhibitor. (Item 219) 218. The antibody or antigen-binding portion thereof of claim 217, wherein the at least one drug is conjugated to the antibody or antigen-binding portion thereof via a linker. (Item 220) 220. The antibody or antigen-binding portion thereof of item 219, wherein the linker is a cleavable linker. (Item 221) 220. The antibody or antigen-binding portion thereof of item 219, wherein the linker is a non-cleavable linker. (Item 222) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 3, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 8, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 7, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 6. (Item 223) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 12, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 11, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 16, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 14. (Item 224) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 19, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 18, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 24, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 22. (Item 225) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 28, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 27, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 31, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 30. (Item 226) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37. (Item 227) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 41, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 47, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 46, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 45. (Item 228) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 51, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 50, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 49, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 55, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 54, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 53. (Item 229) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 59, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 58, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 57, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 63, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 61. (Item 230) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 66, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 65, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69. (Item 231) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 72, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 65, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69. (Item 232) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 77, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 76, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 75, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 81, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 79. (Item 233) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 86, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 85, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 88. (Item 234) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 92, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 91, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 95, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 94. (Item 235) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 92, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 97, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 99, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 79. (Item 236) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 102, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 24, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 105, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 104. (Item 237) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 86, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 107, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 88. (Item 238) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 112, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 111, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 110, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37. (Item 239) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 115. (Item 240) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 117, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37. (Item 241) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 119, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69. (Item 242) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 66, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69. (Item 243) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 66, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69. (Item 244) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 66, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 129, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 69. (Item 245) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 133, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 132, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 131, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 135. (Item 246) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 51, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 50, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 49, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 55, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 139, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 138. (Item 247) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 142, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 141, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 47, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 46, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 45. (Item 248) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 146, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 145, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 150, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 149, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 148. (Item 249) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 153, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 152, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 157, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 156, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 155. (Item 250) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 159, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 145, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 162, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 161, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 148. (Item 251) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 166, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 165, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 164, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 169, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 168, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 155. (Item 252) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 171, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 165, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 164, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 169, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 168, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 155. (Item 253) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 176, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 175, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 174, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 179, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 178, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 79. (Item 254) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 183, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 182, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 181, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 179, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 79. (Item 255) An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 188, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 187, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 186, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 63, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 190. (Item 256) 256. The ADC of any one of items 222 to 255, wherein the antibody or antigen-binding portion thereof is of the IgG1 or IgG4 isotype. (Item 257) A pharmaceutical composition comprising an ADC mixture comprising a plurality of ADCs according to any one of items 222 to 255 and a pharmaceutically acceptable carrier. (Item 258) 258. The pharmaceutical composition of item 257, wherein the ADC mixture has an average drug-to-antibody ratio (DAR) of 0 to 8. (Item 259) A method for treating cancer, comprising administering a therapeutically effective amount of the antibody or antigen-binding portion thereof according to any one of items 1 to 221, or the ADC according to any one of items 222 to 255, to a subject in need thereof. (Item 260) 259. The method of claim 259, wherein the cancer is acute myeloid leukemia (AML). (Item 261) 259. The method of claim 259, wherein the cancer is myelodysplastic syndrome (MDS). (Item 262) 259. The method of claim 259, wherein the cancer is selected from the group consisting of ovarian cancer, lung cancer, and non-small cell lung cancer (NSCLC). (Item 263) A method for inhibiting or reducing solid tumor growth in a subject having a solid tumor, the method comprising administering to the subject having the solid tumor an effective amount of the antibody or antigen-binding portion thereof described in any one of Items 1 to 221, or the ADC described in any one of Items 222 to 255, such that the solid tumor growth is inhibited or reduced. (Item 264) Item 264. The method of item 263, wherein the cancer is lung cancer. (Item 265) 264. The method of claim 263, wherein the cancer is non-small cell lung cancer (NSCLC). (Item 266) Item 264. The method of item 263, wherein the cancer is ovarian cancer. (Item 267) 267. The method of any one of items 259 to 266, wherein the antibody or antigen-binding portion thereof is of the IgG4 isotype. (Item 268) 267. The method of any one of items 259 to 266, wherein the antibody or antigen-binding portion thereof or the ADC is administered in combination with an additional agent or therapy. (Item 269) 269. The method of claim 268, wherein the additional agent is an immune checkpoint inhibitor. (Item 270) 269. The method of claim 269, wherein the immune checkpoint inhibitor is an antibody. (Item 271) 271. The method of claim 270, wherein the antibody is selected from the group consisting of an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody. (Item 272) 269. The method of item 268, wherein the additional therapy is radiation. (Item 273) 269. The method of claim 268, wherein the additional agent is one or more chemotherapeutic agents. (Item 274) 267. The method of any one of items 259 to 266, wherein the cancer or tumor is characterized as having expression or overexpression of IL1RAP. [Brief explanation of the drawings]

[0247] [Figure 1] FIG. 1 shows the surface expression of IL1RAP in human acute myeloid leukemia cell lines EOL1, Monomac 6, OCI / AML1, and KG-1, and the T-cell leukemia cell line Karpas299, as determined by flow cytometry analysis.

[0248] [Figure 2] Figure 2 shows the specific binding of IL1RAP antibody 44E5_15C5 to the IL1RAP positive cell lines EOL1 and Karpas 299. The IL1RAP negative DMS79 cell line shows a lack of binding by IL1RAP antibody 44E5_15C5.

[0249] [Figure 3] FIG. 3 is a diagram showing the arrangement of antibody competition bins.

[0250] [Figure 4A-1] Figures 4A, 4B, 4C, and 4D show binding of anti-IL1RAP antibodies to IL1RAP orthologs. Anti-IL1RAP antibodies were assessed for cell surface binding to 293 cells expressing human (Figure 4A), macaca fascicularis (Figure 4B), rat IL1RAP (Figure 4C), and mouse IL1RAP (Figure 4D) by flow cytometry. 21H5 was the mouse antibody against human IL1RAP. CBlgG1 (anti-hen egg lysozyme antibody, CrownBio™) was included as a negative control. [Figure 4A-2] Same as above [Figure 4A-3] Same as above [Figure 4A-4] Same as above [Figure 4B-1] Same as above [Figure 4B-2] Same as above [Figure 4B-3] Same as above [Figure 4B-4] Same as above [Figure 4C-1] Same as above [Figure 4C-2] Same as above [Figure 4C-3] Same as above [Figure 4C-4] Same as above [Figure 4D-1] Same as above [Figure 4D-2] Same as above [Figure 4D-3] Same as above [Figure 4D-4] Same as above

[0251] [Figure 5] Figure 5 shows the internalization of IL1RAP antibody 44E5_15C5 into EOL1 cells. Live EOL1 cells were incubated with IL1RAP antibody 44E5_15C5 for 0.5 hours at 37°C. After cytospinning, the cells were fixed, permeabilized, and co-stained with LAMP1 antibody.

