Anti-interleukin-1 receptor antibodies with engineered FC mutations

Abstract

The present invention provides, among other things, a half-life extended anti- interleukin-1 receptor type-1 (IL1R1) antibody engineered with Fc mutations that render superior pharmacokinetic profiles without decreasing stability and manufacturability of the anti-IL1R1 antibody.

Description

ATTORNEY DOCKET NO.: KPL-080W01ANTI-INTERLEUKIN-1 RECEPTOR ANTIBODIES WITH ENGINEERED FC MUTATIONSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 761,429, filed February 21, 2025, U.S. Provisional Application No.63 / 785,417, filed April 8, 2025, U.S. Provisional Application No. 63 / 855,855, filed August 1, 2025, and U.S. Provisional Application No. 63 / 957,067, filed January 9, 2026; the disclosure of each of which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] Interleukin-1 (IL-1) plays a key role in the pathophysiology of many inflammatory processes and has been identified as a factor in various inflammatory diseases. IL-1 stimulates cellular responses by interacting with a heterodimeric receptor complex comprises of two transmembrane proteins, IL-1 receptor type I (IL1R1) and IL-1 receptor accessory protein (ILlRAcP). Preventing IL-1 signaling by inhibiting IL-1 from binding to the IL1R1, such as through the anti-ILlRl antibody, is a potential approach for treating inflammatory diseases.

[0003] There are numerous Fc mutations that have been identified and engineered to extend the half-life of therapeutic antibodies. These mutations generally work by enhancing the interaction of the Fc region of the antibody with the neonatal Fc receptor (FcRn), which plays a key role in protecting antibodies from lysosomal degradation and facilitating their recycling. However, not all half-life extension Fc mutation work universally for all antibodies. Such Fc mutations can inadvertently affect the overall stability or conformation of the antibody, alter antigen binding and Fc-mediated functions. The development of therapeutic antibodies is an intricate process that requires a holistic approach, balancing efficacy, safety, stability, and manufacturability.SUMMARY OF THE INVENTION

[0004] The present invention provides, among other things, half-life extended anti-IL1R1 antibodies for more potent treatment of inflammatory diseases. The present inventionATTORNEY DOCKET NO.: KPL-080W01is, in part, based on the discovery that certain Fc mutations, particularly M428L / N434S (LS) and V / L309D / Q311H / N434S (DHS), when combined with anti-ILlRl antibody described herein, resulted in more than doubled in vivo half-life. Significantly, these mutations render superior pharmacokinetic profiles without undermining stability and manufacturability of the anti-ILlRl antibody as compared to other Fc mutations, despite the known challenges in the prior art associated with half-life extending Fc mutations.

[0005] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions M428L and N434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0006] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 12, a HCDR2 of SEQ ID NO: 13, a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions M428L and N434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0007] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 14, a HCDR2 of SEQ ID NO: 15, a HCDR3 of SEQ ID NO: 19; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 16, a LCDR2 of SEQ ID NO: 17, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions M428L and N434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0008] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1, a HCDR2, and a HCDR3 in the VH of SEQ ID NO: 7; a variable light chain (VL) comprising a LCDR1, a LCDR2, and a LCDR3 in the VL of SEQ ID NO: 8; and a modified Fc domain comprisingATTORNEY DOCKET NO.: KPL-080W01amino acid substitutions M428L and N434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0009] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, and N434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0010] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 12, a HCDR2 of SEQ ID NO: 13, a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, and N434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0011] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 14, a HCDR2 of SEQ ID NO: 15, a HCDR3 of SEQ ID NO: 19; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 16, a LCDR2 of SEQ ID NO: 17, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, and N434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0012] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1, a HCDR2, and a HCDR3 in the VH of SEQ ID NO: 7; a variable light chain (VL) comprising a LCDR1, a LCDR2, and a LCDR3 in the VL of SEQ ID NO: 8; and a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, and N434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0013] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3; a variable light chainATTORNEY DOCKET NO.: KPL-080W01(VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, and N434Y as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0014] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: available heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 12, a HCDR2 of SEQ ID NO: 13, a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, and N434Y as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0015] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: available heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 14, a HCDR2 of SEQ ID NO: 15, a HCDR3 of SEQ ID NO: 19; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 16, a LCDR2 of SEQ ID NO: 17, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, and N434Y as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0016] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1, a HCDR2, and a HCDR3 in the VH of SEQ ID NO: 7; a variable light chain (VL) comprising a LCDR1, a LCDR2, and a LCDR3 in the VL of SEQ ID NO: 8; and a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, and N434Y as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0017] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising an amino acid substitution M428L as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0018] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: available heavy chain (VH)ATTORNEY DOCKET NO.: KPL-080W01comprising a HCDR1 of SEQ ID NO: 12, a HCDR2 of SEQ ID NO: 13, a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising an amino acid substitution M428L as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0019] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: available heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 14, a HCDR2 of SEQ ID NO: 15, a HCDR3 of SEQ ID NO: 19; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 16, a LCDR2 of SEQ ID NO: 17, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising an amino acid substitution M428L as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0020] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1, a HCDR2, and a HCDR3 in the VH of SEQ ID NO: 7; a variable light chain (VL) comprising a LCDR1, a LCDR2, and a LCDR3 in the VL of SEQ ID NO: 8; and a modified Fc domain comprising an amino acid substitution M428L as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0021] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions T307A, E380A, and N434A as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0022] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: available heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 12, a HCDR2 of SEQ ID NO: 13, a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions T307A, E380A, and N434A as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.ATTORNEY DOCKET NO.: KPL-080W01

[0023] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 14, a HCDR2 of SEQ ID NO: 15, a HCDR3 of SEQ ID NO: 19; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 16, a LCDR2 of SEQ ID NO: 17, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions T307A, E380A, and N434A as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0024] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1, a HCDR2, and a HCDR3 in the VH of SEQ ID NO: 7; a variable light chain (VL) comprising a LCDR1, a LCDR2, and a LCDR3 in the VL of SEQ ID NO: 8; and a modified Fc domain comprising amino acid substitutions T307A, E380A, and N434A as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0025] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, M428L, and N434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0026] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 12, a HCDR2 of SEQ ID NO: 13, a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, M428L, and N434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0027] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 14, a HCDR2 of SEQ ID NO: 15, a HCDR3 of SEQ ID NO: 19; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 16, a LCDR2 of SEQ ID NO: 17, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprisingATTORNEY DOCKET NO.: KPL-080W01amino acid substitutions V / L309D, Q311H, M428L, and N434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0028] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1, a HCDR2, and a HCDR3 in the VH of SEQ ID NO: 7; a variable light chain (VL) comprising a LCDR1, a LCDR2, and a LCDR3 in the VL of SEQ ID NO: 8; and a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, M428L, and N434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0029] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, M428L, and N434Y as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0030] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 12, a HCDR2 of SEQ ID NO: 13, a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, M428L, and N434Y as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0031] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 14, a HCDR2 of SEQ ID NO: 15, a HCDR3 of SEQ ID NO: 19; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 16, a LCDR2 of SEQ ID NO: 17, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, M428L, and N434Y as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0032] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1, a HCDR2, and a HCDR3 in the VH of SEQ ID NO: 7; a variable light chain (VL) comprising a LCDR1,ATTORNEY DOCKET NO.: KPL-080W01a LCDR2, and a LCDR3 in the VL of SEQ ID NO: 8; and a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, M428L, and N434Y as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0033] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions T250Q and M428L as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0034] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: available heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 12, a HCDR2 of SEQ ID NO: 13, a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions T250Q and M428L as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0035] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: available heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 14, a HCDR2 of SEQ ID NO: 15, a HCDR3 of SEQ ID NO: 19; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 16, a LCDR2 of SEQ ID NO: 17, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions T250Q and M428L as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0036] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1, a HCDR2, and a HCDR3 in the VH of SEQ ID NO: 7; a variable light chain (VL) comprising a LCDR1, a LCDR2, and a LCDR3 in the VL of SEQ ID NO: 8; and a modified Fc domain comprising amino acid substitutions T250Q and M428L as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0037] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ IDATTORNEY DOCKET NO.: KPL-080W01NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, and N434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0038] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 12, a HCDR2 of SEQ ID NO: 13, a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, andN434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0039] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 14, a HCDR2 of SEQ ID NO: 15, a HCDR3 of SEQ ID NO: 19; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 16, a LCDR2 of SEQ ID NO: 17, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, andN434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0040] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1, a HCDR2, and a HCDR3 in the VH of SEQ ID NO: 7; a variable light chain (VL) comprising a LCDR1, a LCDR2, and a LCDR3 in the VL of SEQ ID NO: 8; and a modified Fc domain comprising amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, andN434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0041] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, and N434Y as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.ATTORNEY DOCKET NO.: KPL-080W01

[0042] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 12, a HCDR2 of SEQ ID NO: 13, a HCDR3 of SEQ ID NO: 3; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, and N434Y as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0043] In one aspect, the present invention provides, among other things, an antiinterleukin-1 receptor type- 1 (IL1R1) antibody comprising: a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 14, a HCDR2 of SEQ ID NO: 15, a HCDR3 of SEQ ID NO: 19; a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 16, a LCDR2 of SEQ ID NO: 17, and a LCDR3 of SEQ ID NO: 6; and a modified Fc domain comprising amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, and N434Y as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0044] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a variable heavy chain (VH) comprising a HCDR1, a HCDR2, and a HCDR3 in the VH of SEQ ID NO: 7; a variable light chain (VL) comprising a LCDR1, a LCDR2, and a LCDR3 in the VL of SEQ ID NO: 8; and a modified Fc domain comprising amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, and N434Y as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

[0045] In some embodiments, the modified Fc domain is derived from IgGl, IgG2, IgG3, or IgG4. In some embodiments, the modified Fc domain is derived from IgGl. In some embodiments, the modified Fc domain is derived from IgG2. In some embodiments, the modified Fc domain is derived from IgG3. In some embodiments, the modified Fc domain is derived from IgG4.

[0046] In some embodiments, the modified Fc domain does not comprise amino acid substitutions M252Y, S254T, and T256E. In some embodiments, modified Fc domain is derived from IgGl and does not comprise amino acid substitutions M252Y, S254T, and T256E. In some embodiments, modified Fc domain is derived from IgG2 and does not comprise amino acid substitutions M252Y, S254T, and T256E. In some embodiments, modified Fc domain is derived from IgG3 and does not comprise amino acid substitutionsATTORNEY DOCKET NO.: KPL-080W01M252Y, S254T, and T256E. In some embodiments, modified Fc domain is derived from IgG4 and does not comprise amino acid substitutions M252Y, S254T, and T256E.

[0047] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a VH comprising a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3; a VL comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and an Fc domain means for increasing binding affinity of the anti-ILlRl antibody to human neonatal Fc receptor (FcRn) at acidic pH by at least 5-fold as compared to the binding affinity of an anti-ILlRl antibody with the parent Fc domain.

[0048] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a VH comprising a HCDR1 of SEQ ID NO: 12, a HCDR2 of SEQ ID NO: 13, and a HCDR3 of SEQ ID NO: 3; a VL comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; and an Fc domain means for increasing binding affinity of the anti-ILlRl antibody to human neonatal Fc receptor (FcRn) at acidic pH by at least 5-fold as compared to the binding affinity of an anti-IL1R1 antibody with the parent Fc domain.

[0049] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a VH comprising a HCDR1 of SEQ ID NO: 14, a HCDR2 of SEQ ID NO: 15, and a HCDR3 of SEQ ID NO: 19; a VL comprising a LCDR1 of SEQ ID NO: 16, a LCDR2 of SEQ ID NO: 17, and a LCDR3 of SEQ ID NO: 6; and an Fc domain means for increasing binding affinity of the anti-ILlRl antibody to human neonatal Fc receptor (FcRn) at acidic pH by at least 5-fold as compared to the binding affinity of an anti-IL1R1 antibody with the parent Fc domain.

[0050] In one aspect, the present invention provides, among other things, an anti-IL1R1 antibody comprising: a VH comprising a HCDR1, a HCDR2, and a HCDR3 in the VH of SEQ ID NO: 7; a VL comprising a LCDR1, a LCDR2, and a LCDR3 in the VL of SEQ ID NO: 8; and an Fc domain means for increasing binding affinity of the anti-ILlRl antibody to FcRn at acidic pH by at least 5-fold as compared to the binding affinity of an anti-ILlRl antibody with the parent Fc domain.

[0051] In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 5-fold, at least 7-fold, at least 10-fold, at least 15-ATTORNEY DOCKET NO.: KPL-080W01fold, at least 30-fold, at least 50-fold, or at least 60-fold, or at least 70-fold as compared the binding affinity to FcRn of an anti-ILlRl antibody with the parent Fc domain.

