Anti-IL1RAP antibodies and antibody-drug conjugates

Abstract

To provide interleukin 1 receptor accessory protein (IL1RAP) antibodies and antibody drug conjugates (ADCs), including compositions and methods of using the antibodies and the ADCs.SOLUTION: In certain embodiments of the invention, antibodies or antigen binding portions thereof bind to IL1RAP (SEQ ID NO: 286) or the extracellular domain of IL1RAP. In other embodiments of the invention, anti-IL1RAP antibody drug conjugates (ADCs) of the invention (e.g., the IL1RAP antibodies of the invention conjugated to a toxin) is capable of being internalized. In another embodiment, the anti-IL1RAP antibody drug conjugates (ADCs) of the invention are capable of inducing cell death of cells endogenously expressing IL1RAP.SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Application No. 62 / 518,069, filed on Jun. 12, 2017, the entire content of which is hereby incorporated by reference in its entirety.

[0002] Sequence Listing This application is being filed electronically in ASCII format and includes a sequence listing which is hereby incorporated by reference in its entirety. The ASCII copy was created on Jun. 12, 2018, has a file name of 127913-00820_SL.txt, and is 163,057 bytes in size.

Background Art

[0003] IL1RAP is 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) and is a necessary part of the interleukin 1 (IL-1) receptor complex that initiates signal transduction events leading to the activation of interleukin 1-responsive genes. In addition to IL1-signaling, IL1RAP is important for mediating the effects of IL33 via the ST2 / IL1RAP complex and the effects of IL36 via the IL1Rrp2 / IL1RAP complex (Garlanda et al, Immunity. 2013 Dec 12;39(6):1003-18).

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

[0005] Alternative splicing of IL1RAP results in two transcript variants encoding two different 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 pro-inflammatory cytokine that induces the synthesis of acute-phase proteins and pro-inflammatory 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 monocytes, 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 interleukin-1 receptor antagonist (IL-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 the immune response 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, the production of inflammatory mediators induced by IL-1 leads to fever, headache, hypotension, and weight loss. Additionally, IL-1 is a hematopoietic growth factor and has been shown to reduce the nadir of a patient's leukocytes and platelets during bone marrow transplantation. IL-1 has also been shown to promote angiogenesis by inducing the production of vascular endothelial growth factor, thereby promoting pannus formation and blood supply in rheumatoid joints. Finally, IL-1 has been shown to promote the breakdown of bone and cartilage in rheumatic diseases.

[0008] IL-1 has been implicated in a wide range of diseases and conditions, ranging from gout to cancer, including joint, bone, and muscle diseases such as rheumatoid arthritis and osteoarthritis, hereditary 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 therapies 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) that blocks the activity of both IL-1α and IL-1β. Since then, this therapeutic agent has been used and has demonstrated the role of IL-1 in numerous diseases. It has also been proven effective to neutralize IL-1 with antibodies or soluble receptors, and the soluble decoy receptor rilonacept (Arcalyst™, Regeneron) and the anti-IL-1β neutralizing monoclonal antibody canakinumab (Ilaris™, Novartis) are currently approved. Other therapeutic approaches, including IL-1α neutralization, therapeutic vaccines targeting IL-1β, and chimeric IL-1 Ra, are in clinical trials. In addition, small molecule inhibitors of IL-1 production that are orally active, such as caspase-1 inhibitors, are being developed. Antibody-drug conjugates (ADCs) represent a new class of therapeutic agents that contain an antibody conjugated to a cytotoxic drug via a chemical linker. The therapeutic concept of ADCs is to combine the binding ability of an antibody with a drug and use the antibody to deliver the drug to tumor cells by binding to a target surface antigen.

Prior Art Documents

Patent Documents

[0010]

Patent Document 1

Non-Patent Documents

[0011]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Summary of the Invention

Means for Solving the Problems

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

[0013] In one embodiment, the antibody or antigen-binding portion thereof of the present 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 and binds to IL1RAP.

[0014] In yet other embodiments of the present invention, the anti-IL1RAP antibody-drug conjugate (ADC) of the present invention (e.g., the IL1RAP antibody of the present invention conjugated to a toxin) is capable of internalizing. In another embodiment, the anti-IL1RAP antibody-drug conjugate (ADC) of the present invention is capable of inducing cell death of cells that endogenously express IL1RAP.

[0015] In one aspect of the present invention, the present disclosure provides an isolated antibody that binds to human IL1RAP or an antigen-binding property thereof, 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 any of the amino acid sequences of SEQ ID NO: 6.

[0017] In one aspect of the invention, the present disclosure provides an isolated antibody or antigen-binding 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 any of the amino acid sequences of SEQ ID NO: 14.

[0019] In one aspect of the invention, the present disclosure provides an isolated antibody or antigen-binding 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 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 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 present 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 present 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 present 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 invention, the disclosure provides an isolated antibody or antigen-binding 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 invention, the disclosure provides an isolated antibody or antigen-binding 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 invention, the present disclosure provides an isolated antibody or antigen-binding 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 invention, the present disclosure provides an isolated antibody or antigen-binding 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 invention, the present 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 invention, the present 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 invention, the present 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 invention, the present disclosure provides an isolated antibody that binds to human IL1RAP or an antigen-binding property thereof, 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 invention, the present disclosure provides an isolated antibody that binds to human IL1RAP or an antigen-binding property thereof, 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 invention, the present 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 invention, the present 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 invention, the present 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 invention, the present 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 invention, the present 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 invention, the present disclosure provides an isolated antibody or antigen-binding 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 invention, the present disclosure provides an isolated antibody or antigen-binding 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 invention, the present 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 invention, the present 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 invention, the present 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 invention, the present 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 invention, the present 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 invention, the present disclosure provides an isolated antibody or antigen-binding 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 invention, the present disclosure provides an isolated antibody or antigen-binding 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 invention, the present 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 invention, the present 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 invention, the present disclosure provides an isolated antibody or antigen-binding 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 invention, the present disclosure provides an isolated antibody or antigen-binding 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 of the IgG isotype. In some embodiments, the antibody or antigen-binding portion thereof is of the IgG1 isotype. In another embodiment, the antibody or antigen-binding portion thereof is of the IgG4 isotype. In another embodiment, the antibody or antigen-binding portion thereof is of the IgG2 isotype. In another embodiment, the antibody or antigen-binding portion thereof is of the IgG3 isotype.