[0252] [Figure 6-1] Figures 6A, 6B, and 6C show the internalization and in vitro efficacy of IL1RAP antibodies in the human leukemia cell lines EOL1 (Figure 6A) and Karpas299 (Figure 6B). There was no cytotoxicity in the IL1RAP-negative cell line DMS79 (Figure 6C). [Figure 6-2] Figures 6A, 6B, and 6C show the internalization and in vitro efficacy of IL1RAP antibodies in the human leukemia cell lines EOL1 (Figure 6A) and Karpas299 (Figure 6B). There was no cytotoxicity in the IL1RAP-negative cell line DMS79 (Figure 6C). [Figure 6-3] Figures 6A, 6B, and 6C show the internalization and in vitro efficacy of IL1RAP antibodies in the human leukemia cell lines EOL1 (Figure 6A) and Karpas299 (Figure 6B). There was no cytotoxicity in the IL1RAP-negative cell line DMS79 (Figure 6C).

[0253] [Figure 7-1]Figures 7A, 7B, 7C, 7D, 7E, and 7F show the in vitro efficacy of anti-IL1RAP ADCs in the AML cell lines EOL1 (Figure 7A), MOLM13 (Figure 7B), MOLM14 (Figure 7C), MV(4;11) (Figure 7D), OCI / AML1 (Figure 7E), and KG-1 (Figure 7F). 3,000 cells were seeded in a 96-well plate and treated with Tesirine PBD-conjugated antibodies for 5 days. Cells were then lysed using CellTiter Glo™ 2.0 (Promega), and the results were recorded using a luminometer. hIgG1 (anti-HBV surface Ag antibody, in-house) conjugated antibodies were included as a negative control. IC50 values ​​are listed below each graph. [Figure 7-2] Figures 7A, 7B, 7C, 7D, 7E, and 7F show the in vitro efficacy of anti-IL1RAP ADCs in the AML cell lines EOL1 (Figure 7A), MOLM13 (Figure 7B), MOLM14 (Figure 7C), MV(4;11) (Figure 7D), OCI / AML1 (Figure 7E), and KG-1 (Figure 7F). 3,000 cells were seeded in a 96-well plate and treated with Tesirine PBD-conjugated antibodies for 5 days. Cells were then lysed using CellTiter Glo™ 2.0 (Promega), and the results were recorded using a luminometer. hIgG1 (anti-HBV surface Ag antibody, in-house) conjugated antibodies were included as a negative control. IC50 values ​​are listed below each graph.

[0254] [Figure 8-1] Figures 8A, 8B, and 8C show blockade of IL1α / β signaling by anti-IL1RAP antibodies. IL1RAP antibodies 37E10_15B5, 44E5_15C5, 16H2_17D2, and 36A10_21B6 demonstrated potent inhibition of IL1R1 signaling in a dose-dependent manner (Figure 8A). Antibodies 37E10_15B5 and 44E5_15C5 blocked IL-1β and IL-1α signaling with subnanomolar EC50s (Figures 8B and 8C). [Figure 8-2]Figures 8A, 8B, and 8C show blockade of IL1α / β signaling by anti-IL1RAP antibodies. IL1RAP antibodies 37E10_15B5, 44E5_15C5, 16H2_17D2, and 36A10_21B6 demonstrated potent inhibition of IL1R1 signaling in a dose-dependent manner (Figure 8A). Antibodies 37E10_15B5 and 44E5_15C5 blocked IL-1β and IL-1α signaling with subnanomolar EC50s (Figures 8B and 8C). [Figure 8-3] Figures 8A, 8B, and 8C show blockade of IL1α / β signaling by anti-IL1RAP antibodies. IL1RAP antibodies 37E10_15B5, 44E5_15C5, 16H2_17D2, and 36A10_21B6 demonstrated potent inhibition of IL1R1 signaling in a dose-dependent manner (Figure 8A). Antibodies 37E10_15B5 and 44E5_15C5 blocked IL-1β and IL-1α signaling with subnanomolar EC50s (Figures 8B and 8C).

[0255] [Figure 9] Figures 9A and 9B show blockade of IL-33 signaling by anti-IL1RAP antibody. HEK-Blue IL-33 cells (Invivogen, CA) were harvested and plated in technical duplicates in 96-well plates at a density of 50,000 cells per well. Antibodies or corresponding human IgG1 control antibodies were added to the wells at serial dilutions starting at 10 μg / ml (Figure 9A) or at concentrations of 1 and 10 μg / ml (Figure 9B). After incubating the cells with the antibody for 30 minutes, IL-33 was added to a final concentration of 0.5 ng / ml, and the plates were incubated overnight. After 24 hours, substrate was added to the supernatant, and samples were analyzed for absorbance at 620 nm. CBIgG1 (anti-hen egg lysozyme antibody, CrownBio™) was included as a negative control. DETAILED DESCRIPTION OF THE INVENTION

[0256] Detailed Description Various aspects of the present disclosure relate to anti-IL1RAP antibodies and antibody fragments, anti-IL1RAP ADCs, and pharmaceutical compositions thereof, as well as nucleic acids, recombinant expression vectors, and host cells for making such antibodies and fragments. Methods of using the antibodies and ADCs described herein to detect human IL1RAP, to bind and inhibit human IL1RAP on IL1RAP-expressing cells, to inhibit IL-1, e.g., IL-1β and / or IL-1α signaling in vivo, and / or to treat IL1RAP-associated disorders, e.g., cancer, including, but not limited to, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), lung cancer, including non-small cell lung cancer (NSCLC), and ovarian cancer.

[0257] In one embodiment, the anti-IL1RAP antibodies or ADCs of the invention are administered in combination with one or more immune checkpoint inhibitors (e.g., antibody or small molecule immune checkpoint inhibitors) to treat cancer. In another embodiment of the invention, the anti-IL1RAP antibody drug conjugates (ADCs) of the invention (e.g., IL1RAP antibodies of the invention conjugated to a toxin) are internalized and induce cell death of cells that endogenously express IL1RAP.

[0258] I. Definition In order to make the present invention more readily understandable, certain terms are first defined. In addition, it should be noted that whenever a value or range of values ​​for a parameter is given, it is intended that values ​​intermediate to the given values ​​and intermediate ranges are also part of the present invention.

[0259] The terms "interleukin-1 receptor accessory protein antibody" or "anti-IL1RAP antibody," used interchangeably herein, refer to an antibody that specifically binds to IL1RAP, e.g., human IL1RAP. An antibody that "binds" an antigen of interest, i.e., IL1RAP, is one that is capable of binding to that antigen with sufficient affinity such that the antibody is useful for targeting cells expressing the antigen. In a preferred embodiment, the antibody specifically binds to human IL1RAP (hIL1RAP). Examples of anti-IL1RAP antibodies are disclosed in the Examples below. Unless otherwise specified, the term "anti-IL1RAP antibody" is intended to refer to an antibody that binds to wild-type IL1RAP, a variant or isoform of IL1RAP.