[0052] In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 6-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 7-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 8-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 9-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 10-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 11 -fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 12-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 13-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 14-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 15-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 16-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 18-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 20-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 22-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 24-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 25-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 30-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 35-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 40-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 45-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 50-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 55-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at leastATTORNEY DOCKET NO.: KPL-080W0160-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 65-fold. In some embodiments, the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 70-fold.

[0053] In some embodiments, the anti-ILlRl antibody has a dissociation constant (KD) to FcRn at acidic pH that is at least 5-fold, at least 7-fold, at least 10-fold, at least 15-fold, at least 30-fold, at least 50-fold, at least 60-fold, or at least 70-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain.

[0054] In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 5-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 6-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 7-fold greater than the KD to FcRn at acidic pH of an anti-IL1R1 antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 8-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 9-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 10-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 11 -fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 12-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 13 -fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 14-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 15-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 16-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, theATTORNEY DOCKET NO.: KPL-080W01anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 17-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 18-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 19-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 20-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 21-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 22-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 23-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 24-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 25-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 30-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 35 -fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 40-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 45-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 50-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 55 -fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 60-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent FcATTORNEY DOCKET NO.: KPL-080W01domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 65 -fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is at least 70-fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain.

[0055] In some embodiments, the anti-ILlRl antibody has a dissociation rate constant (KOff) to FcRn at neutral pH that is greater than 0.003 s'1. In some embodiments, the anti-ILlRl antibody has a dissociation rate constant (KOff) to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the anti-ILlRl antibody has a dissociation rate constant (KOff) to FcRn at neutral pH that is greater than 0.008 s'1. In some embodiments, the anti-ILlRl antibody has a dissociation rate constant (KOff) to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the anti-ILlRl antibody has a dissociation rate constant (KOff) to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the anti-ILlRl antibody has a dissociation rate constant (KOff) to FcRn at neutral pH that is greater than 0.03 s'1. In some embodiments, the anti-ILlRl antibody has a dissociation rate constant (KOff) to FcRn at neutral pH that is greater than 0.04 s'1. In some embodiments, the anti-ILlRl antibody has a dissociation rate constant (KOff) to FcRn at neutral pH that is greater than 0.05 s'1.

[0056] In some embodiments, the anti-ILlRl antibody has a dissociation rate constant (KOff) to FcRn at neutral pH that is between 0.01 s'1and 0.05 s'1. In some embodiments, the anti-ILlRl antibody has a dissociation rate constant (KOff) to FcRn at neutral pH that is between 0.02 s'1and 0.05 s'1. In some embodiments, the anti-ILlRl antibody has a dissociation rate constant (KOff) to FcRn at neutral pH that is between 0.01 s'1and 0.04 s'1. In some embodiments, the anti-ILlRl antibody has a dissociation rate constant (KOff) to FcRn at neutral pH that is between 0.02 s'1and 0.03 s'1. In some embodiments, the anti-ILlRl antibody has a dissociation rate constant (KOff) to FcRn at neutral pH that is between 0.01 s'1and 0.03 s'1.

[0057] In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 20 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 15 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the anti-IL1R1 antibody has a KD to FcRn at acidic pH that is below 10 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the anti-ILlRl antibody has aATTORNEY DOCKET NO.: KPL-080W01KD to FcRn at acidic pH that is below 9 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 8 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 7 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the anti-IL1R1 antibody has a KD to FcRn at acidic pH that is below 6 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 5 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 4 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 3 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the anti-IL1R1 antibody has a KD to FcRn at acidic pH that is below 2 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 1 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1.

[0058] In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 20 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 15 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the anti-IL1R1 antibody has a KD to FcRn at acidic pH that is below 10 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 9 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 8 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 7 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the anti-IL1R1 antibody has a KD to FcRn at acidic pH that is below 6 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 5 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 4 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 3 nM, andATTORNEY DOCKET NO.: KPL-080W01a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the anti-IL1R1 antibody has a KD to FcRn at acidic pH that is below 2 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 1 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1.

[0059] In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 20 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 15 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the anti-IL1R1 antibody has a KD to FcRn at acidic pH that is below 10 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 9 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 8 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 7 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the anti-IL1R1 antibody has a KD to FcRn at acidic pH that is below 6 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 5 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 4 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 3 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the anti-IL1R1 antibody has a KD to FcRn at acidic pH that is below 2 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 1 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1.

[0060] In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 20 nM, and a KOff to FcRn at neutral pH that is greater than 0.04 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 15 nM, and a KOff to FcRn at neutral pH that is greater than 0.04 s'1. In some embodiments, the anti-IL1R1 antibody has a KD to FcRn at acidic pH that is below 10 nM, and a KOff to FcRn at neutral pH that is greater than 0.04 s'1. In some embodiments, the anti-ILlRl antibody has aATTORNEY DOCKET NO.: KPL-080W01KD to FcRn at acidic pH that is below 9 nM, and a KOff to FcRn at neutral pH that is greater than 0.04 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 8 nM, and a KOff to FcRn at neutral pH that is greater than 0.04 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 7 nM, and a KOff to FcRn at neutral pH that is greater than 0.04 s'1. In some embodiments, the anti-IL1R1 antibody has a KD to FcRn at acidic pH that is below 6 nM, and a KOff to FcRn at neutral pH that is greater than 0.04 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 5 nM, and a KOff to FcRn at neutral pH that is greater than 0.04 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 4 nM, and a KOff to FcRn at neutral pH that is greater than 0.04 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 3 nM, and a KOff to FcRn at neutral pH that is greater than 0.04 s'1. In some embodiments, the anti-IL1R1 antibody has a KD to FcRn at acidic pH that is below 2 nM, and a KOff to FcRn at neutral pH that is greater than 0.04 s'1. In some embodiments, the anti-ILlRl antibody has a KD to FcRn at acidic pH that is below 1 nM, and a KOff to FcRn at neutral pH that is greater than 0.04 s'1.

[0061] In some embodiments, the acidic pH is below 7.0. In some embodiments, the acidic pH is between 4.5 and 6.8. In some embodiments, the acidic pH is between 4.8 and 6.8. In some embodiments, the acidic pH is between 5.0 and 6.4. In some embodiments, the acidic pH is between 5.4 and 6.0. In some embodiments, the acidic pH is between 5.6 and 6.0. In some embodiments, the acidic pH is 5.0. In some embodiments, the acidic pH is 5.1 In some embodiments, the acidic pH is 5.2. In some embodiments, the acidic pH is 5.3. In some embodiments, the acidic pH is 5.4. In some embodiments, the acidic pH is 5.5. In some embodiments, the acidic pH is 5.6. In some embodiments, the acidic pH is 5.7. In some embodiments, the acidic pH is 5.8. In some embodiments, the acidic pH is 5.9. In some embodiments, the acidic pH is 6.0. In some embodiments, the acidic pH is 6.1. In some embodiments, the acidic pH is 6.2. In some embodiments, the acidic pH is 6.3. In some embodiments, the acidic pH is 6.4. In some embodiments, the acidic pH is 6.5. In some embodiments, the acidic pH is 6.6. In some embodiments, the acidic pH is 6.7. In some embodiments, the acidic pH is 6.8. In some embodiments, the acidic pH is 6.9.

[0062] In some embodiments, the neutral pH is between 7.0 and 8.0. In some embodiments, the neutral pH is between 7.2 and 7.6. In some embodiments, the neutral pH is between 7.3 and 7.5. In some embodiments, the neutral pH is 7.0. In some embodiments, theATTORNEY DOCKET NO.: KPL-080W01neutral pH is 7.1. In some embodiments, the neutral pH is 7.2. In some embodiments, the neutral pH is 7.3. In some embodiments, the neutral pH is 7.4. In some embodiments, the neutral pH is 7.5. In some embodiments, the neutral pH is 7.6. In some embodiments, the neutral pH is 7.7. In some embodiments, the neutral pH is 7.8. In some embodiments, the neutral pH is 7.9. In some embodiments, the neutral pH is 8.0.

[0063] In some embodiments, a modified Fc domain does not adversely impact the ECso value of the anti-ILlRl antibody. In some embodiments, the anti-ILlRl antibody has an EC50 value for inhibition of IL-6 production that is less than 100 nM, less than 80 nM, or less than 60 nM. In some embodiments, the ECsovalue for inhibition of IL-6 production is less than 100 nM. In some embodiments, the ECsovalue for inhibition of IL-6 production is less than 90 nM. In some embodiments, the ECsovalue for inhibition of IL-6 production is less than 85 nM. In some embodiments, the ECsovalue for inhibition of IL-6 production is less than 80 nM. In some embodiments, the ECsovalue for inhibition of IL-6 production is less than 75 nM. In some embodiments, the ECsovalue for inhibition of IL-6 production is less than 70 nM. In some embodiments, the ECsovalue for inhibition of IL-6 production is less than 65 nM. In some embodiments, the ECsovalue for inhibition of IL-6 production is less than 60 nM. In some embodiments, the ECsovalue for inhibition of IL-6 production is less than 55 nM. In some embodiments, the ECsovalue for inhibition of IL-6 production is less than 50 nM.

[0064] In some embodiments, the anti-ILlRl antibody has a half-life (ti / 2 value) that is at least greater than 9 days. In some embodiments, the anti-ILlRl antibody has a half-life (ti / 2 value) that is at least greater than 10 days. In some embodiments, the anti-ILlRl antibody has a half-life (ti / 2 value) that is at least greater than 11 days. In some embodiments, the anti-ILlRl antibody has a half-life (ti / 2 value) that is at least greater than 12 days. In some embodiments, the anti-ILlRl antibody has a half-life (ti / 2 value) that is at least greater than 13 days. In some embodiments, the anti-ILlRl antibody has a half-life (ti / 2 value) that is at least greater than 14 days. In some embodiments, the anti-ILlRl antibody has a half-life (ti / 2 value) that is at least greater than 15 days. In some embodiments, the anti-ILlRl antibody has a half-life (ti / 2 value) that is at least greater than 16 days. In some embodiments, the anti-ILlRl antibody has a half-life (ti / 2 value) that is at least greater than 17 days. In some embodiments, the anti-ILlRl antibody has a half-life (ti / 2 value) that is at least greater than 18 days. In some embodiments, the anti-ILlRl antibody has a half-life (ti / 2 value) thatATTORNEY DOCKET NO.: KPL-080W01is at least greater than 19 days. In some embodiments, the anti-ILlRl antibody has a half-life (ti / 2 value) that is at least greater than 20 days.

[0065] In some embodiments, the VH comprises an amino acid sequence at least 80% identical to SEQ ID NO: 7. In some embodiments, the VH comprises an amino acid sequence at least 85% identical to SEQ ID NO: 7. In some embodiments, the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 7. In some embodiments, the VH comprises an amino acid sequence at least 91% identical to SEQ ID NO: 7. In some embodiments, the VH comprises an amino acid sequence at least 92% identical to SEQ ID NO: 7. In some embodiments, the VH comprises an amino acid sequence at least 93% identical to SEQ ID NO: 7. In some embodiments, the VH comprises an amino acid sequence at least 94% identical to SEQ ID NO: 7. In some embodiments, the VH comprises an amino acid sequence at least 95% identical to SEQ ID NO: 7. In some embodiments, the VH comprises an amino acid sequence at least 96% identical to SEQ ID NO: 7. In some embodiments, the VH comprises an amino acid sequence at least 97% identical to SEQ ID NO: 7. In some embodiments, the VH comprises an amino acid sequence at least 98% identical to SEQ ID NO: 7. In some embodiments, the VH comprises an amino acid sequence at least 99% identical to SEQ ID NO: 7. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 7.

[0066] In some embodiments, the VL comprises an amino acid sequence at least 80% identical to SEQ ID NO: 8. In some embodiments, the VL comprises an amino acid sequence at least 85% identical to SEQ ID NO: 8. In some embodiments, the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 8. In some embodiments, the VL comprises an amino acid sequence at least 91% identical to SEQ ID NO: 8. In some embodiments, the VL comprises an amino acid sequence at least 92% identical to SEQ ID NO: 8. In some embodiments, the VL comprises an amino acid sequence at least 93% identical to SEQ ID NO: 8. In some embodiments, the VL comprises an amino acid sequence at least 94% identical to SEQ ID NO: 8. In some embodiments, the VL comprises an amino acid sequence at least 95% identical to SEQ ID NO: 8. In some embodiments, the VL comprises an amino acid sequence at least 96% identical to SEQ ID NO: 8. In some embodiments, the VL comprises an amino acid sequence at least 97% identical to SEQ ID NO: 8. In some embodiments, the VL comprises an amino acid sequence at least 98% identical to SEQ ID NO: 8. In some embodiments, the VL comprises an amino acid sequenceATTORNEY DOCKET NO.: KPL-080W01at least 99% identical to SEQ ID NO: 8. In some embodiments, the VL comprises the amino acid sequence of SEQ ID NO: 8.

[0067] In some embodiments, the anti-ILlRl antibody comprises the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8.

[0068] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence of SEQ ID NO: 20.