[0086] In one embodiment, the antibody or antigen-binding portion thereof is capable of inducing antibody-dependent cell-mediated cytotoxicity (ADCC). In one embodiment, the antibody or antigen-binding portion thereof is not capable of inducing 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 both ADCC and CDC. In one embodiment, the antibody or antigen-binding portion thereof is not capable of inducing either ADCC or CDC.

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

[0090] In one aspect, the antibody or antigen-binding portion thereof has a K of 200 nM or lower. D It has.

[0091] In another aspect of the 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 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 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 an 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 an 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 present disclosure provides an anti-IL1RAP antibody or an 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 an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 an 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 an 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 an 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 an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 an 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 an 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 an 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 an 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 an 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 an 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 an 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 an 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 an 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 an 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 an 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 an 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 an 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 an 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 an 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 an 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 an antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 188, a CDR2 domain having the amino acid sequence of SEQ ID NO: 187, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 186, and a light chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 63, 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: 190.

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

[0126] In another aspect of the present invention, the present disclosure provides an anti-IL1RAP antibody or an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 present disclosure provides an anti-IL1RAP antibody or an 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 present disclosure provides an anti-IL1RAP antibody or an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 present disclosure provides an anti-IL1RAP antibody or an 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 present disclosure provides an anti-IL1RAP antibody or an 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 present disclosure provides an anti-IL1RAP antibody or an 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 present disclosure provides an anti-IL1RAP antibody or an 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 present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an antigen-binding portion thereof comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an antigen-binding portion thereof comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 present disclosure provides an anti-IL1RAP antibody or an 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 present disclosure provides an anti-IL1RAP antibody or an 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 present disclosure provides an anti-IL1RAP antibody or an 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 present disclosure provides an anti-IL1RAP antibody or an 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 present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an antigen-binding portion thereof comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an antigen-binding portion thereof comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an antigen-binding portion thereof comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an antigen-binding portion thereof comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 present disclosure provides an anti-IL1RAP antibody or an 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 present disclosure provides an anti-IL1RAP antibody or an 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 present disclosure provides an anti-IL1RAP antibody or an 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 present disclosure provides an anti-IL1RAP antibody or an 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 present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 invention, the present disclosure provides an anti-IL1RAP antibody or an 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 embodiment of the invention, the present disclosure provides an antibody or an antigen-binding portion thereof that binds to the same epitope as the antibody or an antigen-binding portion thereof described herein.

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

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

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

[0201] In some aspects, 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 PBD.

[0202] In other embodiments, the at least one drug is conjugated to the antibody or an antigen-binding portion thereof 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 invention, the present disclosure provides a drug conjugate (ADC) comprising an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or an 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 invention, the present disclosure provides a drug conjugate (ADC) comprising an antibody conjugated to at least one drug or an antigen-binding property thereof, wherein the antibody or an 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 invention, the present disclosure provides a drug conjugate (ADC) comprising an antibody conjugated to at least one drug or an antigen-binding property thereof, wherein the antibody or an 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 invention, the present disclosure provides a drug conjugate (ADC) comprising an antibody conjugated to at least one drug or an antigen-binding property thereof, wherein the antibody or an 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 conjugated to at least one drug or an antigen-binding portion thereof, 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 conjugated to at least one drug or an antigen-binding portion thereof, 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 conjugated to at least one drug or an antigen-binding portion thereof, 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 invention, the present disclosure provides an antibody-drug conjugate (ADC) comprising an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 59, a CDR2 domain having the amino acid sequence of SEQ ID NO: 58, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 57, and a light chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 63, 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: 61.

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

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

[0213] In another aspect of the invention, the present disclosure provides an antibody-drug conjugate (ADC) comprising an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody-drug conjugate (ADC) comprising an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody-drug conjugate (ADC) comprising an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or the 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 invention, the present disclosure provides an antibody or an 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, hormonal agents, anti-hormonal agents, corticosteroids, photoactive therapeutic agents, oligonucleotides, radionuclide agents, radiation sensitizers, topoisomerase inhibitors, and tyrosine kinase inhibitors. In one embodiment, the drug is a DNA damaging agent. In one embodiment, the DNA damaging agent is PBD.