[0260] Several different isoforms of IL1RAP have been identified. An exemplary amino acid sequence of wild-type human IL1RAP, containing 570 amino acids, is provided below as SEQ ID NO: 286. The extracellular domain (ECD) of IL1-RAP comprises amino acids 21-367 of SEQ ID NO: 286. [ka]

[0261] The terms "specific binding" or "specifically binds," as used herein with respect to the interaction of an IL1RAP antibody or ADC with a second chemical species, mean that the interaction is dependent on the presence of a particular structure (e.g., an antigenic determinant or epitope) on that chemical species; for example, an antibody recognizes and binds to a particular protein structure, rather than proteins in general. If an antibody or ADC is specific for epitope "A," then in a reaction involving labeled "A," the presence of a molecule containing epitope A (or free, unlabeled A) and an antibody will reduce the amount of labeled A bound to the antibody or ADC.

[0262] In one embodiment, the phrase "specifically binds to hIL1RAP" or "specific binding to hIL1RAP", as used herein, means a specific binding of about 2,000 nM or less, about 1,000 nM or less, about 500 nM or less, about 200 nM or less, about 100 nM or less, about 75 nM or less, about 25 nM or less, about 21 nM or less, about 12 nM or less, about 11 nM or less, about 10 nM or less. The dissociation constant (K) is about 9 nM or lower, about 8 nM or lower, about 7 nM or lower, about 6 nM or lower, about 5 nM or lower, about 4 nM or lower, about 3 nM or lower, about 2 nM or lower, about 1 nM or lower, about 0.5 nM or lower, about 0.3 nM or lower, about 0.1 nM or lower, about 0.01 nM or lower, or about 0.001 nM or lower. D ) refers to the ability of an anti-IL1RAP antibody or ADC to interact with IL1RAP (human or cynomolgus IL1RAP). In another embodiment, the phrase "specifically binds to hIL1RAP" or "specific binding to hIL1RAP" as used herein means that an anti-IL1RAP antibody or ADC has a dissociation constant (K) of about 1 pM (0.001 nM) to 2,000 nM, about 500 pM (0.5 nM) to 1,000 nM, about 500 pM (0.5 nM) to 500 nM, about 1 nM to 200 nM, about 1 nM to 100 nM, about 1 nM to 50 nM, about 1 nM to 20 nM, or about 1 nM to 5 nM. D ) refers to the ability to interact with hIL1RAP. Dis determined by surface plasmon resonance or bio-layer interferometry, or any other method known in the art. Bio-layer interferometry refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by measuring the interference pattern of reflected white light, for example, using the Octet™ system (ForteBio, Pall Corp., Fremont, CA). For further description of the Octet™ system, see Li, B et al. (2011) J. Pharm. Biomed. Anal. 54(2):286-294 and Abdiche, YN et al. (2009) Anal. Biochem. 386(2):172-180, the contents of which are incorporated herein by reference.

[0263] The term "antibody" generally refers to an immunoglobulin (Ig) molecule, which is generally composed of four polypeptide chains, two heavy (H) chains and two light (L) chains, or any functional fragment, mutant, variant, or derivative thereof that retains the essential target-binding characteristics of an Ig molecule. Such mutant, variant, or derivative antibody formats are known in the art. Non-limiting embodiments thereof are discussed below.

[0264] In full-length antibodies, each heavy chain is composed of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is composed of three domains, CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is composed of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed framework regions (FR), interspersed with more conserved regions, termed complementarity-determining regions (CDRs). Each VH and VL is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Immunoglobulin molecules may be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY) and class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) or subclass.

[0265] The term "antigen-binding portion" of an antibody (or simply "antibody portion"), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., hIL1RAP). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Such antibody embodiments may also be bispecific, dual specific, or multispecific in format, i.e., specifically binding to two or more different antigens. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge in the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment comprising a single variable domain (Ward et al., (1989) Nature 341:544-546; Winter et al., PCT Publication WO 90 / 05144 A1, which are incorporated herein by reference); and (vi) isolated complementarity-determining regions (CDRs). Furthermore, although the two domains of an Fv fragment, VL and VH, are encoded by separate genes, they can be joined using recombinant methods by a synthetic linker that allows them to form a single protein chain in which the VL and VH regions pair to form a monovalent molecule (known as a single-chain Fv (scFv); see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single-chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody. In certain embodiments, scFv molecules may be incorporated into fusion proteins. Other forms of single-chain antibodies, such as diabodies, are also encompassed.Diabodies are bivalent, bispecific antibodies in which the VH and VL domains are expressed on a single polypeptide chain, but with a linker that is too short to allow pairing between the two domains on the same chain, thereby forcing them to pair with complementary domains on another chain and creating two antigen-binding sites (see, e.g., Holliger, P. et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, RJ et al. (1994) Structure 2:1121-1123). Such antibody-binding moieties are known in the art (Kontermann and Dubel, eds., Antibody Engineering (2001) Springer-Verlag, New York, p. 790 (ISBN 3-540-41354-5)).

[0266] The term "antibody construct," as used herein, refers to a polypeptide comprising one or more of the antigen-binding moieties disclosed herein linked to a linker polypeptide or immunoglobulin constant domain. A linker polypeptide comprises two or more amino acid residues joined by peptide bonds and is used to link one or more antigen-binding moieties. Such linker polypeptides are well known in the art (see, e.g., Holliger, P. et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, RJ et al. (1994) Structure 2:1121-1123). An immunoglobulin constant domain refers to a heavy or light chain constant domain. Antibody portions, such as Fab and F(ab')2 fragments, can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion of whole antibodies, respectively. Furthermore, antibodies, antibody portions, and immunoadhesion molecules can be obtained using standard recombinant DNA techniques, as described herein.

[0267] An "isolated antibody," as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to IL1RAP is substantially free of antibodies that specifically bind to antigens other than IL1RAP). However, an isolated antibody that specifically binds to IL1RAP may have cross-reactivity with other antigens, such as IL1RAP molecules from other species. Furthermore, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0268] The term "humanized antibody" refers to an antibody comprising heavy and light chain variable region sequences derived from a non-human species (e.g., mouse), but in which at least a portion of the VH and / or VL sequences have been altered to be more "human-like," i.e., more similar to human germline variable sequences. In particular, the term "humanized antibody" refers to an antibody, or a variant, derivative, analog, or fragment thereof, that immunospecifically binds to an antigen of interest and comprises framework (FR) regions having substantially the amino acid sequence of a human antibody and complementarity-determining regions (CDRs) having substantially the amino acid sequence of a non-human antibody. As used herein, the term "substantially," in the context of a CDR, refers to a CDR having an amino acid sequence that is at least 80%, preferably at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of the non-human antibody CDR. A humanized antibody comprises substantially all of at least one, and typically two, variable domains (Fab, Fab', F(ab')2, FabC, Fv), in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin (i.e., donor antibody) and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. Preferably, the humanized antibody also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. In some embodiments, the humanized antibody comprises both a light chain and at least a heavy chain variable domain. The antibody may also comprise the CH1, hinge, CH2, CH3, and CH4 regions of the heavy chain. In some embodiments, the humanized antibody comprises only a humanized light chain. In other embodiments, the humanized antibody comprises only a humanized heavy chain. In certain embodiments, the humanized antibody comprises only a humanized variable domain of the light chain and / or a humanized heavy chain.