[0069] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO:ATTORNEY DOCKET NO.: KPL-080W0121. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence of SEQ ID NO: 21.

[0070] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence of SEQ ID NO: 22.

[0071] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at leastATTORNEY DOCKET NO.: KPL-080W0193% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence of SEQ ID NO: 23.

[0072] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence of SEQ ID NO: 24.

[0073] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises anATTORNEY DOCKET NO.: KPL-080W01amino acid sequence at least 91% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence of SEQ ID NO: 25.

[0074] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence of SEQ ID NO: 26.

[0075] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 27. In some embodiments, the modified FcATTORNEY DOCKET NO.: KPL-080W01domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence of SEQ ID NO: 27.

[0076] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at leastATTORNEY DOCKET NO.: KPL-080W0199% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence of SEQ ID NO: 28.

[0077] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence of SEQ ID NO: 29.

[0078] In some embodiments, the anti-ILlRl antibody comprises a heavy chain of SEQ ID NO: 30 and a light chain of SEQ ID NO: 11. In some embodiments, the anti-ILlRl antibody comprises a heavy chain of SEQ ID NO: 31 and a light chain of SEQ ID NO: 11. In some embodiments, the anti-ILlRl antibody comprises a heavy chain of SEQ ID NO: 32 and a light chain of SEQ ID NO: 11. In some embodiments, the anti-ILlRl antibody comprises a heavy chain of SEQ ID NO: 33 and a light chain of SEQ ID NO: 11. In some embodiments, the anti-ILlRl antibody comprises a heavy chain of SEQ ID NO: 34 and a light chain of SEQ ID NO: 11. In some embodiments, the anti-ILlRl antibody comprises a heavy chain of SEQ ID NO: 35 and a light chain of SEQ ID NO: 11. In some embodiments, the anti-ILlRl antibody comprises a heavy chain of SEQ ID NO: 36 and a light chain of SEQ ID NO: 11. In some embodiments, the anti-ILlRl antibody comprises a heavy chain of SEQ ID NO: 37 and a light chain of SEQ ID NO: 11. In some embodiments, the anti-ILlRl antibody comprises a heavy chain of SEQ ID NO: 38 and a light chain of SEQ ID NO: 11. In some embodiments,ATTORNEY DOCKET NO.: KPL-080W01the anti-ILlRl antibody comprises a heavy chain of SEQ ID NO: 39 and a light chain of SEQ ID NO: 11.

[0079] In one aspect, the present invention provides, among other things, a method of treating an inflammatory disease associated with IL1 or IL1R1, comprising administering the anti-ILlRl antibody described herein to a subject in need thereof. In some embodiments, the inflammatory disease is associated with IL1. In some embodiments, the inflammatory disease is associated with IL1R1.

[0080] In some embodiments, the disease is post-cardiac injury syndrome (PCIS), pericarditis, recurrent pericarditis, refractory pericarditis, idiopathic pericarditis, idiopathic recurrent pericarditis, non-idiopathic pericarditis, myocardial infarction pericarditis, posttraumatic pericarditis, post-pericardiotomy syndrome (PPS), early post-myocardial infarct-associated pericarditis, late post-myocardial infarction pericarditis, non-iatrogenic trauma, iatrogenic trauma, deficiency of interleukin- 1 receptor antagonist (DIRA), rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndromes (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), hi dradenitis suppurativa, ankylosing spondylitis (AS), gout (e.g., acute gout, acute gout flares and preventative gout), hyperimmunoglobulin D syndrome (HIDS), mevalonate kinase deficiency (MKD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), familial mediterranean fever (FMF), atherosclerotic cardiovascular disease (ASCVD), acute respiratory distress syndrome (ARDS), Type 2 diabetes, sterile pancreatitis, sterile prostatitis, myocarditis, inflammatory bowel disease (IBD), cardiac sarcoidosis, VEXAS syndrome, interstitial cystitis, Periodic Fever Syndromes (PFS), Adult-onset Still’s disease (AOSD), endometriosis or macrophage activation syndrome (MAS).

[0081] In some embodiments, the disease is post-cardiac injury syndrome (PCIS). In some embodiments, the disease is pericarditis. In some embodiments, the disease is recurrent pericarditis. In some embodiments, the disease is refractory pericarditis. In some embodiments, the disease is idiopathic pericarditis. In some embodiments, the disease is idiopathic recurrent pericarditis. In some embodiments, the disease is non-idiopathic pericarditis. In some embodiments, the disease is myocardial infarction pericarditis. In some embodiments, the disease is posttraumatic pericarditis. In some embodiments, the disease is post-pericardiotomy syndrome (PPS). In some embodiments, the disease is early post-myocardial infarct-associated pericarditis. In some embodiments, the disease is late post-ATTORNEY DOCKET NO.: KPL-080W01myocardial infarction pericarditis. In some embodiments, the disease is non-iatrogenic trauma. In some embodiments, the disease is iatrogenic trauma. In some embodiments, the disease is deficiency of interleukin- 1 receptor antagonist (DIRA). In some embodiments, the disease is rheumatoid arthritis. In some embodiments, the disease is systemic juvenile idiopathic arthritis (SJIA). In some embodiments, the disease is cryopyrin-associated periodic syndromes (CAPS). In some embodiments, the disease is familial cold autoinflammatory syndrome (FC AS). In some embodiments, the disease is Muckle-Wells syndrome (MWS). In some embodiments, the disease is hidradenitis suppurativa. In some embodiments, the disease is ankylosing spondylitis (AS). In some embodiments, the disease is gout (e.g., acute gout, acute gout flares and preventative gout). In some embodiments, the disease is hyperimmunoglobulin D syndrome (HIDS). In some embodiments, the disease is mevalonate kinase deficiency (MKD). In some embodiments, the disease is tumor necrosis factor receptor-associated periodic syndrome (TRAPS). In some embodiments, the disease is familial mediterranean fever (FMF). In some embodiments, the disease is atherosclerotic cardiovascular disease (ASCVD). In some embodiments, the disease is acute respiratory distress syndrome (ARDS). In some embodiments, the disease is Type 2 diabetes. In some embodiments, the disease is sterile pancreatitis. In some embodiments, the disease is sterile prostatitis. In some embodiments, the disease is myocarditis. In some embodiments, the disease is inflammatory bowel disease (IBD). In some embodiments, the disease is cardiac sarcoidosis. In some embodiments, the disease is VEXAS syndrome. In some embodiments, the disease is interstitial cystitis. In some embodiments, the disease is Periodic Fever Syndromes (PFS). In some embodiments, the disease is Adult-onset Still’s disease (AOSD). In some embodiments, the disease is endometriosis. In some embodiments, the disease is macrophage activation syndrome (MAS).BRIEF DESCRIPTION OF THE DRAWINGS

[0082] The drawings are for illustration purposes only, and are not meant to be limiting.

[0083] FIG. 1A, FIG. IB, and FIG. 1C are exemplary binding curves of wildtype antibody (WT), DHS, and LS antibodies, respectively, to FcRn at acidic pH and neutral pH.

[0084] FIG. 2A and FIG. 2B are exemplary graphs showing % of antibody remaining in Tg276 mouse model at various time points, normalized to the amount of the respectiveATTORNEY DOCKET NO.: KPL-080W01antibody at Day 1. FIG. 2C and FIG. 2D are exemplary graphs showing % of antibody remaining in Tg32 mouse model at various time points, normalized to the amount of the respective antibody at Day 1.DEFINITIONS

[0085] In order for the present invention to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the specification. The publications and other reference materials referenced herein to describe the background of the invention and to provide additional detail regarding its practice are hereby incorporated by reference.

[0086] Any numerical values used in this application are meant to cover any variations within the standard deviation or normal fluctuations appreciated by one of ordinary skill in the relevant art.

[0087] Acidic pH As used herein, the term “acidic pH” refers to a pH that is less than the neutral pH. Acidic pH may also be used to describe the pH in endosomes or lysosomes. In some embodiments, the acidic pH is less than 7.0. In some embodiments, the acidic pH is between 4.5 and 6.8. In some embodiments, the acidic pH is between 4.8 and 6.8. In some embodiments, the acidic pH is between 5.0 and 6.4. In some embodiments, the acidic pH is between 5.4 and 6.0. In some embodiments, the acidic pH is between 5.6 and 6.0. In some embodiments, the acidic pH is 5.8.

[0088] Amino acid. As used herein, term “amino acid,” in its broadest sense, refers to any compound and / or substance that can be incorporated into a polypeptide chain. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid; in some embodiments, an amino acid is a d-amino acid; in some embodiments, an amino acid is an 1-amino acid. “Standard amino acid” refers to any of the twenty standard 1-amino acids commonly found in naturally occurring peptides.“Nonstandard amino acid” refers to any amino acid, other than the standard amino acids, regardless of whether it is prepared synthetically or obtained from a natural source. As used herein, “synthetic amino acid” encompasses chemically modified amino acids, including but not limited to salts, amino acid derivatives (such as amides), and / or substitutions. Amino acids, including carboxyl- and / or amino-terminal amino acids in peptides, can be modified byATTORNEY DOCKET NO.: KPL-080W01methylation, amidation, acetylation, protecting groups, and / or substitution with other chemical groups that can change the peptide’s circulating half-life without adversely affecting their activity. Amino acids may participate in a disulfide bond. Amino acids may comprise one or posttranslational modifications, such as association with one or more chemical entities (e.g., methyl groups, acetate groups, acetyl groups, phosphate groups, formyl moieties, isoprenoid groups, sulfate groups, polyethylene glycol moieties, lipid moieties, carbohydrate moieties, biotin moieties, etc. . The term “amino acid” is used interchangeably with “amino acid residue,” and may refer to a free amino acid and / or to an amino acid residue of a peptide. It will be apparent from the context in which the term is used whether it refers to a free amino acid or a residue of a peptide.

[0089] Association rate constant (Kon): As used herein, the terms “association rate constant,” “Kon,” or grammatical equivalents refer to the rate at which two molecules (e.g., an antibody and a receptor) bind to form a complex, typically expressed in units of T's'1(molar per second).

[0090] Dissociation constant (KD)'. AS used herein, the terms “dissociation constant,” “KD,” “Kd,” or grammatical equivalents indicate the concentration of a protein (e.g., an antibody) at which half of the binding sites on a target molecule are occupied at equilibrium, typically expressed in units of concentration (e.g., moles per liter, or M). Dissociation constant is the reciprocal of the equilibrium constant (Keq) for the dissociation reaction. KD values are typically used to indicate the affinity of the complex, with a lower value indicating higher affinity.

[0091] Dissociation rate constant (K0f): As used herein, the terms “dissociation rate constant,” “KOff,” or grammatical equivalents refer to the rate at which a protein (e.g., an antibody) dissociates from its target (e.g., a receptor), typically expressed in units of s'1.

[0092] Fc domain'. As used herein, the term “Fc domain” is used to define a C-terminal region of an immunoglobulin heavy chain, including native- sequence Fc domains and variant Fc domains. Although the boundaries of the Fc domain of an immunoglobulin heavy chain might vary, the human IgG heavy-chain Fc domain is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. Suitable native-sequence Fc domains for use in the antibodies of the invention include human IgGl, IgG2, IgG3 andIgG4. In some embodiments, the Fc domain described herein is modified relative to the native, or parent, Fc domain. Unless otherwise specifiedATTORNEY DOCKET NO.: KPL-080W01herein, numbering of amino acid residues in the Fc domain is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991.

[0093] Half-life'. As used herein, the term “half-life” is the time required for a quantity such as nucleic acid or protein concentration or activity to fall to half of its value as measured at the beginning of a time period.

[0094] Improve, increase, or reduce'. As used herein, the terms “improve,” “increase” or “reduce,” or grammatical equivalents, indicate values that are relative to a baseline measurement. In some embodiments, the baseline measurement is from a comparable antibody with a native, or parent, Fc domain.

[0095] Neutral pH: As used herein, the term “neutral pH” refers to the pH that is neither acidic nor alkaline. In some embodiments, neutral pH refers to the physiological pH, or the normal range of pH levels in the body’s essential fluids and tissues. In some embodiments, the neutral pH is between 7.0 and 8.0. In some embodiments, the neutral pH is between 7.2 and 7.6. In some embodiments, the neutral pH is between 7.3 and 7.5. In some embodiments, the neutral pH is 7.4.