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

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

[0241] In another aspect of the invention, the present 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-to-antibody ratio (DAR) of 0 to 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 an 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 a 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 the ADC, is administered in combination with an additional agent or additional 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 embodiments 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) 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) The antibody or antigen-binding portion thereof according to item 1 or 2, wherein 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 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) 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) The antibody or antigen-binding portion thereof according to item 4 or 5, wherein 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. (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) 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) 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 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 10 or 11, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 13 or 14, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 16 or 17, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 19 or 20, wherein 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. (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) The antibody or antigen-binding portion thereof according to item 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) The antibody or antigen-binding portion thereof according to item 22 or 23, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 25 or 26, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 28 or 29, wherein 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. (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) The antibody or antigen-binding portion thereof according to item 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) The antibody or antigen-binding portion thereof according to item 31 or 32, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 34 or 35, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 37 or 38, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 40 or 41, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 43 or 44, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 46 or 47, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 49 or 50, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 52 or 53, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 55 or 56, wherein 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. (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) The antibody or antigen-binding portion thereof according to item 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) The antibody or antigen-binding portion thereof according to item 58 or 59, wherein 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. (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) The antibody or antigen-binding portion thereof according to item 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) The antibody or antigen-binding portion thereof according to item 61 or 62, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 64 or 65, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 67 or 68, wherein 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. (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) The antibody or antigen-binding portion thereof according to item 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) The antibody or antigen-binding portion thereof according to item 70 or 71, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 73 or 74, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 76 or 77, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 79 or 80, wherein 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. (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) The antibody or antigen-binding portion thereof according to item 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) The antibody or antigen-binding portion thereof according to item 82 or 83, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 85 or 86, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 88 or 89, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 91 or 92, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 94 or 95, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 97 or 98, wherein 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. (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) The antibody or antigen-binding portion thereof according to 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) The antibody or antigen-binding portion thereof according to item 100 or 101, wherein 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. (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 according to item 103, 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: 187 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 62. (Item 105) The antibody or antigen-binding portion thereof according to item 103 or 104, wherein 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. (Item 106) The antibody or antigen-binding portion thereof according to any one of the preceding items, wherein the antibody or antigen-binding portion thereof is of the IgG isotype. (Item 107) The antibody or antigen-binding portion thereof according to any one of the preceding items, wherein the antibody or antigen-binding portion thereof has a K of 200 nM or less 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 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 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 an 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 an 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 an 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 an 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. (Item 114) An anti-IL1RAP antibody or an 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 an 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 an 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 an 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 an 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 an 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 an 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 an 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 an 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. (Item 123) An anti-IL1RAP antibody or an 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 an 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 an 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 an 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 an 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 an 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 an 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 an 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. (Item 131) An anti-IL1RAP antibody or an 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 an 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 an 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 an 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 an 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 an 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 an 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 an 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 an 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 an 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 an 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 an antigen-binding portion thereof, comprising a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 5. (Item 143) An anti-IL1RAP antibody or an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an 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) An anti-IL1RAP antibody or an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown in SEQ ID NO: 184 or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 184. (Item 212) An anti-IL1RAP antibody or an 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 an antigen-binding portion thereof, comprising a heavy chain comprising the amino acid sequence shown 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 shown 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 an antigen-binding portion thereof that binds to the same epitope as the antibody or the antigen-binding portion thereof according to any one of the above items. (Item 215) An isolated nucleic acid encoding the antibody or the antigen-binding portion thereof according to any one of the above items. (Item 216) A pharmaceutical composition comprising the antibody or the antigen-binding portion thereof according to any one of the above items and a pharmaceutically acceptable carrier. (Item 217) An antibody or an antigen-binding portion thereof according to any one of the above items conjugated to at least one drug. (Item 218) The antibody or the antigen-binding portion thereof according to Item 217, wherein the at least one drug is selected from the group consisting of a DNA-damaging agent, an anti-apoptotic agent, a mitosis inhibitor, an antitumor antibiotic, an immunomodulator, 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) The antibody or the antigen-binding portion thereof according to Item 217, wherein the at least one drug is conjugated to the antibody or the antigen-binding portion thereof via a linker. (Item 220) The antibody or the antigen-binding portion thereof according to Item 219, wherein the linker is a cleavable linker. (Item 221) The antibody or the antigen-binding portion thereof according to Item 219, wherein the linker is a non-cleavable linker. (Item 222) An antibody-drug conjugate (ADC) comprising an antibody conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the antigen-binding portion thereof comprises 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 223) An antibody-drug conjugate (ADC) comprising an antibody conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 12, a CDR2 domain having the amino acid sequence of SEQ ID NO: 11, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 16, a CDR2 domain having the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 14. (Item 224) An antibody-drug conjugate (ADC) comprising an antibody conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the antigen-binding portion thereof comprises 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: 19, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 18, 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: 23, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 22. (Item 225) An antibody-drug conjugate (ADC) comprising an antibody conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 51, a CDR2 domain having the amino acid sequence of SEQ ID NO: 50, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 49, and a light chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 55, a CDR2 domain having the amino acid sequence of SEQ ID NO: 54, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 53. (Item 229) An antibody-drug conjugate (ADC) comprising an antibody conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 59, a CDR2 domain having the amino acid sequence of SEQ ID NO: 58, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 57, and a light chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 63, 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: 61. (Item 230) An antibody-drug conjugate (ADC) comprising an antibody conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the antigen-binding portion thereof comprises 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: 65, and a light chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 70, 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 231) An antibody-drug conjugate (ADC) comprising an antibody conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the 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 conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 171, a CDR2 domain having the amino acid sequence of SEQ ID NO: 165, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 164, and a light chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 169, a CDR2 domain having the amino acid sequence of SEQ ID NO: 168, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 155. (Item 253) An antibody-drug conjugate (ADC) comprising an antibody conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 176, a CDR2 domain having the amino acid sequence of SEQ ID NO: 175, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 174, and a light chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 179, a CDR2 domain having the amino acid sequence of SEQ ID NO: 178, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 79. (Item 254) An antibody-drug conjugate (ADC) comprising an antibody conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or the antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 183, a CDR2 domain having the amino acid sequence of SEQ ID NO: 182, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 181, and a light chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 179, a CDR2 domain having the amino acid sequence of SEQ ID NO: 80, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 79. (Item 255) An antibody-drug conjugate (ADC) comprising an antibody conjugated to at least one drug or an antigen-binding portion thereof, wherein the antibody or its antigen-binding portion comprises a heavy chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 188, a CDR2 domain having the amino acid sequence of SEQ ID NO: 187, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 186, and a light chain variable region comprising a CDR3 domain having the amino acid sequence of SEQ ID NO: 63, 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: 190, ADC. (Item 256) The ADC according to any one of Items 222 to 255, wherein the antibody or its antigen-binding portion is of the IgG1 isotype 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) The pharmaceutical composition according to Item 257, wherein the average drug-to-antibody ratio (DAR) of the ADC mixture is 0 to 8. (Item 259) A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody according to any one of Items 1 to 221 or an antigen-binding portion thereof, or an ADC according to any one of Items 222 to 255. (Item 260) The method according to Item 259, wherein the cancer is acute myeloid leukemia (AML). (Item 261) The method according to Item 259, wherein the cancer is myelodysplastic syndrome (MDS). (Item 262) The method according to Item 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, comprising administering to the subject having the solid tumor an effective amount of an antibody or an antigen-binding portion thereof according to any one of items 1 to 221, or an ADC according to any one of items 222 to 255, such that the solid tumor growth is inhibited or reduced. (Item 264) The method according to item 263, wherein the cancer is lung cancer. (Item 265) The method according to item 263, wherein the cancer is non-small cell lung cancer (NSCLC). (Item 266) The method according to item 263, wherein the cancer is ovarian cancer. (Item 267) The method according to any one of items 259 to 266, wherein the antibody or an antigen-binding portion thereof is of the IgG4 isotype. (Item 268) The method according to any one of items 259 to 266, wherein the antibody or an antigen-binding portion thereof or the ADC is administered in combination with an additional agent or additional therapy. (Item 269) The method according to item 268, wherein the additional agent is an immune checkpoint inhibitor. (Item 270) The method according to item 269, wherein the immune checkpoint inhibitor is an antibody. (Item 271) The method according to item 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) The method according to item 268, wherein the additional therapy is radiation. (Item 273) The method according to item 268, wherein the additional agent is one or more chemotherapeutic agents. (Item 274) The method according to any one of items 259 to 266, wherein the cancer or tumor is characterized by expression or overexpression of IL1RAP.