[0269] The humanized antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA, and IgE, and any isotype, including but not limited to IgG1, IgG2, IgG3, and IgG4. The humanized antibody may comprise sequences from more than one class or isotype, and particular constant domains can be selected to optimize desired effector functions using techniques well known in the art.

[0270] The terms "Kabat numbering," "Kabat definition," and "Kabat notation" are used interchangeably herein. These terms are art-recognized and refer to a system for numbering amino acid residues that are more variable (i.e., hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody, or antigen-binding portion thereof (Kabat et al. (1971) Ann. NY Acad. Sci. 190:382-391, and Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest, 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242). For the heavy chain variable region, the hypervariable region ranges from amino acid positions 31 to 35 for CDR1, from amino acid positions 50 to 65 for CDR2, and from amino acid positions 95 to 102 for CDR3. In the light chain variable region, the hypervariable region ranges from amino acid positions 24 to 34 in CDR1, from amino acid positions 50 to 56 in CDR2, and from amino acid positions 89 to 97 in CDR3.

[0271] As used herein, the term "CDR" refers to a complementarity-determining region in an antibody variable sequence. Each of the variable regions of the heavy chain (HC) and light chain (LC) has three CDRs, designated CDR1, CDR2, and CDR3 (or specifically, HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3). As used herein, the term "CDR set" refers to a group of three CDRs occurring in a single variable region capable of binding to an antigen. The exact boundaries of these CDRs are defined differently by different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any antibody variable region, but also provides precise residue boundaries defining the three CDRs. These CDRs are sometimes referred to as Kabat CDRs. Chothia and coworkers (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987) and Chothia et al., Nature 342:877-883 (1989)) have used the Kabat CDRs to It has been found that certain sub-portions within the CDRs adopt nearly identical peptide backbone conformations despite the large diversity at the amino acid sequence level. These sub-portions are designated L1, L2, and L3, or H1, H2, and H3, where "L" and "H" refer to the light chain and heavy chain regions, respectively. These regions are sometimes called Chothia CDRs and have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs that overlap with Kabat CDRs have been described by Padlan (FASEB J. 9:133-139 (1995)) and MacCallum (J Mol Biol 262(5):732-45 (1996)).Still other CDR boundary definitions may not strictly adhere to one of the above systems, but may be shortened or lengthened in light of predictions or experimental findings that particular residues or groups of residues, or even entire CDRs, do not significantly affect antigen binding, yet still overlap with the Kabat CDRs. The methods used herein can use CDRs defined according to any of these systems, although preferred embodiments use Kabat-defined or Chothia-defined CDRs.

[0272] As used herein, the term "framework" or "framework sequence" refers to the remaining sequence of a variable region excluding CDRs. The precise definition of a CDR sequence can be determined by various systems, and the meaning of a framework sequence is subject to correspondingly various interpretations. The six CDRs (CDR-L1, CDR-L2, and CDR-L3 in the light chain and CDR-H1, CDR-H2, and CDR-H3 in the heavy chain) divide the framework regions of the light and heavy chains into four subregions (FR1, FR2, FR3, and FR4) of each chain, with CDR1 located between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. As referred to elsewhere, the framework region represents the combination of FRs in the variable region of a single naturally occurring immunoglobulin chain, without specifying the specific subregions as FR1, FR2, FR3, or FR4. As used herein, FR refers to one of the four subregions, and FR refers to two or more of the four subregions that make up a framework region.

[0273] The framework and CDR regions of a humanized antibody need not correspond exactly to the parent sequences. For example, the donor antibody CDR or consensus framework may be mutagenized by substitution, insertion, and / or deletion of at least one amino acid residue so that the CDR or framework residue at that site does not correspond to either the donor antibody or the consensus framework. However, in preferred embodiments, such mutations are not extensive. Typically, at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% of the humanized antibody residues correspond to those of the parent FR and CDR sequences. As used herein, the term "consensus framework" refers to the framework region of a consensus immunoglobulin sequence. As used herein, the term "consensus immunoglobulin sequence" refers to a sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related immunoglobulin sequences (see, e.g., Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, Germany, 1987)). In a family of immunoglobulins, each position in the consensus sequence is occupied by the amino acid that occurs most frequently at that position in the family. If two amino acids occur equally frequently, either can be included in the consensus sequence.

[0274] "Percent (%) amino acid sequence identity" with respect to a peptide or polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in a particular peptide or polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways that are within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms required to achieve maximum alignment over the entire length of the sequences being compared. In one embodiment, the present disclosure includes an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence set forth in any one of SEQ ID NOs: 1-190.

[0275] In one embodiment, the antibody or antigen-binding portion thereof is capable of inducing antibody-dependent cellular cytotoxicity (ADCC). In one embodiment, the antibody or antigen-binding portion thereof is unable to induce ADCC.

[0276] In one embodiment, the antibody or antigen-binding portion thereof is capable of inducing complement-dependent cytotoxicity (CDC). In one embodiment, the antibody or antigen-binding portion thereof is not capable of inducing CDC.

[0277] In one embodiment, the antibody or antigen-binding portion thereof is capable of inducing ADCC and CDC. In one embodiment, the antibody or antigen-binding portion thereof is unable to induce ADCC or CDC.

[0278] The term "multivalent antibody" is used herein to refer to an antibody that comprises two or more antigen-binding sites. In certain embodiments, multivalent antibodies may be engineered to have three or more antigen-binding sites and are generally not naturally occurring antibodies.

[0279] The term "multispecific antibody" refers to an antibody capable of binding to two or more unrelated antigens.

[0280] The terms "dual variable domain" or "DVD" are used interchangeably herein and refer to an antigen-binding protein that contains two or more antigen-binding sites and is a tetravalent or multivalent binding protein. Such DVDs may be monospecific, i.e., capable of binding to one antigen, or multispecific, i.e., capable of binding to two or more antigens. A DVD-binding protein containing two heavy chain DVD polypeptides and two light chain DVD polypeptides is called a DVD Ig. Each half of a DVD Ig contains a heavy chain DVD polypeptide and a light chain DVD polypeptide and two antigen-binding sites. Each binding site contains a heavy chain variable domain and a light chain variable domain, with a total of six CDRs per antigen-binding site involved in antigen binding. In one embodiment, the CDRs described herein are used in an anti-IL1RAP DVD.