[0096] Substantial identity: The phrase "substantial identity" is used herein to refer to a comparison between amino acid or nucleic acid sequences. As will be appreciated by those of ordinary skill in the art, two sequences are generally considered to be "substantially identical" if they contain identical residues in corresponding positions. As is well known in this art, amino acid or nucleic acid sequences may be compared using any of a variety of algorithms, including those available in commercial computer programs such as BLAS TN for nucleotide sequences and BLASTP, gapped BLAST, and PSI-BLAST for amino acid sequences. Exemplary such programs are described in Altschul, et al., Basic local alignment search tool, J Mol. Biol., 215(3): 403-410, 1990; Altschul, et al., Methods in Enzymology; Altschul etal., Nucleic Acids Res. 25:3389-3402, 1997; Baxevanis etal., Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins, Wiley, 1998; and Misener, et al., (eds.), Bioinformatics Methods and Protocols (Methods in Molecular Biology, Vol. 132), Humana Press, 1999. In addition to identifying identical sequences, the programs mentioned above typically provide an indication of the degree of identity. In some embodiments, two sequences are considered to be substantially identical if at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more of theirATTORNEY DOCKET NO.: KPL-080W01corresponding residues are identical over a relevant stretch of residues. In some embodiments, the relevant stretch is a complete sequence. In some embodiments, the relevant stretch is at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 or more residues.

[0097] Pharmaceutically acceptable'. The term “pharmaceutically acceptable” as used herein, refers to substances that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0098] Subject'. As used herein, the term “subject” refers to a human or any nonhuman animal (e.g., mouse, rat, rabbit, dog, cat, cattle, swine, sheep, horse or primate). A human includes pre- and post-natal forms. In many embodiments, a subject is a human being. A subject can be a patient, which refers to a human presenting to a medical provider for diagnosis or treatment of a disease. The term “subject” is used herein interchangeably with “individual” or “patient.” A subject can be afflicted with or is susceptible to a disease or disorder but may or may not display symptoms of the disease or disorder.

[0099] Substantially. As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0100] Treating'. As used herein, the term “treat,” “treatment,” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of and / or reduce incidence of one or more symptoms or features of a particular disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease and / or exhibits only early signs of the disease for the purpose of decreasing the risk of developing pathology associated with the disease.ATTORNEY DOCKET NO.: KPL-080W01DETAILED DESCRIPTION

[0101] The present invention provides, among other things, an anti-IL-lRl antibodies engineered with Fc mutations. In particular, the present invention is, in part, based on the discovery that certain Fc mutations, for example, M428L / N434S (LS) and V / L309D / Q311H / N434S (DHS), when combined with anti-ILlRl antibody described herein, resulted in more than doubled in vivo half-life, without undermining stability and manufacturability of the anti-ILlRl antibody.

[0102] Various aspects of the invention are described in detail in the following sections. The use of sections is not meant to limit the invention. Each section can apply to any aspect of the invention. In this application, the use of “or” means “and / or” unless stated otherwise, and in the context of a range of values, the use of the term “between” means a range between X and Y that includes the endpoints X and Y.Anti-Interleukin 1 Receptor 1 Antibodies

[0103] The anti-interleukin-1 receptor type- 1 (IL1R1) antibodies provide an advantageous mechanism of action for antagonizing both IL-la and IL-ip signaling and are beneficial for treating disease associated with IL-1 or IL1R1 signaling.

[0104] In one aspect, the present invention provides, among other things, anti-ILlRl antibodies with superior pharmacokinetic (PK) properties rendered by certain Fc mutations that result in (1) decreased dissociation constant (KD) of the antibody to FcRn at acidic pH (e.g., < 5 nM), (2) sufficiently high dissociation rate constant (KOff) at neutral pH (e.g., >0.02 s-1), (3) increased in vivo half-life (e.g., >15 days), and (4) increased in vivo volume of distribution (e.g., >100 mL / kg), while minimizing adverse impact on stability and manufacturability of the anti-ILlRl antibody.Antibody

[0105] A traditional antibody, also known as an immunoglobulin, is a Y-shaped structuring consisting of four polypeptides, two heavy chains and two light chains. The light chain consists of one variable region (VL) and one constant region (CL). The heavy chain consists of one variable region (VH) and at least three constant regions (CHI, CH2, CH3). The two light and two heavy chains are joined by disulfide bonds in the Y-shaped structure, with the light chains bracketing the heavy chains at the mouth of the Y-shape and continuing through the variable region. The variable regions determine the binding specificity of theATTORNEY DOCKET NO.: KPL-080W01antibody. Each variable region contains three hypervariable regions known as complementarity determining regions (CDRs) flanked by four relatively conserved regions known as framework regions (FRs). The three CDRs, referred to as CDR1, CDR2, and CDR3, contribute to the antibody binding specificity. Naturally occurring antibodies have often been used as starting material for engineered antibodies, such as chimeric antibodies and humanized antibodies. As used herein, an antibody described herein include antigenbinding fragments, including but not limited to Fab, Fab’, (Fab’)2, Fv, single chain antibodies (e.g., scFv), single-domain antibodies (e.g., sdAbs, VHH, nanobodies), Fd (fragment antigenbinding domain), dAb (domain antibody), biFab (bivalent Fab), minibodies, diabodies, and any other antigen-binding fragments known in the art. Examples of antibodies that have been modified or engineered include chimeric antibodies, humanized antibodies, and multispecific antibodies (e.g., bispecific antibodies).

[0106] Different antibody numbering schemes have been developed for accurate identification and subsequent comparison of variable regions of different antibodies. The most commonly used numbering schemes include Kabat, Chothia, and IMGT.

[0107] The Kabat numbering scheme was one of the first systems used to identify CDRs and is based on the analysis of antibody sequences, particularly the immunoglobulin variable (V) regions. In this scheme, CDRs are defined based on sequence variability, with CDRs being those segments of the variable regions that show the highest variability across different antibodies. Typically, in the Kabat numbering system, LCDR1 spans residues 24- 34, LCDR2 spans residues 50-56, LCDR3 spans residues 89-97, HCDR1 spans residues 31- 35, HCDR2 spans residues 50-65, and HCDR3 spans residues 95-102.

[0108] The Chothia numbering system is based on a structural analysis of antibody sequences and structures. It assigns residue numbers based on the positions of the amino acids in the context of the three-dimensional structure of the antibody. CDRs in Chothia numbering system scheme are defined based on structural features, primarily the loop regions that are responsible for binding to antigens. Typically, in the Chothia numbering system, LCDR1 spans residues 24-34, LCDR2 spans residues 50-56, LCDR3 spans residues 89-97, HCDR1 spans residues 27-35, HCDR2 spans residues 52-56, and HCDR3 spans residues 95-102.

[0109] The IMGT numbering scheme is based on an extensive analysis of the immunoglobulin sequences in the IMGT database, which includes human and other species'ATTORNEY DOCKET NO.: KPL-080W01sequences. This scheme is a more recent development and is the most widely used in genomics and bioinformatics tools. It defines CDRs based on the concept of framework regions and focuses on the sequence alignment of antibodies. Typically, in the IMGT numbering system, LCDR1 spans residues 27-38, LCDR2 spans residues 56-65, LCDR3 spans residues 105-117, HCDR1 spans residues 27-38, HCDR2 spans residues 56-65, and HCDR3 spans residues 105-117.

[0110] Table 1 below shows a summary of typical CDR residue numbers by different numbering schemes.Table 1. Amino Acid Residues of CDRs by Different Numbering Schemes.[oni] CDR sequences of an antibody can be determined by a known method in the art, for example, at website: http: / / aligncdr.labshare.cn / aligncdr / abrsa.php.

[0112] In some embodiments, a LCDR1, a LCDR2, and a LCDR3 of an antibody comprise amino acid residues 24-34, 50-56, and 89-97, respectively, of a variable light chain (VL). In some embodiments, a HCDR1, a HCDR2, and a HCDR3 of an antibody comprise amino acid residues 31-35, 50-65, and 95-102, respectively, of a variable heavy chain (VH).

[0113] In some embodiments, a LCDR1, a LCDR2, and a LCDR3 of an antibody comprise amino acid residues 24-34, 50-56, and 89-97, respectively, of a variable light chain (VL). In some embodiments, a HCDR1, a HCDR2, and a HCDR3 of an antibody comprise amino acid residues 27-35, 52-56, and 95-102, respectively, of a variable heavy chain (VH).

[0114] In some embodiments, a LCDR1, a LCDR2, and a LCDR3 of an antibody comprise amino acid residues 27-38, 56-65, and 105-117, respectively, of a variable light chain (VL). In some embodiments, a HCDR1, a HCDR2, and a HCDR3 of an antibody comprise amino acid residues 27-38, 56-65, and 105-117, respectively, of a variable heavy chain (VH).ATTORNEY DOCKET NO.: KPL-080W01Exemplary Anti-ILIRI Antibody Sequences

[0115] In some embodiments, the anti-ILlRl antibody comprises a variable heavy chain (VH) of SEQ ID NO: 7.Anti-ILIRI Variable Heavy Chain (VH) Amino Acid Sequence:EVQLMQSGAEVKKPGESLKISCKGSGYSFSFHWIAWVRQMPGKGLEWMGII HPGASDTRYSPSFQGQVTISADNSNSATYLQWSSLKASDTAMYFCARQRELD YFD YWGQGTL VT VS S (SEQ ID NO: 7)

[0116] In some embodiments, an anti-ILlRl antibody comprises a VH that is at least 85% identical to SEQ ID NO: 7. In some embodiments, an anti-ILlRl antibody comprises a VH that is at least 90% identical to SEQ ID NO: 7. In some embodiments, an anti-ILlRl antibody comprises a VH that is at least 92% identical to SEQ ID NO: 7. In some embodiments, an anti-ILlRl antibody comprises a VH that is at least 93% identical to SEQ ID NO: 7. In some embodiments, an anti-ILlRl antibody comprises a VH that is at least 94% identical to SEQ ID NO: 7. In some embodiments, an anti-ILlRl antibody comprises a VH that is at least 95% identical to SEQ ID NO: 7. In some embodiments, an anti-ILlRl antibody comprises a VH that is at least 96% identical to SEQ ID NO: 7. In some embodiments, an anti-ILlRl antibody comprises a VH that is at least 97% identical to SEQ ID NO: 7. In some embodiments, an anti-ILlRl antibody comprises a VH that is at least 98% identical to SEQ ID NO: 7. In some embodiments, an anti-ILlRl antibody comprises a VH that is at least 99% identical to SEQ ID NO: 7. In some embodiments, an anti-ILlRl antibody comprises a VH of SEQ ID NO: 7.

[0117] In some embodiments, the anti-ILlRl antibody comprises aHCDRl, a HCDR2, and a HCDR3 in the VH of SEQ ID NO: 7, as shown by underlining, respectively: EVQLMQSGAEVKKPGESLKISCKGSGYSFSFHWIAWVRQMPGKGLEWMGII HPGASDTRYSPSFOGQVTISADNSNSATYLQWSSLKASDTAMYFCARQREL D YFD YWGQGTL VT VS S (SEQ ID NO: 7)

[0118] In some embodiments, the anti-ILlRl antibody comprises aHCDRl, a HCDR2, and a HCDR3 in the VH of SEQ ID NO: 7, as shown by underlining, respectively: EVQLMQSGAEVKKPGESLKISCKGSGYSFSFHWIAWVRQMPGKGLEWMGII HPGASDTRYSPSFQGQVTISADNSNSATYLQWSSLKASDTAMYFCARQREL D YFD YWGQGTL VT VS S (SEQ ID NO: 7)ATTORNEY DOCKET NO.: KPL-080W01

[0119] In some embodiments, the anti-ILlRl antibody comprises aHCDRl, a HCDR2, and a HCDR3 in the VH of SEQ ID NO: 7, as shown by underlining, respectively: EVQLMQSGAEVKKPGESLKISCKGSGYSFSFHWIAWVRQMPGKGLEWMGII HPGASDTRYSPSFQGQVTISADNSNSATYLQWSSLKASDTAMYFCARQREL D YFD YWGOGTL VT VS S (SEQ ID NO: 7)

[0120] In some embodiments, the anti-ILlRl antibody comprises a variable light chain (VL) of SEQ ID NO: 8.Anti-ILlRl Variable Light Chain (VL) Amino Acid Sequence:EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSLHWYQQKPDQSPKLLIKYASQS FSGVPSRFSGSGSGTDFTLTINSLEAEDAAAYYCHQSSSLPLTFGGGTKVEIK(SEQ ID NO: 8)

[0121] In some embodiments, an anti-ILlRl antibody comprises a VL that is at least 85% identical to SEQ ID NO: 8. In some embodiments, an anti-ILlRl antibody comprises a VL that is at least 90% identical to SEQ ID NO: 8. In some embodiments, an anti-ILlRl antibody comprises a VL that is at least 92% identical to SEQ ID NO: 8. In some embodiments, an anti-ILlRl antibody comprises a VL that is at least 93% identical to SEQ ID NO: 8. In some embodiments, an anti-ILlRl antibody comprises a VL that is at least 94% identical to SEQ ID NO: 8. In some embodiments, an anti-ILlRl antibody comprises a VL that is at least 95% identical to SEQ ID NO: 8. In some embodiments, an anti-ILlRl antibody comprises a VL that is at least 96% identical to SEQ ID NO: 8. In some embodiments, an anti-ILlRl antibody comprises a VL that is at least 97% identical to SEQ ID NO: 8. In some embodiments, an anti-ILlRl antibody comprises a VL that is at least 98% identical to SEQ ID NO: 8. In some embodiments, an anti-ILlRl antibody comprises a VL that is at least 99% identical to SEQ ID NO: 8. In some embodiments, an anti-ILlRl antibody comprises a VL of SEQ ID NO: 8.