Brief Description of the Drawings

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Mode for Carrying Out 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. The antibodies and ADCs described herein are used to detect human IL1RAP, to bind and inhibit human IL1RAP on IL1RAP-expressing cells, to inhibit the signaling of IL-1, such as IL-1β and / or IL-1α, in vivo, and / or to treat IL1RAP-related disorders, such as, but not limited to, acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), lung cancer including non-small cell lung cancer (NSCLC), and cancer including ovarian cancer.

[0257] In one embodiment, the anti-IL1RAP antibody or ADC of the present invention is administered in combination with one or more immune checkpoint inhibitors (e.g., antibodies or small molecule immune checkpoint inhibitors) for treating cancer. In another embodiment of the present invention, the anti-IL1RAP antibody-drug conjugate (ADC) of the present invention (e.g., the IL1RAP antibody of the present invention conjugated to a toxin) is internalized and induces cell death of cells that endogenously express IL1RAP.

[0258] I. Definitions To more readily understand the present invention, certain terms are first defined. In addition, it should be noted that whenever a value or range of values of a parameter is recited, values intermediate the recited values and ranges intermediate the recited ranges are also meant to be part of the present invention.

[0259] As used interchangeably herein, the terms "interleukin 1 receptor accessory protein antibody" or "anti-IL1RAP antibody" refer to an antibody that specifically binds to IL1RAP, such as human IL1RAP. An antibody that "binds" to the 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 that express the antigen. In preferred embodiments, 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.

Chemical Structure

[0261] As used herein with respect to the interaction of an IL1RAP antibody or ADC with a second chemical species, the terms "specific binding" or "specifically binds" mean that the interaction depends on the presence of a particular structure (e.g., an antigenic determinant or epitope) on that chemical species, such that, for example, the antibody recognizes and binds to a particular protein structure rather than proteins generally. If an antibody or ADC is specific for an epitope "A", in a reaction containing the label "A", the amount of label A bound to the antibody or ADC will decrease in the presence of molecules containing epitope A (or free unlabeled A) and the antibody.

[0262] In one embodiment, the phrase "specifically binds to hIL1RAP" or "specific binding to hIL1RAP", as used herein, refers to a dissociation constant (K D ) of about 2,000 nM or lower, about 1,000 nM or lower, about 500 nM or lower, about 200 nM or lower, about 100 nM or lower, about 75 nM or lower, about 25 nM or lower, about 21 nM or lower, about 12 nM or lower, about 11 nM or lower, about 10 nM or lower, 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, and 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, refers to a dissociation constant (K D ) 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, and refers to the ability of an anti-IL1RAP antibody or ADC to interact with hIL1RAP. In one embodiment, K DIt is 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 enables the analysis of real-time biospecific interactions by measuring the interference pattern of reflected white light, for example, using an 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, Y.N. et al. (2009) Anal. Biochem. 386(2):172-180. The contents of these references are incorporated herein by reference.

[0263] The term “antibody” generally refers to an immunoglobulin (Ig) molecule typically composed of four polypeptide chains, i.e., two heavy (H) chains and two light (L) chains, or any functional fragment, variant, variant, or derivative thereof that retains the essential target-binding characteristics of the Ig molecule. Such variant, variant, or derivative antibody forms are known in the art. Their non-limiting embodiments are discussed below.

[0264] In a full-length antibody, 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 hypervariable regions named complementarity-determining regions (CDRs) that are interspersed with more conserved regions named framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs arranged in the order of FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from the amino terminus to the carboxy terminus. The immunoglobulin molecule 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" (or simply "antibody portion") of an antibody, 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 in bispecific, dual specific, or multispecific formats, i.e., specifically bind to two or more different antigens. Examples of binding fragments included within the term "antigen-binding portion" of an antibody include the following: (i) Fab fragment, i.e., a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) F(ab’)2 fragment, i.e., a divalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region; (iii) Fd fragment consisting of the VH and CH1 domains; (iv) Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) dAb fragment containing a single variable domain (Ward et al., (1989) Nature 341:544-546; Winter et al., PCT Publication WO90 / 05144 A1, these references are incorporated herein by reference); and (vi) isolated complementarity-determining regions (CDRs). Furthermore, the two domains of the Fv fragment, VL and VH, are encoded by separate genes, but they can be joined using recombinant methods by a synthetic linker that enables them to form a single protein chain in which the VL and VH regions pair to form a monovalent molecule (known as single-chain Fv (scFv). See, for example, 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 included within the term "antigen-binding portion" of an antibody. In certain embodiments, the scFv molecule may be incorporated into a fusion protein. Other forms of single-chain antibodies, such as diabodies, are also included.The diabody has VH and VL domains expressed in a single polypeptide chain, but a linker that is too short to allow pairing between the two domains on the same chain is used, such that the domains are forced to pair with complementary domains on another chain, generating two antigen-binding sites, i.e., a bivalent bispecific antibody (see, e.g., Holliger, P. et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R.J. 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 portions disclosed herein linked to a linker polypeptide or immunoglobulin constant domain. A linker polypeptide contains two or more amino acid residues joined by peptide bonds and is used to link one or more antigen-binding portions. 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, R.J. et al. (1994) Structure 2:1121-1123). Immunoglobulin constant domains refer to heavy or light chain constant domains. 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 the whole antibody, respectively. Further, antibodies, antibody portions, and immunoadhesion molecules can be obtained using standard recombinant DNA techniques as described herein.

[0267] "Isolated antibody," as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigen 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 materials and / or chemical substances.