[0281] The term "activity" includes activity such as the binding specificity / affinity of an antibody or ADC against an antigen, e.g., an anti-hIL1RAP antibody or ADC that binds to the IL1RAP antigen. In one embodiment, anti-IL1RAP antibody or anti-IL1RAP ADC activity includes, but is not limited to, binding to IL1RAP in vitro, binding to IL1RAP in cells expressing IL1RAP in vivo, modulating (e.g., inhibiting) IL-1, e.g., IL-1β and / or IL-1α signaling, inducing cell death in cells expressing IL1RAP, including leukemia cells, inhibiting cancer cell invasion and metastasis, reducing or inhibiting cancer, e.g., acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), lung cancer, including non-small cell lung cancer (NSCLC), and ovarian cancer, and reducing or inhibiting tumor cell proliferation or tumor growth in vivo. In one embodiment, the anti-IL1RAP antibody or ADC is capable of internalization and / or induction of cytotoxicity in cells expressing IL1RAP.

[0282] In one embodiment, the antibody or antigen-binding portion thereof is capable of inducing antibody-dependent cellular cytotoxicity (ADCC). In one embodiment, the antibody or antigen-binding portion thereof is unable to induce ADCC.

[0283] In one embodiment, the antibody or antigen-binding portion thereof is capable of inducing complement-dependent cytotoxicity (CDC). In one embodiment, the antibody or antigen-binding portion thereof is not capable of inducing CDC.

[0284] In one embodiment, the antibody or antigen-binding portion thereof is capable of inducing ADCC and CDC. In one embodiment, the antibody or antigen-binding portion thereof is unable to induce ADCC or CDC.

[0285] The term "epitope" refers to the region of an antigen to which an antibody, antibody fragment, or ADC binds. In certain embodiments, epitopic determinants include chemically active surface groups of molecules, such as amino acids, sugar side chains, phosphoryl, or sulfonyl, and in certain embodiments, may have specific three-dimensional structural and / or specific charge characteristics. In certain embodiments, an antibody is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and / or macromolecules.

[0286] The term "surface plasmon resonance," as used herein, refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by detecting changes in protein concentration within a biosensor matrix, for example, using a BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden, and Piscataway, NJ). For further explanation, see Joensson, U. et al. (1993) Ann. Biol. Clin. 51:19-26; Joensson, U. et al. (1991) Biotechniques 11:620-627; Johnson, B. et al. (1995) J. Mol. Recognit. 8:125-131; and Johnson, B. et al. (1991 Anal. Biochem. 198:268-277).

[0287] The term "k" on " or "k a " as used herein is intended to refer to the binding rate constant for an antibody to associate with an antigen to form an antibody / antigen complex.

[0288] The term "k" off " or "k d ", as used herein, is intended to refer to the dissociation rate constant for dissociation of an antibody from the antibody / antigen complex.

[0289] The term “K D", as used herein, is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen interaction. D is k a / k d It is calculated as follows. In one embodiment, an antibody of the invention has a K of about 2,000 nM or less, about 1,000 nM or less, about 500 nM or less, about 200 nM or less, about 100 nM or less, about 75 nM or less, about 25 nM or less, about 21 nM or less, about 12 nM or less, about 11 nM or less, about 10 nM or less, about 9 nM or less, about 8 nM or less, about 7 nM or less, about 6 nM or less, about 5 nM or less, about 4 nM or less, about 3 nM or less, about 2 nM or less, about 1 nM or less, about 0.5 nM or less, about 0.3 nM or less, about 0.1 nM or less, about 0.01 nM or less, or about 0.001 nM or less. D It has.

[0290] The term "competitive binding," as used herein, refers to a situation in which a first antibody competes with a second antibody for the binding site of a third molecule, such as an antigen. In one embodiment, competitive binding between two antibodies is determined using FACS analysis.

[0291] The term "competitive binding assay" refers to an assay used to determine whether two or more antibodies bind to the same epitope. In one embodiment, a competitive binding assay is a competitive fluorescence-activated cell sorting (FACS) assay used to determine whether two or more antibodies bind to the same epitope by determining whether the fluorescent signal of a labeled antibody is reduced by the introduction of an unlabeled antibody, where competition for the same epitope reduces the level of fluorescence.

[0292] The term "labeled antibody," as used herein, refers to an antibody or antigen-binding portion thereof having an incorporated label that provides identification of the binding protein, e.g., antibody. Preferably, the label is a detectable marker, such as the incorporation of a radioisotope-labeled amino acid or the attachment of a biotinyl moiety to the polypeptide that can be detected by labeled avidin (e.g., streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or colorimetric methods). Examples of labels for polypeptides include, but are not limited to, the following: radioisotopes or radionuclides (e.g., 3 H, 14 C. 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131 I, 177 Lu, 166 Ho, or 153 Sm); fluorescent labels (e.g., FITC, rhodamine, lanthanide fluorophores), enzymatic labels (e.g., horseradish peroxidase, luciferase, alkaline phosphatase); chemiluminescent markers; biotinyl groups; predetermined polypeptide epitopes recognized by secondary reporters (e.g., leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags); and magnetic agents such as gadolinium chelates.

[0293] The term "antibody-drug conjugate" or "ADC" refers to a binding protein, such as an antibody or antigen-binding fragment thereof, chemically linked to one or more chemical drugs (also referred to herein as drugs), which may optionally be therapeutic or cytotoxic agents. In a preferred embodiment, an ADC comprises an antibody, a cytotoxic or therapeutic agent, and a linker that allows for attachment or conjugation of the drug to the antibody. ADCs typically have one to eight drugs conjugated to the antibody, including two, four, six, or eight drug-loaded species. Non-limiting examples of drugs that may be included in an ADC include antimitotic agents, antitumor antibiotics, immunomodulators, vectors for gene therapy, alkylating agents, antiangiogenic agents, antimetabolites, boron-containing agents, chemoprotectants, hormones, antihormonal agents, corticosteroids, photoactive therapeutic agents, oligonucleotides, radionuclide agents, topoisomerase inhibitors, tyrosine kinase inhibitors, and radiosensitizers.

[0294] The terms "T-cell activation inhibitor-1 antibody drug conjugate containing V-pair domain," "anti-IL1RAP antibody drug conjugate," or "anti-IL1RAP ADC," as used interchangeably herein, refer to an ADC that includes an antibody that specifically binds to IL1RAP, where the antibody is conjugated to one or more chemical agents or payloads. In one embodiment, the chemical agents are linked to the antibody via a linker.

[0295] The term "drug-antibody ratio" or "DAR" refers to the number of drugs, e.g., IGNs, auristatins, or maytansinoids, that are conjugated to the antibodies of an ADC. The DAR of an ADC can range from 1 to 8, although higher loadings, e.g., 10, are possible depending on the number of attachment sites on the antibody. The term DAR can be used in reference to the number of drugs loaded on an individual antibody, or alternatively, in reference to the average or mean DAR of a group of ADCs.