[0122] In some embodiments, the anti-ILlRl antibody comprises aLCDRl, a LCDR2, and a LCDR3 in the VL of SEQ ID NO: 8, as shown by underlining, respectively: EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSLHWYQQKPDQSPKLLIKYASQS FSGVPSRFSGSGSGTDFTLTINSLEAEDAAAYYCHQSSSLPLTFGGGTKVEIK(SEQ ID NO: 8)ATTORNEY DOCKET NO.: KPL-080W01

[0123] In some embodiments, the anti-ILlRl antibody comprises aLCDRl, a LCDR2, and a LCDR3 in the VL of SEQ ID NO: 8, as shown by underlining, respectively: EIVLTQSPDFQSVTPKEKVTITCRASOSIGSSLHWYQQKPDQSPKLLIKYASOS FSGVPSRFSGSGSGTDFTLTINSLEAEDAAAYYCHQSSSLPLTFGGGTKVEIK(SEQ ID NO: 8)Anti-ILlRl CDR Amino Acid Sequences

[0124] In some embodiments, the anti-ILlRl antibody comprises aHCDRl, a HCDR2, and a HCDR3 as shown in any one of Tables 2-4. In some embodiments, the anti-IL1R1 antibody comprises a LCDR1, a LCDR2, and a LCDR3 as shown in any one of Tables 2-4.

[0125] In some embodiments, the anti-ILlRl antibody comprises aHCDRl, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 as shown in any one of Tables 2-4. Table 2. CDR Sequence of Anti-ILlRl Antibody by Kabat Numbering.Table 3. CDR Sequence of Anti-ILlRl Antibody by Chothia Numbering.ATTORNEY DOCKET NO.: KPL-080W01Table 4. CDR Sequence of Anti-ILIRI Antibody by IMGT Numbering.

[0126] In some embodiments, the anti-ILlRl antibody comprises a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6.

[0127] In some embodiments, the anti-ILlRl antibody comprises a HCDR1 of SEQ ID NO: 12, a HCDR2 of SEQ ID NO: 13, a HCDR3 of SEQ ID NO: 3, a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6.

[0128] In some embodiments, the anti-ILlRl antibody comprises a HCDR1 of SEQ ID NO: 14, a HCDR2 of SEQ ID NO: 15, a HCDR3 of SEQ ID NO: 19, a LCDR1 of SEQ ID NO: 16, a LCDR2 of SEQ ID NO: 17, and a LCDR3 of SEQ ID NO: 6.

[0129] In some embodiments, the anti-ILlRl antibody comprises aHCDRl, a HCDR2, and a HCDR3 comprising amino acid residues 31-35, 50-65, and 95-102, respectively, of SEQ ID NO: 7 according to Kabat numbering. In some embodiments, the anti-ILlRl antibody comprises aLCDRl, aLCDR2, and aLCDR3 comprising amino acid residues 24-34, 50-56, and 89-97, respectively, of SEQ ID NO: 8 according to Kabat numbering.

[0130] In some embodiments, the anti-ILlRl antibody comprises aHCDRl, a HCDR2, and a HCDR3 comprising amino acid residues 27-35, 52-56, and 95-102, respectively, of SEQ ID NO: 7 according to Chothia numbering. In some embodiments, the anti-ILlRl antibody comprises aLCDRl, aLCDR2, and aLCDR3 comprising amino acid residues 24-34, 50-56, and 89-97, respectively, of SEQ ID NO: 8 according to Chothia numbering.

[0131] In some embodiments, the anti-ILlRl antibody comprises aHCDRl, a HCDR2, and a HCDR3 comprising amino acid residues 27-38, 56-65, and 105-117, respectively, of SEQ ID NO: 7 according to IMGT numbering. In some embodiments, theATTORNEY DOCKET NO.: KPL-080W01anti-ILlRl antibody comprises aLCDRl, aLCDR2, and aLCDR3 comprising amino acid residues 27-38, 56-65, and 105-117, respectively, of SEQ ID NO: 8 according to IMGT numbering.

[0132] In some embodiments, the anti-ILlRl antibody comprises aHCDRl, a HCDR2, and a HCDR3 amino acid sequences in SEQ ID NO: 7 as determined by any convention known in the art. In some embodiments, the anti-ILlRl antibody comprises a LCDR1, a LCDR2, and a LCDR3 amino acid sequences in SEQ ID NO: 8 as determined by any convention known in the art.

[0133] In some embodiments, the anti-ILlRl antibody comprises a light chain of SEQ ID NO: 11.Anti-ILlRl Light Chain Amino Acid Sequence:EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSLHWYQQKPDQSPKLLIKYASQS FSGVPSRFSGSGSGTDFTLTINSLEAEDAAAYYCHQSSSLPLTFGGGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 11)

[0134] In some embodiments, an anti-ILlRl antibody comprises a light chain that is at least 85% identical to SEQ ID NO: 11. In some embodiments, an anti-ILlRl antibody comprises a light chain that is at least 90% identical to SEQ ID NO: 11. In some embodiments, an anti-ILlRl antibody comprises a light chain that is at least 92% identical to SEQ ID NO: 11. In some embodiments, an anti-ILlRl antibody comprises a light chain that is at least 93% identical to SEQ ID NO: 11. In some embodiments, an anti-ILlRl antibody comprises a light chain that is at least 94% identical to SEQ ID NO: 11. In some embodiments, an anti-ILlRl antibody comprises a light chain that is at least 95% identical to SEQ ID NO: 11. In some embodiments, an anti-ILlRl antibody comprises a light chain that is at least 96% identical to SEQ ID NO: 11. In some embodiments, an anti-ILlRl antibody comprises a light chain that is at least 97% identical to SEQ ID NO: 11. In some embodiments, an anti-ILlRl antibody comprises a light chain that is at least 98% identical to SEQ ID NO: 11. In some embodiments, an anti-ILlRl antibody comprises a light chain that is at least 99% identical to SEQ ID NO: 11. In some embodiments, an anti-ILlRl antibody comprises a light chain of SEQ ID NO: 11.ATTORNEY DOCKET NO.: KPL-080W01Fc Domains

[0135] In some embodiments, the anti-ILlRl antibody described herein further comprises a modified Fc domain. An Fc domain may be substantially encoded by immunoglobulin genes belonging to any of the antibody classes, including but not limited to sequences belonging to the IgG (including human subclasses IgGl, IgG2, IgG3, or IgG4), IgA (including human subclasses IgAl and IgA2), IgD, IgE, IgG, or IgM classes of antibodies.

[0136] Fc engineering can be applied to many antibodies, but it does not work the same way for every antibody. The success and effectiveness of Fc engineering depend on several factors, including the specific antibody, its target, and the intended therapeutic application. The engineered Fc mutations might not always lead to improved therapeutic outcomes if other aspects of the antibody's function are compromised, for example, by reducing target binding efficiency or increasing viscosity. For instance, introducing M428L / N434S mutations increased the viscosity of Omalizumab by 1.5-fold (e.g., >260 cP). Heisler, J., Kovner, D., Izadi, S., Zarzar, J., & Carter, P. J. (2024). “Modulation of the high concentration viscosity of IgGl antibodies using clinically validated Fc mutations.” mAbs, 16(1).

[0137] In some embodiments, an anti-ILlRl antibody comprises a modified Fc domain as compared to a parent Fc domain. In some embodiments, the parent Fc domain is a wild-type Fc domain. In some embodiments, the parent Fc domain is a wild-type IgG2 Fc domain. In some embodiments, the parent Fc domain comprises an amino acid sequence of SEQ ID NO: 9. In some embodiments, the amino acid sequence of the parent Fc domain is SEQ ID NO: 9.

[0138] In some embodiments, the Fc domain is modified to increase half-life as compared to the parent Fc domain. In some embodiments, the Fc domain is modified to increase binding to human neonatal Fc receptor (FcRn) as compared to the parent Fc domain. In some embodiments, the Fc domain is modified to increase binding to FcRn at acidic pH as compared to the parent Fc domain. In some embodiments, the Fc domain is modified to increase binding to FcRn at acidic pH with minimal to no increase in binding to FcRn at neutral pH, as compared to the parent Fc domain. In some embodiments, the Fc domain is modified to increase binding to FcRn at a pH of 5.8 as compared to the parent Fc domain. In some embodiments, the Fc domain is modified to increase binding to FcRn at a pH of 5.8ATTORNEY DOCKET NO.: KPL-080W01with minimal to no increase in binding to FcRn at a pH of 7.4, as compared to the parent Fc domain.

[0139] In some embodiments, the modified Fc domain comprises one or more amino acid substitutions to increase half-life as compared to the parent Fc domain. In some embodiments, the modified Fc domain comprises one or more amino acid substitutions to increase binding to FcRn as compared to the parent Fc domain. In some embodiments, the modified Fc domain comprises one or more amino acid substitutions to increase binding to FcRn at acidic pH as compared to the parent Fc domain. In some embodiments, the modified Fc domain comprises one or more amino acid substitutions to increase binding to FcRn at acidic pH with minimal to no increase in binding to FcRn at neutral pH, as compared to the parent Fc domain.

[0140] In some embodiments, the modified Fc domain comprises one or more amino acid substitutions to increase binding to FcRn at a pH of 5.8 as compared to the parent Fc domain. In some embodiments, the modified Fc domain comprises one or more amino acid substitutions to increase binding to FcRn at a pH of 5.8 with minimal to no increase in binding to FcRn at a pH of 7.4, as compared to the parent Fc domain.

[0141] In some embodiments, the modified Fc domain comprises one or more amino acid substitutions at positions T250, M252, S254, T256, H285, H286, T307, V308, L / V309, Q311, N315, A378, E380, M428, and / or N434, wherein the numbering is according to the EU index in Kabat. Unless otherwise specified herein, numbering of amino acid residues in the modified Fc domain is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991.

[0142] In some embodiments, the modified Fc domain comprises an amino acid substitution at position T250. In some embodiments, the amino acid substitution at position T250 comprises T250Q.

[0143] In some embodiments, the modified Fc domain comprises an amino acid substitution at position M252. In some embodiments, the amino acid substitution at position M252 comprises M252Y.

[0144] In some embodiments, the modified Fc domain comprises an amino acid substitution at position S254. In some embodiments, the amino acid substitution at position S254 comprises S254T.ATTORNEY DOCKET NO.: KPL-080W01

[0145] In some embodiments, the modified Fc domain comprises an amino acid substitution at position T256. In some embodiments, the amino acid substitution at position T256 comprises T256E. In some embodiments, the amino acid substitution at position T256 comprises T256D.

[0146] In some embodiments, the modified Fc domain comprises an amino acid substitution at position H285. In some embodiments, the amino acid substitution at position H285 comprises H285N.

[0147] In some embodiments, the modified Fc domain comprises an amino acid substitution at position H286. In some embodiments, the amino acid substitution at position H286 comprises H286D.

[0148] In some embodiments, the modified Fc domain comprises an amino acid substitution at position T307. In some embodiments, the amino acid substitution at position T307 comprises T307A. In some embodiments, the amino acid substitution at position T307 comprises T307Q. In some embodiments, the amino acid substitution at position T307 comprises T307W. In some embodiments, the amino acid substitution at position T307 comprises T307R.

[0149] In some embodiments, the modified Fc domain comprises an amino acid substitution at position V308. In some embodiments, the amino acid substitution at position V308 comprises V308P.

[0150] In some embodiments, the modified Fc domain comprises an amino acid substitution at position L / V309. In some embodiments, the amino acid substitution at position L / V309 comprises L / V309D.

[0151] In some embodiments, the modified Fc domain comprises an amino acid substitution at position Q311. In some embodiments, the amino acid substitution at position Q311 comprises Q311H. In some embodiments, the amino acid substitution at position Q311 comprises Q311V.

[0152] In some embodiments, the modified Fc domain comprises an amino acid substitution at position N315. In some embodiments, the amino acid substitution at position N315 comprises N315D.ATTORNEY DOCKET NO.: KPL-080W01

[0153] In some embodiments, the modified Fc domain comprises an amino acid substitution at position A378. In some embodiments, the amino acid substitution at position A378 comprises A378V.

[0154] In some embodiments, the modified Fc domain comprises an amino acid substitution at position E380. In some embodiments, the amino acid substitution at position E380 comprises E380A.

[0155] In some embodiments, the modified Fc domain comprises an amino acid substitution at position M428. In some embodiments, the amino acid substitution at position M428 comprises M428L.