[0268] The term "humanized antibody" refers to an antibody that contains heavy and light chain variable region sequences derived from a non-human species (e.g., mouse), but at least portions 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 that immunospecifically binds to an antigen of interest and has a framework (FR) region having substantially the amino acid sequence of a human antibody and a complementarity-determining region (CDR) having substantially the amino acid sequence of a non-human antibody, or a variant, derivative, analog, or fragment thereof. 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 a non-human antibody CDR. A humanized antibody comprises substantially all of at least one, typically two, variable domains (Fab, Fab’, F(ab’)2, FabC, Fv) in which all or substantially all of the CDR regions correspond to the CDR regions of a non-human immunoglobulin (i.e., the donor antibody) and all or substantially all of the framework regions are framework regions of a human immunoglobulin consensus sequence. Also preferably, a humanized antibody comprises an immunoglobulin constant region (Fc), typically at least a portion of the constant region of a human immunoglobulin. In some embodiments, a humanized antibody comprises both a light chain and at least a heavy chain variable domain. Also, the antibody may comprise the CH1, hinge, CH2, CH3, and CH4 regions of the heavy chain. In some embodiments, a humanized antibody comprises only a humanized light chain. In other embodiments, a humanized antibody comprises only a humanized heavy chain. In certain embodiments, a 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 contain sequences derived from more than one class or isotype, and specific constant domains can be selected to optimize the desired effector function using techniques well known in the art.

[0270] The terms "Kabat numbering", "Kabat definition", and "Kabat notation" are used synonymously herein. These terms are recognized in the art 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 its antigen-binding portion (Kabat et al. (1971) Ann. NY Acad, Sci. 190:382-391, and Kabat, E.A. et al. (1991) Sequences of Proteins of Immunological Interest, 5th ed., U.S. Department of Health and Human Services, NIH Publication No. 91-3242). In the case of the heavy chain variable region, the hypervariable regions are in the range of amino acids 31-35 for CDR1, 50-65 for CDR2, and 95-102 for CDR3. In the case of the light chain variable region, the hypervariable regions are in the range of amino acids 24-34 for CDR1, 50-56 for CDR2, and 89-97 for CDR3.

[0271] As used herein, the term "CDR" refers to the complementarity determining regions within an antibody variable sequence. Each of the variable regions of the heavy chain (HC) and light chain (LC) has three CDRs, named CDR1, CDR2, and CDR3 for each of the variable regions (or specifically, HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3). The term "CDR set" as used herein refers to the group of three CDRs that occur 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 a clear residue numbering system applicable to any variable region of an antibody, but also provides the exact residue boundaries that define the three CDRs. Such CDRs may be referred to as Kabat CDRs. Chothia and co-workers (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987), and Chothia et al., Nature, 342:877-883 (1989)) found that certain sub-portions within the Kabat CDRs adopt almost identical peptide backbone conformations despite high diversity at the amino acid sequence level. Such sub-portions are named L1, L2, and L3, or H1, H2, and H3, where "L" and "H" refer to the light chain and heavy chain regions, respectively. Such regions may be referred to as Chothia CDRs and have boundaries that overlap with the Kabat CDRs. Other boundaries that define CDRs overlapping with the Kabat CDRs are 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 follow one of the above systems, but overlap with Kabat CDRs nonetheless, and can be shortened or extended in light of predictions or experimental findings that a particular residue or group of residues, or even an entire CDR, does not significantly affect antigen binding. In the methods used herein, CDRs defined according to any of these system schemes can be used, but in preferred embodiments, CDRs defined by Kabat or by Chothia are used.

[0272] As used herein, the terms "framework" or "framework sequence" refer to the remaining sequence of a variable region excluding the CDRs. Since the exact definition of the CDR sequences can be determined by various systems, the meaning of the framework sequences is subject to various corresponding interpretations. Also, the six CDRs (CDR-L1, CDR-L2, and CDR-L3 of the light chain, and CDR-H1, CDR-H2, and CDR-H3 of 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 located between FR2 and FR3, and CDR3 located between FR3 and FR4. The framework regions, as otherwise referenced, represent the combination of FRs within the variable region of a single naturally occurring immunoglobulin chain without designating a particular subregion as FR1, FR2, FR3, or FR4. As used herein, FR represents one of the four subregions, and FR represents two or more of the four subregions that make up the framework region.

[0273] The framework region and CDR region of a humanized antibody need not exactly correspond to the parental 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 such that the CDR or framework residue at that site does not correspond to either the donor antibody or the consensus framework. However, in a preferred embodiment, such mutations are not extensive. Usually, 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 the residues of the parental 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 amino acids (or nucleotides) that occur most frequently among 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 of the consensus sequence is occupied by the amino acid that occurs most frequently at that position in the family. When two amino acids occur with equal frequency, either can be included in the consensus sequence.

[0274] The "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 the amino acid residues of a particular peptide or polypeptide sequence, after aligning the sequences, introducing gaps if necessary to achieve the maximum percent sequence identity, and without considering any conservative substitutions as part of the sequence identity. Alignments for the purpose of determining percent amino acid sequence identity can be achieved in a variety of ways within the skill in the art using publicly available computer software such as, for example, BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. One of ordinary skill in the art can determine appropriate parameters for measuring the alignment, including any algorithms necessary to achieve the maximum alignment over the full length of the sequences being compared. In one embodiment, the disclosure includes amino acid sequences 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 an antigen-binding portion thereof is capable of inducing antibody-dependent cell-mediated cytotoxicity (ADCC). In one embodiment, the antibody or an antigen-binding portion thereof is not capable of inducing ADCC.

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

[0277] In one embodiment, the antibody or an antigen-binding portion thereof is capable of inducing both ADCC and CDC. In one embodiment, the antibody or an antigen-binding portion thereof is not capable of inducing either ADCC or CDC.

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

[0279] The term "bispecific antibody" refers to an antibody that is 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 a DVD may be monospecific, i.e., capable of binding to one antigen, or bispecific, i.e., capable of binding to two or more antigens. A DVD-binding protein that contains two heavy-chain DVD polypeptides and two light-chain DVD polypeptides is referred to as a DVD Ig. Each half of the DVD Ig contains a heavy-chain DVD polypeptide, 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 and has a total of six CDRs per antigen-binding site that are involved in antigen binding. In one embodiment, the CDRs described herein are used for an anti-IL1RAP DVD.