[0296] The term "IL1RAP-associated disorder," as used herein, includes any disorder or disease (including proliferative disorders, e.g., cancer) that is indicated, diagnosed, detected, or identified by a phenotypic or genotypic abnormality in IL1RAP gene components or expression during the course or pathogenesis of the disease or disorder. In this regard, an IL1RAP phenotypic abnormality or determinant can include, for example, an increased or decreased level of IL1RAP protein expression in one cell population, e.g., a cancer cell population, compared to another cell population, e.g., a normal cell population, or an increased or decreased level of IL1RAP protein expression in a specific, identifiable cell population, or an increased or decreased level of IL1RAP protein expression at an inappropriate phase or stage of the cell life cycle. It is also understood that similar expression patterns of genotypic determinants of IL1RAP (e.g., mRNA transcription levels) can be used to classify or detect IL1RAP-associated disorders. In one embodiment, the IL1RAP-associated disorder is leukemia, e.g., acute myeloid leukemia (AML). In another embodiment, the IL1RAP-associated disorder is myelodysplastic syndrome (MDS). In another embodiment, the IL1RAP-associated disorder is lung cancer. In another embodiment, the IL1RAP-associated disorder is non-small cell lung cancer (NSCLC). In another embodiment, the IL1RAP-associated disorder is ovarian cancer.

[0297] The term "cancer," as used herein, is intended to refer to or describe a physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia, or lymphoid malignancies. More specific examples of such cancers include, but are not limited to, breast cancer (luminal A, TNBC, ductal), prostate cancer, squamous cell tumors, squamous cell carcinomas (e.g., squamous cell lung cancer or squamous cell head and neck cancer), neuroendocrine tumors, urothelial cancer, vulvar cancer, mesothelioma, liver cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, cutaneous or intraocular malignant melanoma, and kidney cancer. , uterine cancer, ovarian cancer, colorectal cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, cancer of the fallopian tubes, cancer of the endometrium, cancer of the cervix, cancer of the vagina, cancer of the vulva, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, cancer of the renal pelvis, neoplasms of the central nervous system (CNS), primary C NS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, environmentally induced cancers including those induced by asbestos, e.g., multiple myeloma, B-cell lymphoma, Hodgkin's lymphoma / primary mediastinal B-cell lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), myeloproliferative disorders (MPD), Hematological malignancies including chronic lymphocytic leukemia, follicular lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, acute lymphoblastic leukemia, mycosis fungoides, anaplastic large cell lymphoma, T-cell lymphoma, and precursor T-lymphoblastic lymphoma, PVNS, acute myeloid leukemia, adrenal cortical carcinoma, and bladder urothelial carcinomacarcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, diffuse large B-cell lymphoma, glioblastoma multiforme, chronic lymphocytic leukemia, brain low-grade glioma, head and neck squamous cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, large squamous cell carcinoma, cutaneous melanoma, ovarian serous cystadenocarcinoma, gastric cancer, soft tissue sarcoma, testicular germ cell carcinoma, thymoma, thyroid cancer, endometrial cancer, uterine carcinosarcoma, renal clear cell carcinoma, and renal papillary cell carcinoma, and any combination of the above cancers. The present invention is also applicable to the treatment of metastatic cancers.

[0298] In one embodiment, an antibody or ADC of the invention is administered to a patient with a solid tumor, including an advanced solid tumor. In one embodiment, an antibody or ADC of the invention is administered to a patient with leukemia. In another embodiment, administration of an antibody or ADC of the invention induces cell death of IL1RAP-expressing cells.

[0299] The term "IL1RAP-expressing tumor" as used herein refers to a tumor that expresses the IL1RAP protein (including tumors containing tumor-infiltrating cells that express the IL1RAP protein). In one embodiment, IL1RAP expression in a tumor is determined using immunohistochemical staining of tumor cell membranes, and any immunohistochemical staining higher than background levels in a tumor sample indicates that the tumor is an IL1RAP-expressing tumor. In another embodiment, an IL1RAP-expressing tumor is identified in a patient if more than 1%, more than 2%, more than 3%, more than 4%, more than 5%, more than 6%, more than 7%, more than 8%, more than 9%, more than 10%, more than 15%, more than 20%, more than 25%, or more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or more cells in a tumor sample are positive for IL1RAP expression. In another embodiment, IL1RAP positive expression is determined based on membrane staining, for example, as determined by immunohistochemistry (IHC) analysis.

[0300] An IL1RAP-expressing tumor is identified as having "elevated levels of IL1RAP" or "expressing IL1RAP at elevated levels" if the level of IL1RAP is higher in tissues surrounding the cancer. In some embodiments, an "elevated level of IL1RAP" is one in which 5% or more of the cells in a tumor sample have membrane staining. In some embodiments, a "high level" for IL1RAP is 5% or more staining, e.g., 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% of the cells in a tumor sample are stained. In some embodiments, protein expression levels can be measured by IHC analysis.

[0301] IL1RAP-expressing tumors are identified as having "low levels of IL1RAP" or "expressing IL1RAP at low levels," with membrane staining in 5% or fewer of the cells in the tumor sample. In some embodiments, a "low level" with respect to IL1RAP is 5% or fewer staining, e.g., 4.9, 4.5, 4, 3, 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1% or fewer of the cells in the tumor sample. In some embodiments, protein expression levels can be measured by IHC analysis.

[0302] Cells that do not express IL1RAP may also be described as expressing "low levels of IL1RAP." Thus, the phrase "expressing low levels of IL1RAP" encompasses not expressing IL1RAP. In some embodiments, low levels of IL1RAP are within background staining levels. In some embodiments, a sample that is IL1RAP "negative" has no IL1RAP expression or has low levels of IL1RAP. In some embodiments, IL1RAP staining is negative if there is no membrane staining for IL1RAP or if less than 5%, 4%, 3%, 2%, or 1% of the cells have membrane staining for IL1RAP.

[0303] As used herein, the term "tumor sample" refers to a tumor tissue or cell sample obtained from a solid tumor. The sample may contain both tumor cells and tumor-infiltrating cells, such as tumor-infiltrating immune cells.

[0304] As used herein, the term "non-cancer sample" or "normal sample" refers to a sample derived from normal tissue (e.g., a lung or ovarian tissue sample or a normal cell sample). In some embodiments, the non-cancer sample is derived from the same subject, but from a different part of the subject than that being tested. In some embodiments, the non-cancer sample is derived from a tissue area surrounding or adjacent to the cancer. In some embodiments, the non-cancer sample is a sample not from the subject being tested, but from a subject known to have or not have the disorder in question (e.g., a particular cancer, such as an IL1RAP-associated disorder). In some embodiments, the non-cancer sample is derived from the same subject, but from a time before the subject developed cancer. In some embodiments, the reference sample is derived from a benign cancer sample (e.g., a benign ovarian cancer sample) from the same or a different subject.

[0305] Methods for detecting IL1RAP expression in tumors are known in the art.