[0156] In some embodiments, the modified Fc domain comprises an amino acid substitution at position N434. In some embodiments, the amino acid substitution at position N434 comprises N434S. In some embodiments, the amino acid substitution at position N434 comprises N434Y. In some embodiments, the amino acid substitution at position N434 comprises N434A.

[0157] In some embodiments, the modified Fc domain comprises amino acid substitution M428L. In some embodiments, the modified Fc domain comprises amino acid substitutions M428L and N434S. In some embodiments, the modified Fc domain comprises amino acid substitutions L / V309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises amino acid substitutions L / V309D, Q311H, and N434Y. In some embodiments, the modified Fc domain comprises amino acid substitutions T307A, E380A, and N434A. In some embodiments, the modified Fc domain comprises amino acid substitutions L / V309D, Q311H, M428L, and N434S. In some embodiments, the modified Fc domain comprises amino acid substitutions L / V309D, Q311H, M428L, and N434Y. In some embodiments, the modified Fc domain comprises amino acid substitution T250Q. In some embodiments, the modified Fc domain comprises amino acid substitutions T250Q and M428L. In some embodiments, the modified Fc domain further comprises amino acid substitutions M252Y, S254T, and T256E. In some embodiments, the modified Fc domain does not comprise amino acid substitutions M252Y, S254T, and T256E.

[0158] In some embodiments, the modified Fc domain comprises amino acid substitutions M252Y, S254T, T256E, L / V309D, Q311H, andN434S. In some embodiments, the modified Fc domain comprises amino acid substitutions M252Y, S254T, T256E,ATTORNEY DOCKET NO.: KPL-080WO1L / V309D, Q311H, and N434Y. In some embodiments, the modified Fc domain comprises amino acid substitutions M252Y, S254T, T256E, M428L, andN434S.

[0159] In some embodiments, the modified Fc domain comprises an amino acid sequence shown in Table 5.Table 5. Exemplary Fc Domain Amino Acid Sequences.ATTORNEY DOCKET NO.: KPL-080WO1ATTORNEY DOCKET NO.: KPL-080W01

[0160] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 9. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 9. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 9. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 9. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 9. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 9. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 9. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 9. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 9. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 9. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 9. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 9. In some embodiments, the modified Fc domain comprises the amino acid sequence of SEQ ID NO: 9.

[0161] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95%ATTORNEY DOCKET NO.: KPL-080W01identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 20. In some embodiments, the modified Fc domain further comprises amino acid substitutions T307A, E380A, and N434A relative to the parent Fc domain. In some embodiments, the modified Fc domain does not comprise amino acid substitutions M252Y, S254T, and T256E relative to the parent Fc domain. In some embodiments, the modified Fc domain comprises the amino acid sequence of SEQ ID NO: 20.

[0162] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 20 and amino acid substitutions T307A, E380A, and N434A. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 20 and amino acid substitutions T307A, E380A, and N434A. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 20 and amino acid substitutions T307A, E380A, and N434A. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 20 and amino acid substitutions T307A, E380A, and N434A. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 20 and amino acid substitutions T307A, E380A, and N434A. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 20 and amino acid substitutions T307A, E380A, and N434A. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 20 and amino acid substitutions T307A, E380A, and N434A. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 20 and amino acid substitutions T307A, E380A, and N434A. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 20 and amino acid substitutions T307A, E380A, and N434A. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 20 and amino acid substitutions T307A, E380A, and N434A. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 20 and amino acid substitutions T307A,ATTORNEY DOCKET NO.: KPL-080W01E380A, and N434A. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 20 and amino acid substitutions T307A, E380A, andN434A.

[0163] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 21. In some embodiments, the modified Fc domain further comprises the amino acid substitutions V / L309D, Q311H, and N434S relative to the parent Fc domain. In some embodiments, the modified Fc domain does not comprise amino acid substitutions M252Y, S254T, and T256E relative to the parent Fc domain. In some embodiments, the modified Fc domain does not comprise an amino acid substitution M428L relative to the parent Fc domain. In some embodiments, the modified Fc domain comprises the amino acid sequence of SEQ ID NO: 21.

[0164] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 21 and amino acid substitutions V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 21 and amino acid substitutions V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 21 and amino acid substitutions V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acidATTORNEY DOCKET NO.: KPL-080W01sequence at least 91% identical to SEQ ID NO: 21 and amino acid substitutions V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 21 and amino acid substitutions V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 21 and amino acid substitutions V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 21 and amino acid substitutions V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 21 and amino acid substitutions V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 21 and amino acid substitutions V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 21 and amino acid substitutions V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 21 and amino acid substitutions V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 21 and amino acid substitutions V / L309D, Q311H, andN434S.

[0165] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at leastATTORNEY DOCKET NO.: KPL-080W0198% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 22. In some embodiments, the modified Fc domain further comprises amino acid substitutions V / L309D, Q311H, M428L, and N434S relative to the parent Fc domain. In some embodiments, the modified Fc domain does not comprise amino acid substitutions M252Y, S254T, and T256E relative to the parent Fc domain. In some embodiments, the modified Fc domain comprises the amino acid sequence of SEQ ID NO: 22.

[0166] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 22 and amino acid substitutions V / L309D, Q311H, M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 22 and amino acid substitutions V / L309D, Q311H, M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 22 and amino acid substitutions V / L309D, Q311H, M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 22 and amino acid substitutions V / L309D, Q311H, M428L, andN434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 22 and amino acid substitutions V / L309D, Q311H, M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 22 and amino acid substitutions V / L309D, Q311H, M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 22 and amino acid substitutions V / L309D, Q311H, M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 22 and amino acid substitutions V / L309D, Q311H, M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 22 and amino acid substitutions V / L309D, Q311H, M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 22 and amino acid substitutions V / L309D, Q311H, M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 22 and amino acid substitutions V / L309D, Q311H, M428L, andN434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 22 and amino acid substitutions V / L309D, Q311H, M428L, and N434S.ATTORNEY DOCKET NO.: KPL-080W01

[0167] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 23. In some embodiments, the modified Fc domain further comprises amino acid substitutions M428L, and N434S relative to the parent Fc domain. In some embodiments, the modified Fc domain does not comprise amino acid substitutions M252Y, S254T, and T256E relative to the parent Fc domain. In some embodiments, the modified Fc domain does not comprise amino acid substitutions L / V309D and Q311H relative to the parent Fc domain. In some embodiments, the modified Fc domain comprises the amino acid sequence of SEQ ID NO: 23.

[0168] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 23 and amino acid substitutions M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 23 and amino acid substitutions M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 23 and amino acid substitutions M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 23 and amino acid substitutions M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 23 and amino acid substitutions M428L, and N434S. In someATTORNEY DOCKET NO.: KPL-080W01embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 23 and amino acid substitutions M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 23 and amino acid substitutions M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 23 and amino acid substitutions M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 23 and amino acid substitutions M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 23 and amino acid substitutions M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 23 and amino acid substitutions M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 23 and amino acid substitutions M428L, and N434S.

[0169] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 24. In some embodiments, the Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 24. In some embodiments, the Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 24. In some embodiments, the modified Fc domain further comprises an amino acid substitution M428L relative to the parent Fc domain. In some embodiments, the modified Fc domain does not comprise amino acid substitutions M252Y,ATTORNEY DOCKET NO.: KPL-080W01S254T, and T256E relative to the parent Fc domain. In some embodiments, the modified Fc domain comprises the amino acid sequence of SEQ ID NO: 24.

[0170] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 24 and an amino acid substitution M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 24 and an amino acid substitution M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 24 and an amino acid substitution M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 24 and an amino acid substitution M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 24 and an amino acid substitution M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 24 and an amino acid substitution M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 24 and an amino acid substitution M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 24 and an amino acid substitution M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 24 and an amino acid substitution M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 24 and an amino acid substitution M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 24 and an amino acid substitution M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 24 and an amino acid substitution M428L.

[0171] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domainATTORNEY DOCKET NO.: KPL-080W01comprises an amino acid sequence at least 94% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 25. In some embodiments, the modified Fc domain further comprises an amino acid substitution T250Q relative to the parent Fc domain. In some embodiments, the modified Fc domain does not comprise amino acid substitutions M252Y, S254T, and T256E relative to the parent Fc domain. In some embodiments, the modified Fc domain comprises the amino acid sequence of SEQ ID NO: 25.

[0172] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 25 and an amino acid substitution T250Q. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 25 and an amino acid substitution T250Q. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 25 and an amino acid substitution T250Q. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 25 and an amino acid substitution T250Q. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 25 and an amino acid substitution T250Q. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 25 and an amino acid substitution T250Q. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 25 and an amino acid substitution T250Q. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 25 and an amino acid substitution T250Q. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 25 and an amino acid substitution T250Q. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 25 and an amino acid substitution T250Q. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 25 and an amino acid substitution T250Q. In someATTORNEY DOCKET NO.: KPL-080W01embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 25 and an amino acid substitution T250Q.

[0173] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 26. In some embodiments, the modified Fc domain further comprises amino acid substitutions T250Q and M428L relative to the parent Fc domain. In some embodiments, the modified Fc domain does not comprise amino acid substitutions M252Y, S254T, and T256E relative to the parent Fc domain. In some embodiments, the modified Fc domain comprises the amino acid sequence of SEQ ID NO: 26.

[0174] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 26 and amino acid substitutions T250Q and M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 26 and amino acid substitutions T250Q and M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 26 and amino acid substitutions T250Q and M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 26 and amino acid substitutions T250Q and M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92%ATTORNEY DOCKET NO.: KPL-080W01identical to SEQ ID NO: 26 and amino acid substitutions T250Q and M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 26 and amino acid substitutions T250Q and M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 26 and amino acid substitutions T250Q and M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 26 and amino acid substitutions T250Q and M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 26 and amino acid substitutions T250Q and M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 26 and amino acid substitutions T250Q and M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 26 and amino acid substitutions T250Q and M428L. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 26 and amino acid substitutions T250Q and M428L.

[0175] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 27. In some embodiments, the modified Fc domain further comprises amino acid substitutions M252Y, S254T, and T256EATTORNEY DOCKET NO.: KPL-080W01relative to the parent Fc domain. In some embodiments, the modified Fc domain comprises the amino acid sequence of SEQ ID NO: 27.

[0176] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 27 and amino acid substitutions M252Y, S254T, and T256E. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 27 and amino acid substitutions M252Y, S254T, and T256E. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 27 and amino acid substitutions M252Y, S254T, and T256E. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 27 and amino acid substitutions M252Y, S254T, and T256E. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 27 and amino acid substitutions M252Y, S254T, and T256E. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 27 and amino acid substitutions M252Y, S254T, and T256E. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 27 and amino acid substitutions M252Y, S254T, and T256E. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 27 and amino acid substitutions M252Y, S254T, and T256E. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 27 and amino acid substitutions M252Y, S254T, and T256E. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 27 and amino acid substitutions M252Y, S254T, and T256E. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 27 and amino acid substitutions M252Y, S254T, and T256E. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 27 and amino acid substitutions M252Y, S254T, and T256E.

[0177] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 28. In some embodiments, theATTORNEY DOCKET NO.: KPL-080W01modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 28. In some embodiments, the modified Fc domain further comprises amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, and N434S relative to the parent Fc domain. In some embodiments, the modified Fc domain comprises the amino acid sequence of SEQ ID NO: 28.

[0178] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 28 and amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 28 and amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, andN434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 28 and amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 28 and amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 28 and amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, andN434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 28 and amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 28 and amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 28 and amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, andN434S. In someATTORNEY DOCKET NO.: KPL-080W01embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 28 and amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 28 and amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 28 and amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, andN434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 28 and amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, andN434S.

[0179] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 29. In some embodiments, the modified Fc domain further comprises amino acid substitutions M252Y, S254T, T256E, M428L, and N434S relative to the parent Fc domain. In some embodiments, the modified Fc domain comprises the amino acid sequence of SEQ ID NO: 29.

[0180] In some embodiments, the modified Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 29 and amino acid substitutions M252Y, S254T, T256E, M428L, and N434S. In some embodiments, the modified Fc domainATTORNEY DOCKET NO.: KPL-080W01comprises an amino acid sequence at least 85% identical to SEQ ID NO: 29 and amino acid substitutions M252Y, S254T, T256E, M428L, andN434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 29 and amino acid substitutions M252Y, S254T, T256E, M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 29 and amino acid substitutions M252Y, S254T, T256E, M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 29 and amino acid substitutions M252Y, S254T, T256E, M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 29 and amino acid substitutions M252Y, S254T, T256E, M428L, andN434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 29 and amino acid substitutions M252Y, S254T, T256E, M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 29 and amino acid substitutions M252Y, S254T, T256E, M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 29 and amino acid substitutions M252Y, S254T, T256E, M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 29 and amino acid substitutions M252Y, S254T, T256E, M428L, andN434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 29 and amino acid substitutions M252Y, S254T, T256E, M428L, and N434S. In some embodiments, the modified Fc domain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 29 and amino acid substitutions M252Y, S254T, T256E, M428L, andN434S.