[0281] The term "activity" includes activities such as the binding specificity / affinity of an antibody or ADC against an antigen, for example, an anti-hIL1RAP antibody or ADC that binds to the IL1RAP antigen. In one embodiment, the anti-IL1RAP antibody or anti-IL1RAP ADC activity includes, but is not limited to, the following: binding to IL1RAP in vitro, binding to IL1RAP of cells expressing IL1RAP in vivo, modulation (e.g., inhibition) of IL-1, such as IL-1β and / or IL-1α signaling, induction of cell death in cells expressing IL1RAP, including leukemia cells, inhibition of cancer cell invasion and metastasis, reduction or inhibition of cancer, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), lung cancer including non-small cell lung cancer (NSCLC), and ovarian cancer, as well as reduction or inhibition of tumor cell proliferation or tumor growth in vivo. In one embodiment, the anti-IL1RAP antibody or ADC can be internalized into cells expressing IL1RAP and / or can induce cytotoxicity.

[0282] In one embodiment, the antibody or its antigen-binding portion can induce antibody-dependent cell-mediated cytotoxicity (ADCC). In one embodiment, the antibody or its antigen-binding portion cannot induce ADCC.

[0283] In one embodiment, the antibody or its antigen-binding portion can induce complement-dependent cytotoxicity (CDC). In one embodiment, the antibody or its antigen-binding portion cannot induce CDC.

[0284] In one embodiment, the antibody or its antigen-binding portion can induce both ADCC and CDC. In one embodiment, the antibody or its antigen-binding portion can induce neither ADCC nor CDC.

[0285] The term "epitope" refers to the region of an antigen to which an antibody, antibody fragment, or ADC binds. In certain embodiments, epitope determinants include chemically active surface groups of a molecule such as amino acids, sugar side chains, phosphoryls, or sulfonyls, and in certain embodiments may have specific three-dimensional structural features and / or specific charge features. In certain embodiments, an antibody is said to specifically bind an antigen if 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 enables the analysis of real-time biospecific interactions, for example, by detecting changes in protein concentration within a biosensor matrix using a BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden, and Piscataway, NJ). Further explanation can be found in Joensson, U. et al. (1993) Ann. Biol. Clin. 51:19-26; Joensson, U. et al. (1991) Biotechniques 11:620-627; Johnsson, B. et al. (1995) J. Mol. Recognit. 8:125-131; and Johnnson, 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 association rate constant at which an antibody associates 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 at which an antibody dissociates from an 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. K D is k a / k d calculated by. In one embodiment, the antibodies of the invention have a K D 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.

[0290] The term "competitive binding", as used herein, refers to a situation where 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" is an assay used to determine whether two or more antibodies bind to the same epitope. In one embodiment, a competitive binding assay is used to determine whether two or more antibodies bind to the same epitope by determining whether the fluorescence signal of a labeled antibody is reduced by the introduction of an unlabeled antibody, and the competition for the same epitope is a competitive fluorescence-activated cell sorting (FACS) assay that reduces the level of fluorescence.

[0292] As used herein, the term "labeled antibody" refers to an antibody or an antigen-binding portion thereof having an incorporated label that provides for the identification of the binding protein, e.g., an antibody. Preferably, the label is a detectable marker, e.g., incorporation of a radioisotope-labeled amino acid or binding of a biotinyl moiety to a polypeptide that can be detected by a labeled avidin (e.g., streptavidin containing a fluorescent marker or enzyme 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 phosphors), enzyme labels (e.g., horseradish peroxidase, luciferase, alkaline phosphatase); chemiluminescent markers; biotinyl groups; predetermined polypeptide epitopes recognized by secondary reporters (e.g., leucine zipper pairing 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 an antigen-binding fragment thereof that is chemically linked to one or more chemical drugs (also referred to herein as agents), which may be a therapeutic agent or a cytotoxic agent as required. In a preferred embodiment, the ADC comprises an antibody, a cytotoxic drug or a therapeutic drug, and a linker that enables the binding or conjugation of the drug to the antibody. The ADC typically contains 2, 4, 6, or 8 drug-loaded species, with 1 to 8 drugs conjugated to the antibody per ADC. Non-limiting examples of drugs that may be included in the ADC include mitotic inhibitors, antitumor antibiotics, immunomodulators, vectors for gene therapy, alkylating agents, antiangiogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, hormones, antihormonal agents, corticosteroids, photoactive therapeutic agents, oligonucleotides, radionuclide agents, topoisomerase inhibitors, tyrosine kinase inhibitors, and radiation sensitizers.

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

[0295] The term "drug-antibody ratio" or "DAR" refers to the number of drugs, such as IGN, auristatin, or maytansinoid, conjugated to the antibody of the ADC. The DAR of the ADC can range from 1 to 8, but higher loading amounts, such as 10, are also possible depending on the number of conjugation sites on the antibody. The term DAR may be used with respect to the number of drugs carried by an individual antibody, or alternatively with respect to the average or mean DAR of a population of ADCs.

[0296] As used herein, the term "IL1RAP-related disorder" includes any disorder or disease (including proliferative disorders such as cancer) that is marked, diagnosed, detected, or identified by an IL1RAP gene component or a phenotypic or genotypic abnormality of expression during the course or etiology of the disorder or disease. In this regard, an IL1RAP phenotypic abnormality or determinant can include, for example, an increase or decrease in the level of IL1RAP protein expression in one cell population, such as a cancer cell population, compared to another cell population, such as a normal cell population, or an increase or decrease in the level of IL1RAP protein expression in a particular definable cell population, or an increase or decrease in the level of IL1RAP protein expression at an inappropriate phase or stage of the cell life cycle. It is also understood that IL1RAP-related disorders can be classified or detected using similar expression patterns of IL1RAP genotypic determinants (e.g., mRNA transcript levels). In one embodiment, the IL1RAP-related disorder is leukemia, such as acute myeloid leukemia (AML). In another embodiment, the IL1RAP-related disorder is myelodysplastic syndrome (MDS). In another embodiment, the IL1RAP-related disorder is lung cancer. In another embodiment, the IL1RAP-related disorder is non-small cell lung cancer (NSCLC). In another embodiment, the IL1RAP-related disorder is ovarian cancer.