[0306] The terms "overexpress," "overexpression," or "overexpressed" refer synonymously to a gene that is typically transcribed or translated at detectably higher levels in cancer cells compared to normal cells. Thus, overexpression refers to both protein and RNA overexpression (due to increased transcription, post-transcriptional processing, translation, post-translational processing, altered stability, and altered proteolysis) as well as localized overexpression due to altered protein trafficking patterns (increased nuclear localization) and enhanced functional activity, such as increased enzymatic hydrolysis of a substrate. Thus, overexpression refers to either the protein or RNA level. Overexpression may also be 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or higher compared to normal or comparison cells. In certain embodiments, anti-IL1RAP antibodies or ADCs are used to treat solid tumors that may overexpress IL1RAP.

[0307] The term "administering," as used herein, is intended to refer to delivery of a substance (e.g., an anti-IL1RAP antibody or ADC) to achieve a therapeutic objective (e.g., treatment of an IL1RAP-associated disorder or inhibition or reduction of a tumor). Modes of administration may be parenteral, enteral, and topical. Parenteral administration is usually by injection and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0308] The term "combination therapy," as used herein, refers to the administration of two or more therapeutic agents, e.g., an anti-IL1RAP antibody or ADC and an additional therapeutic agent. The additional therapeutic agent may be administered simultaneously with, before, or after administration of the anti-IL1RAP antibody or ADC. In one embodiment, an anti-IL1RAP antibody or ADC of the invention is administered in combination with one or more immune checkpoint inhibitors (e.g., one or more antibody or small molecule immune checkpoint inhibitors) to treat cancer.

[0309] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a drug, e.g., an antibody or ADC, sufficient to reduce or ameliorate the severity and / or duration of a disorder, e.g., cancer, or one or more symptoms thereof, prevent progression of the disorder, cause regression of the disorder, prevent the recurrence, onset, onset, or worsening of one or more symptoms associated with the disorder, detect the disorder, or enhance or improve the prophylactic or therapeutic effect(s) of another treatment (e.g., a prophylactic or therapeutic agent). An effective amount of an antibody or ADC can, for example, inhibit tumor growth (e.g., inhibit an increase in tumor volume), reduce tumor growth (e.g., reduce tumor volume), reduce the number of cancer cells, and / or alleviate to some extent one or more symptoms associated with cancer. An effective amount may, for example, improve disease-free survival (DFS), improve overall survival (OS), or reduce the likelihood of recurrence.

[0310] Various aspects of the invention are described in further detail in the following subsections.

[0311] II. Anti-IL1RAP antibody One aspect disclosed herein provides a humanized anti-IL1RAP antibody, or antigen-binding portion thereof. Another aspect disclosed herein provides a human anti-IL1RAP antibody, or antigen-binding portion thereof. In one embodiment, the antibody disclosed herein binds to human IL1RAP. In another embodiment, the antibody disclosed herein binds to cynomolgus monkey IL1RAP. In another embodiment, the antibody disclosed herein binds to human IL1RAP expressed on tumor cells.

[0312] Another aspect disclosed herein features an antibody-drug conjugate (ADC) comprising an anti-IL1RAP antibody described herein and at least one drug. The antibody or ADC disclosed herein has characteristics including, but not limited to, binding to human IL1RAP in vitro, modulating, e.g., inhibiting IL-1 signaling, inducing cell death in cells expressing IL1RAP, including, but not limited to, leukemia cells, and reducing or inhibiting cancer, tumor cell proliferation or tumor growth, or tumor invasion and metastasis. In particular, the ADC disclosed herein has characteristics including, but not limited to, inducing cell death in cells expressing IL1RAP, e.g., leukemia cells expressing IL1RAP. In one embodiment, the anti-IL1RAP antibody or ADC disclosed herein is capable of internalization into cells expressing IL1RAP.

[0313] In one embodiment, as described in the Examples below, an anti-IL1RAP antibody capable of binding to IL1RAP is disclosed. These novel antibodies are collectively referred to herein as "IL1RAP antibodies." The anti-IL1RAP antibody, ADC, or antigen-binding fragment thereof can inhibit or reduce tumor growth in vivo. The tumor may be an IL1RAP-negative tumor or an IL1RAP-expressing tumor. In various embodiments, the anti-IL1RAP antibody, ADC, or antigen-binding fragment thereof can modulate the biological function of IL1RAP. In other embodiments of the above aspects, the anti-IL1RAP antibody, ADC, or antigen-binding fragment thereof binds to IL1RAP on cells expressing IL1RAP. Accordingly, the present disclosure includes an anti-IL1RAP antibody, ADC, or antigen-binding fragment thereof that is effective in inhibiting or reducing tumor growth. Without wishing to be bound by any particular theory, in one embodiment, anti-IL1RAP antibodies, antigen-binding portions thereof, and ADCs can inhibit multiple IL1RAP activities, including, but not limited to, IL-1β signaling via IL1RAP, IL-1α, IL-1β, and IL-38 signaling via IL-1R, IL-33 signaling via IL-33R, and IL-36Rα, IL-36β, and IL-36γ signaling via IL-36R. Blocking IL-1β signaling is known in the art to be effective in treating lung cancer (see, e.g., Ridker et al., Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease, New England J. Med., 2017 and Ridker et al., The Lancet, 390:1833-1842, 2017, the contents of each of which are expressly incorporated herein by reference in their entirety). Thus, in one embodiment, the anti-IL1RAP antibodies, antigen-binding portions thereof, and ADCs described herein are useful for downstream inhibition of the IL-1β pathway to treat cancer, e.g., lung cancer.

[0314] Furthermore, the present inventors have further demonstrated that IL1RAP is expressed by leukemia cells (see Example 1). Therefore, anti-IL1RAP antibodies, ADCs, and antigen-binding portions thereof can be used to treat leukemia, such as acute myeloid leukemia, in a subject. Anti-IL1RAP antibodies, ADCs, and antigen-binding portions thereof can be used to treat bone marrow disorders such as myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), ovarian cancer, lung cancer, and non-small cell lung cancer. In one embodiment, more than 1%, more than 2%, more than 3%, more than 4%, more than 5%, more than 6%, more than 7%, more than 8%, more than 9%, more than 10%, more than 15%, more than 20%, more than 25%, or more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or more cells in a leukemia sample are positive for IL1RAP expression. In another embodiment, the leukemia or tumor sample has a high level of IL1RAP expression. For example, in one embodiment, at least 5% or more of the cells in the leukemia or tumor sample have membrane staining. In another embodiment, the tumor sample obtained from the subject exhibits a low level of IL1RAP expression. The expression level of IL1RAP can be determined by any method known in the art. For example, the expression level of IL1RAP can be determined by immunohistochemical analysis. In another embodiment, the cancer has previously been treated with another anti-cancer agent or anti-cancer therapy, for example, chemotherapy. In one embodiment, the cancer is resistant to chemotherapy.

[0315] Antibodies having any combination of the above-described characteristics are contemplated as embodiments of the present disclosure. Additionally, ADCs, described in more detail below, may have any of the above-described characteristics.