[0181] In some embodiments, a modified Fc domain does not adversely impact the functional property of the anti-ILlRl antibody. In some embodiments, a modified Fc domain does not increase ECso value of the anti-ILlRl antibody. In some embodiments, a modified Fc domain does not increase KD value of the anti-ILlRl antibody to IL1R1. In some embodiments, a modified Fc domain does not adversely impact the safety of the anti-ILlRl antibody. In some embodiments, a modified Fc domain does not adversely impact the stability of the anti-ILlRl antibody. In some embodiments, a modified Fc domain does not adversely impact the manufacturability of the anti-ILlRl antibody.ATTORNEY DOCKET NO.: KPL-080WO1Anti-ILIRI Heavy Chain Amino Acid Sequence:

[0182] In some embodiments, the anti-ILlRl antibody comprises a heavy chain comprises the modified Fc domain described herein. In some embodiments, the heavy chain comprises an amino acid sequence shown in Table 6.Table 6. Exemplary Heavy Chain Amino Acid Sequences.ATTORNEY DOCKET NO.: KPL-080WO1ATTORNEY DOCKET NO.: KPL-080W01

[0183] In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 10. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 10. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 10. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 10. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 10. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 10. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 94% identical to SEQ IDATTORNEY DOCKET NO.: KPL-080W01NO: 10. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 10. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 10. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 10. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 10. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 10. In some embodiments, the anti-ILlRl heavy chain comprises the amino acid sequence of SEQ ID NO: 10.

[0184] In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 30. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 30. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 30. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 30. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 30. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 30. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 30. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 30. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 30. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 30. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 30. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 30. In some embodiments, the modified Fc domain further comprises amino acid substitutions T307A, E380A, and N434A relative to the parent Fc domain. In some embodiments, the modified Fc domain does not comprise amino acid substitutions M252Y, S254T, and T256E relative to the parent Fc domain. In some embodiments, the anti-ILlRl heavy chain comprises the amino acid sequence of SEQ ID NO: 30.ATTORNEY DOCKET NO.: KPL-080W01

[0185] In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 31. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 31. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 31. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 31. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 31. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 31. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 31. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 31. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 31. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 31. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 31. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 31. In some embodiments, the modified Fc domain further comprises the amino acid substitutions V / L309D, Q311H, and N434S relative to the parent Fc domain. In some embodiments, the modified Fc domain does not comprise amino acid substitutions M252Y, S254T, and T256E relative to the parent Fc domain. In some embodiments, the modified Fc domain does not comprise an amino acid substitution M428L relative to the parent Fc domain. In some embodiments, the anti-ILlRl heavy chain comprises the amino acid sequence of SEQ ID NO: 31.

[0186] In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 32. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 32. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 32. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 32. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 32. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 32. In some embodiments, theATTORNEY DOCKET NO.: KPL-080W01anti-ILlRl heavy chain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 32. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 32. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 32. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 32. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 32. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 32. In some embodiments, the modified Fc domain further comprises amino acid substitutions V / L309D, Q311H, M428L, and N434S relative to the parent Fc domain. In some embodiments, the modified Fc domain does not comprise amino acid substitutions M252Y, S254T, and T256E relative to the parent Fc domain. In some embodiments, the anti-ILlRl heavy chain comprises the amino acid sequence of SEQ ID NO: 32.

[0187] In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 33. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 33. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 33. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 33. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 33. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 33. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 33. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 33. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 33. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 33. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 33. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 33. In some embodiments, the modified Fc domain further comprises amino acid substitutions M428L, and N434S relative to the parent Fc domain. InATTORNEY DOCKET NO.: KPL-080W01some embodiments, the modified Fc domain does not comprise amino acid substitutions M252Y, S254T, and T256E relative to the parent Fc domain. In some embodiments, the modified Fc domain does not comprise amino acid substitutions L / V309D and Q311H relative to the parent Fc domain. In some embodiments, the anti-ILlRl heavy chain comprises the amino acid sequence of SEQ ID NO: 33.

[0188] In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 34. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 34. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 34. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 34. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 34. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 34. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 34. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 34. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 34. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 34. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 34. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 34. In some embodiments, the modified Fc domain further comprises amino acid substitution M428L relative to the parent Fc domain. In some embodiments, the modified Fc domain does not comprise amino acid substitutions M252Y, S254T, and T256E relative to the parent Fc domain. In some embodiments, the anti-ILlRl heavy chain comprises the amino acid sequence of SEQ ID NO: 34.

[0189] In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 35. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 35. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 35. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 35. In someATTORNEY DOCKET NO.: KPL-080W01embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 35. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 35. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 35. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 35. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 35. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 35. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 35. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 35. In some embodiments, the modified Fc domain further comprises amino acid substitution T250Q relative to the parent Fc domain. In some embodiments, the modified Fc domain does not comprise amino acid substitutions M252Y, S254T, and T256E relative to the parent Fc domain. In some embodiments, the anti-ILlRl heavy chain comprises the amino acid sequence of SEQ ID NO: 35.

[0190] In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 36. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 36. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 36. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 36. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 36. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 36. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 36. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 36. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 36. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 36. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 36. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 99%ATTORNEY DOCKET NO.: KPL-080W01identical to SEQ ID NO: 36. In some embodiments, the modified Fc domain further comprises amino acid substitutions T250Q and M428L relative to the parent Fc domain. In some embodiments, the modified Fc domain does not comprise amino acid substitutions M252Y, S254T, and T256E relative to the parent Fc domain. In some embodiments, the anti-IL1R1 heavy chain comprises the amino acid sequence of SEQ ID NO: 36.

[0191] In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 37. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 37. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 37. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 37. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 37. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 37. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 37. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 37. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 37. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 37. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 37. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 37. In some embodiments, the modified Fc domain further comprises amino acid substitutions M252Y, S254T, and T256E relative to the parent Fc domain. In some embodiments, the anti-ILlRl heavy chain comprises the amino acid sequence of SEQ ID NO: 37.

[0192] In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 38. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 38. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 38. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 38. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 92%ATTORNEY DOCKET NO.: KPL-080W01identical to SEQ ID NO: 38. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 38. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 38. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 38. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 38. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 38. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 38. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 38. In some embodiments, the modified Fc domain further comprises amino acid substitutions M252Y, S254T, T256E, V / L309D, Q311H, andN434S relative to the parent Fc domain. In some embodiments, the anti-ILlRl heavy chain comprises the amino acid sequence of SEQ ID NO: 38.

[0193] In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 39. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 39. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 39. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 91% identical to SEQ ID NO: 39. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 39. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 39. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 39. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 39. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 39. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 39. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 39. In some embodiments, the anti-ILlRl heavy chain comprises an amino acid sequence at least 99% identical to SEQ ID NO: 39. In some embodiments, the modified Fc domain further comprises amino acid substitutions M252Y, S254T, T256E, M428L, and N434S relative toATTORNEY DOCKET NO.: KPL-080W01the parent Fc domain. In some embodiments, the anti-ILlRl heavy chain comprises the amino acid sequence of SEQ ID NO: 39.Pharmacokinetic (PK) Properties

[0194] Developing therapeutic products (e.g., an anti-ILlRl antibody) requires consideration of several factors beyond therapeutic activity such as, for example and without limitation, the duration of therapeutic activity, safety, stability, and manufacturability. Each of these aspects plays a role in the drug’s initial selection and in the drug’s eventual success, safety, and efficacy.

[0195] The following standard abbreviations are used to represent the associated pharmacokinetic parameters.Cmax maximum concentrationtmax time to maximum concentrationAUCo-t area under the concentration-time curve (AUC) from time zero to the last measurable concentration, calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrationsAUCo- / AUC from time zero to infinity calculated using the formula:where Ct is the last measurable concentration and Az is the apparent terminal elimination rate constantkz apparent terminal elimination rate constant, where Az is the magnitude of the slope of the linear regression of the log concentration versus time profile during the terminal phaseti / 2 apparent terminal elimination half-life (whenever possible), whereti / 2 = natural log (ln)(2) / AzCL clearanceVd volume of distribution (IV doses only)Vd / F apparent volume of distribution (SC doses only)ATTORNEY DOCKET NO.: KPL-080W01

[0196] Various methods may be used to measure anti-ILlRl antibody concentration in serum. As a non-limiting example, enzyme-linked immunosorbent assay (ELISA) methods are used.

[0197] In present application, an anti-ILlRl antibody comprising a modified Fc domain is also referred to as a modified anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises an increased half-life as compared to the anti-ILlRl antibody with the parent Fc domain (e.g., the parent anti-ILlRl antibody). Half-live can be attributed, at least in part, to the binding of the Fc domain to FcRn. Although FcRn was originally characterized as a neonatal transport receptor for maternal IgG, it also functions in adults to protect antibodies from degradation. FcRn binds to pinocytosed antibodies and protects the antibodies from transport to degradative lysosomes by recycling them back to the extracellular compartment, where they are released from FcRn and can resume their biological function. This recycling is facilitated by the pH dependent binding of the Fc domain to FcRn, where the Fc domain / FcRn interaction is strong at acidic pH (z.e., endosomal pH), but is weak to non-existent at neutral pH (z.e., extracellular physiological pH). Therefore, at neutral pH the antibody is released from binding to FcRn and is recycled, thus prolonging the antibody’s half-life.

[0198] In some embodiments, the modified anti-ILlRl antibody comprises a half-life that is at least greater than 10 days. In some embodiments, the modified anti-ILlRl comprises a half-life that is at least greater than 11 days. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least greater than 12 days. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least greater than 13 days. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least greater than 14 days. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least greater than 15 days. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least greater than 16 days. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least greater than 17 days. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least greater than 18 days. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least greater than 19 days. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least greater than 20 days.

[0199] In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 1.2-fold greater than the anti-ILlRl antibody with a parent Fc domain. In someATTORNEY DOCKET NO.: KPL-080W01embodiments, the modified anti-ILlRl comprises a half -life that is at least 1.3-fold greater than the anti-ILlRl antibody with a parent Fc domain. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 1.4-fold greater than the anti-ILlRl antibody with a parent Fc domain. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 1.5-fold greater than the anti-ILlRl antibody with a parent Fc domain. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 1.6-fold greater than the anti-ILlRl antibody with a parent Fc domain. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 1.7-fold greater than the anti-ILlRl antibody with a parent Fc domain. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 1.8-fold greater than the anti-ILlRl antibody with a parent Fc domain. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 1.9-fold greater than the anti-ILlRl antibody with a parent Fc domain. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 2.0-fold greater than the anti-ILlRl antibody with a parent Fc domain. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 2.1-fold greater than the anti-ILlRl antibody with a parent Fc domain. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 2.2-fold greater than the anti-ILlRl antibody with a parent Fc domain. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 2.3-fold greater than the anti-ILlRl antibody with a parent Fc domain. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 2.4-fold greater than the anti-ILlRl antibody with a parent Fc domain. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 2.5-fold greater than the anti-ILlRl antibody with a parent Fc domain. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 2.6-fold greater than the anti-ILlRl antibody with a parent Fc domain. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 2.7-fold greater than the anti-ILlRl antibody with a parent Fc domain. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 2.8-fold greater than the anti-ILlRl antibody with a parent Fc domain. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 2.9-fold greater than the anti-ILlRl antibody with a parent Fc domain. In some embodiments, the modified anti-ILlRl comprises a half -life that is at least 3.0-fold greater than the anti-ILlRl antibody with a parent Fc domain.

[0200] In some embodiments, the modified anti-ILlRl antibody comprises increased binding to FcRn as compared to the parent anti-ILlRl antibody. In some embodiments, theATTORNEY DOCKET NO.: KPL-080W01modified anti-ILlRl antibody comprises increased binding to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises increased binding to FcRn at acidic pH with minimal to no increase in binding to FcRn at neutral pH, as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises increased binding to FcRn at a pH of 5.8 as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises increased binding to FcRn at a pH of 5.8 with minimal to no increase in binding to FcRn at a pH of 7.4, as compared to the parent anti-ILlRl antibody.

[0201] In some embodiments, the modified anti-ILlRl antibody comprises at least 5-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 6-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 7-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 8-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 9-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 10-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 15-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 20-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 25-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 30-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 35-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 40-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 45-foldATTORNEY DOCKET NO.: KPL-080W01increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 50-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 55-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 60-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 65-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 70-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises at least 75-fold increased binding affinity to FcRn at acidic pH as compared to the parent anti-ILlRl antibody.