[0297] As used herein, the term "cancer" is typically intended to refer to or describe a physiological state in a mammal 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, the following: breast cancer (luminal A, TNBC, ductal), prostate cancer, squamous cell neoplasms, squamous cell carcinoma (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 uveal malignant melanoma, kidney cancer, uterine cancer, ovarian cancer, colorectal cancer, colon cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, non-Hodgkin lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, pediatric solid tumors, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, tumor angiogenesis, spinal cord axis tumors, brainstem gliomas, pituitary adenomas, Kaposi sarcoma, epidermoid cancer, environmentally induced cancers including those induced by asbestos, e.g., multiple myeloma, B cell lymphoma, Hodgkin lymphoma / primary mediastinal B cell lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), myeloproliferative disorders (MPD), chronic lymphocytic leukemia, follicular lymphoma, diffuse large B cell lymphoma, Burkitt 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, blood malignancies, PVNS, acute myeloid leukemia, adrenocortical cancer, bladder urothelial cancer (ladder urothelialcarcinoma), cervical squamous cell carcinoma, endocervical adenocarcinoma, diffuse large B-cell lymphoma, glioblastoma multiforme, chronic lymphocytic leukemia, low-grade glioma of the brain, 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 cancer, thymoma, thyroid cancer, endometrial cancer of the uterus, carcinosarcoma of the uterus, clear cell renal cell carcinoma of the kidney, and papillary renal cell carcinoma of the kidney, and any combination of said cancers. Further, the present invention is applicable to the treatment of metastatic cancer.

[0298] In one embodiment, the antibody or ADC of the present invention is administered to a patient having a solid tumor including a progressive solid tumor. In one embodiment, the antibody or ADC of the present invention is administered to a patient having leukemia. In another embodiment, administration of the antibody or ADC of the present 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 that include tumor-infiltrating cells that express the IL1RAP protein). In one embodiment, IL1RAP expression in the tumor is determined using immunohistochemical staining of the tumor cell membrane, and any immunohistochemical staining higher than the background level in the tumor sample indicates that the tumor is an IL1RAP-expressing tumor. In another embodiment, an IL1RAP-expressing tumor is identified in a patient when 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 of the cells in the tumor sample are positive for IL1RAP expression. In another embodiment, IL1RAP positive expression is determined based on membrane staining determined by, for example, immunohistochemical (IHC) analysis.

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

[0301] IL1RAP-expressing tumors are identified as having "low levels of IL1RAP" or "expressing IL1RAP at low levels" and are those in which 5% or fewer of the cells in the tumor sample have membrane staining. In some embodiments, "low levels" with respect to IL1RAP are 5% or fewer staining, for example, 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 are stained. In some embodiments, the protein expression level 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 the background staining level. In some embodiments, a sample that is IL1RAP "negative" does not have 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 a part of the subject that is from the same subject but different from 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 derived from a subject that is not from the subject being tested but is known to have or not have the disorder in question (e.g., a specific cancer such as an IL1RAP-related disorder). In some embodiments, the non-cancer sample is derived from the same subject but at a time point prior to the subject developing 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 the expression of IL1RAP in tumors are known in the art.

[0306] The terms "overexpressed," "overexpression," or "overexpressing" are used interchangeably to refer to a gene that is transcribed or translated at a level that is typically detectably higher in cancer cells compared to normal cells. Thus, overexpression refers to both overexpression of protein and RNA (due to increased transcription, post-transcriptional processing, translation, post-translational processing, changes in stability, and changes in proteolysis) as well as local overexpression due to changes in protein transport 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. Also, overexpression may be 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or higher compared to normal or comparator cells. In certain embodiments, an anti-IL1RAP antibody or ADC is used to treat solid tumors that may overexpress IL1RAP.

[0307] As used herein, the term "administering" is intended to refer to the delivery of a substance (e.g., an anti-IL1RAP antibody or ADC) for the purpose of achieving a therapeutic goal (e.g., treating an IL1RAP-related disorder or inhibiting or reducing a tumor). The mode of administration may be parenteral, enteral, and topical. Parenteral administration typically 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] As used herein, the term "combination therapy" refers to the administration of two or more therapeutic substances, e.g., an anti-IL1RAP antibody or ADC and an additional therapeutic agent. The additional therapeutic agent may be administered simultaneously with, prior to, or after administration of the anti-IL1RAP antibody or ADC. In one embodiment, the anti-IL1RAP antibody or ADC of the invention is administered in combination with one or more immune checkpoint inhibitors (e.g., one or more antibodies or small molecule immune checkpoint inhibitors) for treating cancer.

[0309] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a drug, such as an antibody or an ADC, that is sufficient to reduce or ameliorate the severity and / or duration of a disorder, such as cancer, or one or more of its symptoms, prevent progression of the disorder, cause regression of the disorder, prevent recurrence, onset, or worsening of one or more of the 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 reduce to some extent one or more of the symptoms associated with cancer. The 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 Antibodies One aspect disclosed herein provides a humanized anti-IL1RAP antibody or an antigen-binding portion thereof. Another aspect disclosed herein provides a human anti-IL1RAP antibody or an 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 binds, but is not limited to, to human IL1RAP in Characterized by binding in vitro, modulating, for example 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 ADCs disclosed herein are characterized by, including but not limited to, inducing cell death in cells expressing IL1RAP, such as leukemia cells expressing IL1RAP. In one embodiment, the anti-IL1RAP antibodies or ADCs disclosed herein are capable of internalizing into cells expressing IL1RAP.

[0313] In one embodiment, as described in the following examples, anti-IL1RAP antibodies having the ability to bind to IL1RAP are disclosed. The 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-described aspects, the anti-IL1RAP antibody, ADC, or antigen-binding fragment thereof binds to IL1RAP on cells expressing IL1RAP. Accordingly, the present disclosure includes anti-IL1RAP antibodies, ADCs, or antigen-binding fragments thereof effective for inhibiting or reducing tumor growth. Without wishing to be bound by any particular theory, in one embodiment, the anti-IL1RAP antibody, antigen-binding portion thereof, and ADC 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 the treatment of 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 entire contents of each of which are expressly incorporated herein by reference). Accordingly, in one embodiment, the anti-IL1RAP antibodies, antigen-binding portions thereof, and ADCs described herein are useful for inhibition downstream of the IL-1β pathway for treating cancer, such as lung cancer.