[0316] One aspect of the present disclosure features an anti-human IL1RAP (anti-hIL1RAP) antibody-drug conjugate (ADC) comprising an anti-hIL1RAP antibody conjugated to a drug via a linker. Exemplary anti-IL1RAP antibodies (and their sequences) that can be used in the ADC are described herein.

[0317] The anti-IL1RAP antibodies described herein have the ability to bind to IL1RAP, and provide ADCs that can deliver cytotoxic molecules conjugated to the antibodies to IL1RAP-expressing cells, particularly IL1RAP-expressing cancer cells.

[0318] It should be noted that while the term "antibody" is used throughout this specification, antibody fragments (i.e., antigen-binding portions of anti-IL1RAP antibodies) are also included in this disclosure and may be included in the embodiments (methods and compositions) described throughout this specification. For example, anti-IL1RAP antibody fragments may be conjugated to drugs as described herein. In certain embodiments, the anti-IL1RAP antibody-binding portion is a Fab, Fab', F(ab')2, Fv, disulfide-linked Fv, scFv, single-domain antibody, or diabody.

[0319] Example 2 describes the generation of fully human IL1RAP antibodies directed against the extracellular domain of human IL1RAP. The heavy and light chain variable region amino acid sequences of these human antibodies are shown in Table 5. The heavy and light chain variable region nucleotide sequences of these human antibodies are shown in Table 6.

[0320] Thus, in one embodiment, the disclosure provides a method for the production of a mAb-specific antibody comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 9, 17, 25, 32, 40, 48, 56, 64, 71, 74, 83, 90, 96, 100, 106, 109, 116, 118, 121, 123, 125, 127, 130, 136, 140, 144, 151, 158, 163, 170, 173, 180, and 185; and a light chain variable region comprising an amino acid sequence selected from the group consisting of: 21, 29, 36, 44, 52, 60, 68, 73, 78, 82, 87, 93, 98, 103, 108, 113, 114, 120, 122, 124, 126, 128, 134, 137, 143, 147, 154, 160, 167, 172, 177, 184, and 189.

[0321] In one embodiment, the disclosure includes a human anti-IL1RAP antibody, or antigen-binding portion thereof, comprising a HC CDR set (CDR1, CDR2, and CDR3) selected from those shown in Table 5 and a LC CDR set (CDR1, CDR2, and CDR3) selected from those shown in Table 5.

[0322] In one embodiment, the anti-IL1RAP antibody, or antigen-binding portion thereof, is human antibody 5G8_18A1. The 5G8_18A1 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 3, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 8, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 7, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 6. In a further embodiment, disclosed herein is an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 5.

[0323] In some embodiments, the anti-IL1RAP antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 1, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 5, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 5.

[0324] In one embodiment, the disclosure features an anti-IL1RAP antibody, or antigen-binding portion thereof, that is human antibody 10C8_15A1. The 10C8_15A1 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 12, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 11, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 16, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 14. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 13.

[0325] In some embodiments, the anti-IL1RAP antibody, or antigen-binding portion thereof, comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 9, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 9, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 13, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 13.

[0326] In one embodiment, the disclosure features an anti-IL1RAP antibody, or antigen-binding portion thereof, that is human antibody 12F3_17C2. The 12F3_17C2 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 19, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 18, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 24, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 22. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 17 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 21.

[0327] In some embodiments, the anti-IL1RAP antibody, or antigen-binding portion thereof, comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 17, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 17, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 21, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 21.

[0328] In one embodiment, the disclosure features an anti-IL1RAP antibody, or antigen-binding portion thereof, that is human antibody 16H2_17D2. The 16H2_17D2 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:28, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:27, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:32, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:31. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:25 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:29.

[0329] In some embodiments, the anti-IL1RAP antibody, or antigen-binding portion thereof, comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:25, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:25, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO:29, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:29.

[0330] In one embodiment, the anti-IL1RAP antibody, or antigen-binding portion thereof, is human antibody 32C12_21A4. The 32C12_21A4 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37. In a further embodiment, disclosed herein is an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 32 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36.

[0331] In some embodiments, the anti-IL1RAP antibody, or antigen-binding portion thereof, comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 32, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 32, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 36, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 36.

[0332] In one embodiment, the anti-IL1RAP antibody, or antigen-binding portion thereof, is human antibody 34C11_21B2. The 34C11_21B2 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain compris...

Claims

1. 1. An anti-IL1RAP antibody or antigen-binding portion thereof, a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:66, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:65; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:69; or a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:51, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:50, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:49; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:55, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:54, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:

53. An antibody or antigen-binding portion thereof comprising:

2. 1. An anti-IL1RAP antibody or antigen-binding portion thereof, a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:64, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:68; or A heavy chain variable region comprising the amino acid sequence of SEQ ID NO:48, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

52. An antibody or antigen-binding portion thereof comprising:

3. 1. An anti-IL1RAP antibody or antigen-binding portion thereof, a heavy chain comprising an amino acid sequence set forth in SEQ ID NO:64, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:64, comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:67, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:66, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:65, and a light chain comprising an amino acid sequence set forth in SEQ ID NO:68, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:68, comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:62, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:69; or a heavy chain comprising an amino acid sequence set forth in SEQ ID NO:48, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:48, comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:51, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:50, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:49; and a light chain comprising an amino acid sequence set forth in SEQ ID NO:52, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:52, comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:55, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:54, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:

53. An antibody or antigen-binding portion thereof comprising:

4. An isolated nucleic acid encoding the antibody or antigen-binding portion thereof of claim 1.

5. A pharmaceutical composition comprising the antibody or antigen-binding portion thereof of claim 1 and a pharma- ceutically acceptable carrier.

6. The antibody or antigen-binding portion thereof described in claim 1 conjugated to at least one drug.

7. The antibody or antigen-binding portion thereof of claim 1, wherein the antibody or antigen-binding portion thereof is an IgG1, IgG2, IgG3 or IgG4 isotype.

8. The antibody or antigen-binding portion thereof of claim 1 , wherein the antibody or antigen-binding portion thereof is a bispecific antibody or a multispecific antibody.

9. A composition for treating cancer, comprising the antibody or antigen-binding portion thereof described in claim 1.

10. 10. The composition of claim 9, wherein the cancer is selected from the group consisting of ovarian cancer, lung cancer, non-small cell lung cancer (NSCLC), acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

11. A composition for inhibiting or reducing solid tumor growth in a subject having a solid tumor, the composition comprising an antibody or an antigen-binding portion thereof described in claim 1.

12. The composition of claim 11 , wherein the cancer is lung cancer, non-small cell lung cancer (NSCLC) or ovarian cancer.

13. 10. The composition of claim 9, wherein the composition is administered in combination with an additional drug or therapy.

14. 14. The composition of claim 13, wherein the additional agent is an immune checkpoint inhibitor, an antibody, a VEGF-specific antibody, or one or more chemotherapeutic agents, and the additional therapy is radiation.

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