[0314] Furthermore, the inventors further demonstrated that IL1RAP is expressed by leukemia cells (see Example 1). Accordingly, anti-IL1RAP antibodies, ADCs, and antigen-binding portions thereof can be used for the treatment of leukemia, such as acute myeloid leukemia, in a subject. Anti-IL1RAP antibodies, ADCs, and antigen-binding portions thereof can be used for the treatment of myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), ovarian cancer, lung cancer, and non-small cell lung cancer, and other bone marrow disorders. 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 than the 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 a leukemia or tumor sample have membrane staining. In another embodiment, a tumor sample obtained from a 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 been previously treated with another anti-cancer agent or anti-cancer treatment, such as chemotherapy. In one embodiment, the cancer is resistant to chemotherapy.

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

[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 an ADC that can deliver a cytotoxic molecule conjugated to the antibody to IL1RAP-expressing cells, particularly IL1RAP-expressing cancer cells.

[0318] The term "antibody" is used throughout this specification, but it should be noted that antibody fragments (i.e., the antigen-binding portions of the anti-IL1RAP antibodies) are also included in the present disclosure and can be included in the embodiments (methods and compositions) described throughout this specification. For example, anti-IL1RAP antibody fragments may be conjugated to a drug 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 a fully human IL1RAP antibody against the extracellular domain of human IL1RAP. The heavy and light chain variable region amino acid sequences of such human antibodies are shown in Table 5. The heavy and light chain variable region nucleotide sequences of such human antibodies are shown in Table 6.

[0320] Thus, in one embodiment, the present disclosure includes 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 SEQ ID NOs: 5, 13, 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, or an antigen-binding portion thereof, of a human anti-IL1RAP antibody.

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

[0322] In one embodiment, the anti-IL1RAP antibody or an antigen-binding portion thereof is the 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, 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 is disclosed herein.

[0323] In some embodiments, the anti-IL1RAP antibody or an antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence shown 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 shown 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 present disclosure features an anti-IL1RAP antibody or an antigen-binding portion thereof that is the 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 present 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 an antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence shown 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 shown 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 present disclosure features an anti-IL1RAP antibody that is the human antibody 12F3_17C2 or an antigen-binding portion thereof. 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 present 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 an 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 present disclosure features an anti-IL1RAP antibody that is the human antibody 16H2_17D2 or an antigen-binding portion thereof. 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 present 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 the 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, antibodies are disclosed herein 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 sequ...

Claims

1. An anti-IL1RAP antibody or an antigen-binding portion thereof, comprising a CDR3 domain containing the amino acid sequence of SEQ ID NO: 12, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 11, and a CDR1 domain containing the amino acid sequence of SEQ ID NO: 10 in the heavy chain variable region; and a CDR3 domain containing the amino acid sequence of SEQ ID NO: 16, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain containing the amino acid sequence of SEQ ID NO: 14 in the light chain variable region; or a heavy chain variable region containing a CDR3 domain having the amino acid sequence of SEQ ID NO: 59, a CDR2 domain having the amino acid sequence of SEQ ID NO: 58, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 57; and a light chain variable region containing a CDR3 domain having the amino acid sequence of SEQ ID NO: 63, 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: 61; or a heavy chain variable region containing a CDR3 domain having the amino acid sequence of SEQ ID NO: 176, a CDR2 domain having the amino acid sequence of SEQ ID NO: 175, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 174; and a light chain variable region containing a CDR3 domain having the amino acid sequence of SEQ ID NO: 179, a CDR2 domain having the amino acid sequence of SEQ ID NO: 178, and a CDR1 domain having the amino acid sequence of SEQ ID NO: 79 An antibody or an antigen-binding portion thereof comprising the same.

2. An anti-IL1RAP antibody or an antigen-binding portion thereof, a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 9, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 82; a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 56, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 60; or a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 173, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 177 An antibody or an antigen-binding portion thereof comprising the same.

3. An anti-IL1RAP antibody or an antigen-binding portion thereof, comprising: a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 9, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 9, the heavy chain 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 comprising the amino acid sequence shown in SEQ ID NO: 82, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 82, the light chain 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; a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 56, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 56, the heavy chain 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 comprising the amino acid sequence shown in SEQ ID NO: 60, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 60, the light chain 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; or A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 173, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 173, 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 comprising the amino acid sequence shown in SEQ ID NO: 177, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 177, 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 An antibody or an antigen-binding portion thereof comprising the same.

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

5. A pharmaceutical composition comprising the antibody or an antigen-binding portion thereof according to claim 1 and a pharmaceutically acceptable carrier.

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

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

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

9. A composition for treating cancer, comprising the antibody or an antigen-binding portion thereof according to claim 1.

10. The composition according to 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 the antibody according to claim 1 or an antigen-binding portion thereof.

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

13. The composition according to claim 9, characterized in that it is administered in combination with an additional agent or additional therapy.

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

15. An antibody-drug conjugate (ADC) comprising the anti-IL1RAP antibody according to claim 1 or an antigen-binding portion thereof conjugated to at least one drug, wherein the drug is selected from the group consisting of a DNA-damaging agent, an anti-apoptotic agent, a mitosis inhibitor, an antitumor antibiotic, an immunomodulatory agent, an anti-angiogenic agent, an antimetabolite, a boron-containing agent, a chemoprotective agent, a hormonal agent, an anti-hormonal agent, a photoactive therapeutic agent, an oligonucleotide, a radionuclide agent, a radiosensitizer, a topoisomerase inhibitor, and a tyrosine kinase inhibitor.

16. The ADC according to claim 15, wherein the oligonucleotide is a nucleic acid for gene therapy and the hormonal agent is a corticosteroid.

17. The ADC according to claim 15, wherein the at least one drug is conjugated to the antibody or an antigen-binding portion thereof via a linker.

18. The ADC according to claim 17, wherein the linker is a cleavable linker.

19. The ADC according to claim 17, wherein the linker is a non-cleavable linker.

20. The ADC according to claim 15, wherein the antibody or antigen-binding portion thereof is of the IgG1 isotype or IgG4 isotype.

21. The ADC according to claim 15, wherein the ADC has an average drug-to-antibody ratio (DAR) of 1 to 8.

22. Use of the antibody or antigen-binding portion thereof according to claim 1 or the ADC according to claim 15 in the manufacture of a medicament for treating cancer, wherein the cancer is acute myeloid leukemia (AML).

23. A composition for treating cancer, comprising the antibody or antigen-binding portion thereof according to claim 1 or the ADC according to claim 15.

24. The composition according to claim 23, wherein the cancer is acute myeloid leukemia (AML).

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