[0202] In some embodiments, the modified anti-ILlRl antibody comprises a dissociation constant (KD) to FcRn at acidic pH at least 3-fold greater than the KD to FcRn of the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises a dissociation constant (KD) to FcRn at acidic pH at least 4-fold greater than the KD to FcRn of the parent anti-ILlRl antibody. In some embodiments, the modified anti-IL1R1 antibody comprises a dissociation constant (KD) to FcRn at acidic pH at least 5-fold greater than the KD to FcRn of the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH at least 6-fold greater than the KD to FcRn of the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH at least 7-fold greater than the KD to FcRn of the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH at least 8-fold greater than the KD to FcRn of the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH at least 9-fold greater than the KD to FcRn of the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH at least 10-fold greater than the KD to FcRn of the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH at least 15-fold greater than the KD to FcRn of the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pHATTORNEY DOCKET NO.: KPL-080W01at least 20-fold greater than the KD to FcRn of the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH at least 25-fold greater than the KD to FcRn of the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH at least 30-fold greater than the KD to FcRn of the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH at least 40-fold greater than the KD to FcRn of the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH at least 50-fold greater than the KD to FcRn of the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH at least 60-fold greater than the KD to FcRn of the parent anti-ILlRl antibody. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH at least 70-fold greater than the KD to FcRn of the parent anti-ILlRl antibody. In some embodiments, the greater KD to FcRn at acidic pH is associated with minimal to no greater KD to FcRn at neutral pH.

[0203] In some embodiments, the modified anti-ILlRl antibody comprises a dissociation rate constant (KOff) to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KOff to FcRn at neutral pH that is greater than 0.03 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KOff to FcRn at neutral pH that is greater than 0.04 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KOff to FcRn at neutral pH that is greater than 0.05 s'1.

[0204] In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 20 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 10 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s' f In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 7 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 6 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that isATTORNEY DOCKET NO.: KPL-080W01below 5 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 4 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 3 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 2 nM, and a KOff to FcRn at neutral pH that is greater than 0.005 s'1.

[0205] In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 20 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 10 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 7 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 6 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 5 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 4 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 3 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 2 nM, and a KOff to FcRn at neutral pH that is greater than 0.01 s'1.

[0206] In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 20 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 10 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 7 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 6 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 5 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In someATTORNEY DOCKET NO.: KPL-080W01embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 4 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 3 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1. In some embodiments, the modified anti-ILlRl antibody comprises a KD to FcRn at acidic pH that is below 2 nM, and a KOff to FcRn at neutral pH that is greater than 0.02 s'1.

[0207] In some embodiments, the acidic pH is below 7.0. In some embodiments, the acidic pH is between 4.5 and 6.8. In some embodiments, the acidic pH is between 4.8 and 6.8. In some embodiments, the acidic pH is between 5.0 and 6.4. In some embodiments, the acidic pH is between 5.4 and 6.0. In some embodiments, the acidic pH is between 5.6 and 6.0. In some embodiments, the acidic pH is 5.0. In some embodiments, the acidic pH is 5.1 In some embodiments, the acidic pH is 5.2. In some embodiments, the acidic pH is 5.3. In some embodiments, the acidic pH is 5.4. In some embodiments, the acidic pH is 5.5. In some embodiments, the acidic pH is 5.6. In some embodiments, the acidic pH is 5.7. In some embodiments, the acidic pH is 5.8. In some embodiments, the acidic pH is 5.9. In some embodiments, the acidic pH is 6.0. In some embodiments, the acidic pH is 6.1. In some embodiments, the acidic pH is 6.2. In some embodiments, the acidic pH is 6.3. In some embodiments, the acidic pH is 6.4. In some embodiments, the acidic pH is 6.5. In some embodiments, the acidic pH is 6.6. In some embodiments, the acidic pH is 6.7. In some embodiments, the acidic pH is 6.8. In some embodiments, the acidic pH is 6.9.

[0208] In some embodiments, the neutral pH is between 7.0 and 8.0. In some embodiments, the neutral pH is between 7.2 and 7.6. In some embodiments, the neutral pH is between 7.3 and 7.5. In some embodiments, the neutral pH is 7.0. In some embodiments, the neutral pH is 7.1. In some embodiments, the neutral pH is 7.2. In some embodiments, the neutral pH is 7.3. In some embodiments, the neutral pH is 7.4. In some embodiments, the neutral pH is 7.5. In some embodiments, the neutral pH is 7.6. In some embodiments, the neutral pH is 7.7. In some embodiments, the neutral pH is 7.8. In some embodiments, the neutral pH is 7.9. In some embodiments, the neutral pH is 8.0.

[0209] In some embodiments, PK parameters include clearance of the drug from plasma. Clearance is the rate at which a drug is removed from plasma (mg / hr) divided by the concentration of the drug in the plasma (mg / mL). In some embodiments, the clearance is assessed by per bodyweight (mL / hr / kg). In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.5 mL / hr / kg. In some embodiments, theATTORNEY DOCKET NO.: KPL-080W01modified anti-ILlRl antibody comprises a clearance rate of less than 0.48 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.46 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.44 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.42 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.4 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.38 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.36 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.34 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.32 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.3 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.28 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.26 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.24 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.22 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.2 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.18 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.16 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of less than 0.14 mL / hr / kg.

[0210] In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of 0.1-0.5 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of 0.12-0.46 mL / hr / kg. In some embodiments, the modified anti-IL1R1 antibody comprises a clearance rate of 0.12-0.3 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of 0.12-0.26 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of 0.16-0.46 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of 0.16-0.3 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of 0.16-0.26 mL / hr / kg. In some embodiments, the modified anti-IL1R1 antibody comprises a clearance rate of 0.2-0.5 mL / hr / kg. In some embodiments, theATTORNEY DOCKET NO.: KPL-080W01modified anti-ILlRl antibody comprises a clearance rate of 0.2-0.46 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of 0.2-0.3 mL / hr / kg. In some embodiments, the modified anti-ILlRl antibody comprises a clearance rate of 0.2-0.26 mL / hr / kg.

[0211] In some embodiments, PK parameters include maximum serum concentration (Cmax) of a drug plays a role in its therapeutic efficacy. In some embodiments, the modified anti-ILlRl comprises a Cmax of at least 35 pg / mL. In some embodiments, the modified anti-IL1R1 comprises a Cmax of at least 40 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 45 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 50 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 55 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 60 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 65 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 70 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 75 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 80 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 85 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 90 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 95 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 100 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 105 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 110 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 115 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 120 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 125 pg / mL. In some embodiments, the modified anti- IL1R1 comprises a Cmax of at least 130 pg / mL.

[0212] In some embodiments, PK parameters include AUC. In some embodiments, the modified anti-ILlRl antibody comprises an AUC of at least 300 pg-days / mL. In some embodiments, the modified anti-ILlRl antibody comprises an AUC of at least 350 pg-days / mL. In some embodiments, the modified anti-ILlRl antibody comprises an AUC of at least 400 pg-days / mL. In some embodiments, the modified anti-ILlRl antibody comprises an AUC of at least 450 pg-days / mL. In some embodiments, the modified anti-ILlRl antibody comprises an AUC of at least 500 pg-days / mL. In some embodiments, the modified anti-ATTORNEY DOCKET NO.: KPL-080W01IL1R1 antibody comprises an AUC of at least 550 pg-days / mL. In some embodiments, the modified anti-ILlRl antibody comprises an AUC of at least 600 pg-days / mL. In some embodiments, the modified anti-ILlRl antibody comprises an AUC of at least 650 pg-days / mL. In some embodiments, the modified anti-ILlRl antibody comprises an AUC of at least 700 pg-days / mL. In some embodiments, the modified anti-ILlRl antibody comprises an AUC of at least 750 pg-days / mL. In some embodiments, the modified anti-ILlRl antibody comprises an AUC of at least 800 pg-days / mL. In some embodiments, the modified anti-IL1R1 antibody comprises an AUC of at least 850 pg-days / mL. In some embodiments, the modified anti-ILlRl antibody comprises an AUC of at least 900 pg-days / mL. In some embodiments, the modified anti-ILlRl antibody comprises an AUC of at least 950 pg-days / mL. In some embodiments, the modified anti-ILlRl antibody comprises an AUC of at least 1000 pg-days / mL. In some embodiments, the modified anti-ILlRl antibody comprises an AUC of at least 1050 pg-days / mL.

[0213] In some embodiments, PK parameters include distribution of the drug throughout the body. Volume of distribution refers to the ratio of the amount of drug in the body to the concentration of the drug in serum. For example, a drug with a high volume of distribution is more likely to be found in the tissues of the body, whereas a drug with a low volume of distribution is more likely to be found in the serum or circulatory system. In some embodiments, the modified anti-ILlRl antibody comprises a volume of distribution greater than 70 mL / kg. In some embodiments, the modified anti-ILlRl antibody comprises a volume of distribution greater than 75 mL / kg. In some embodiments, the modified anti-ILlRl antibody comprises a volume of distribution greater than 80 mL / kg. In some embodiments, the modified anti-ILlRl antibody comprises a volume of distribution greater than 85 mL / kg. In some embodiments, the modified anti-ILlRl antibody comprises a volume of distribution greater than 90 mL / kg. In some embodiments, the modified anti-ILlRl antibody comprises a volume of distribution greater than 100 mL / kg. In some embodiments, the modified anti-IL1R1 antibody comprises a volume of distribution greater than 110 mL / kg. In some embodiments, the modified anti-ILlRl antibody comprises a volume of distribution greater than 120 mL / kg. In some embodiments, the modified anti-ILlRl antibody comprises a volume of distribution greater than 130 mL / kg. In some embodiments, the modified anti-IL1R1 antibody comprises a volume of distribution greater than 140 mL / kg. In some embodiments, the modified anti-ILlRl antibody comprises a volume of distribution greater than 150 mL / kg. In some embodiments, the modified anti-ILlRl antibody comprises aATTORNEY DOCKET NO.: KPL-080W01volume of distribution greater than 175 mL / kg. In some embodiments, the modified anti-IL1R1 antibody comprises a volume of distribution greater than 200 mL / kg. In some embodiments, the modified anti-ILlRl antibody comprises a volume of distribution greater than 225 mL / kg. In some embodiments, the modified anti-ILlRl antibody comprises a volume of distribution greater than 250 mL / kg. In some embodiments, the modified anti-IL1R1 antibody comprises a volume of distribution greater than 275 mL / kg.Manufacturability

[0214] Manufacturability is an important factor in the development of therapeutic drugs. In some embodiments, manufacturability is assessed, at least in part, by protein stability, yield, viscosity, and / or aggregation. Efficacy and half-life must also be balanced by a drug’s manufacturability. In some embodiments, manufacturability refers to the ability to produce protein at high scale with high purity, consistent quality, and reasonable costs. Challenges in manufacturability, such as, for example, high rates of aggregation or protein instability, can negatively affect the accessibility and affordability of the drug.

[0215] In some embodiments, manufacturability is determined, at least in part, by protein stability. In some embodiments, the protein stability is measured by the conformational stability (e.g., TonSet, Tm, and / or Tagg). In some embodiments, the protein stability is measured by the colloidal stability (e.g., hydrodynamic radius or kD).

[0216] In some embodiments, the anti-ILlRl antibody comprises a TonSet of at least 50°C. In some embodiments, the anti-ILlRl antibody comprises a TonSet of at least 51°C. In some embodiments, the anti-ILlRl antibody comprises a TonSet of at least 52°C. In some embodiments, the anti-ILlRl antibody comprises a TonSet of at least 53°C. In some embodiments, the anti-ILlRl antibody comprises a TonSet of at least 54°C. In some embodiments, the anti-ILlRl antibody comprises a TonSet of at least 54.5°C. In some embodiments, the anti-ILlRl antibody comprises a TonSet of at least 55°C. In some embodiments, the anti-ILlRl antibody comprises a TonSet of at least 55.2°C. In some embodiments, the anti-ILlRl antibody comprises a TonSet of at least 55.4°C. In some embodiments, the anti-ILlRl antibody comprises a TonSet of at least 55.6°C. In some embodiments, the anti-ILlRl antibody comprises a TonSet of at least 55.8°C. In some embodiments, the anti-ILlRl antibody comprises a TonSet of at least 60°C.

[0217] In some embodiments, the viscosity of a composition comprising the antibody relates to manufacturability. In some embodiments, the modified anti-ILlRl antibodyATTORNEY DOCKET NO.: KPL-080W01composition comprises a viscosity of less than 7.5 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 7.4 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 7.3 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 7.2 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 7.1 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 7 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 6.9 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 6.8 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 6.7 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 6.6 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 6.5 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 6.4 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 6.3 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 6.2 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 6.1 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 6.0 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 5.9 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 5.8 cP at 20°C. In some embodiments, the modified anti-ILlRl antibody composition comprises a viscosity of less than 5.7 cP at 20°C.

[0218] In some embodiments, the aggregation is measured by the appearance of the composition comprising the anti-ILlRl antibody. In some embodiments, the composition comprising the anti-ILlRl antibody appears clear upon storage at 40 °C for at least 15 days. In some embodiments, the composition comprising the anti-ILlRl antibody appears clear upon storage at 40 °C for at least 20 days. In some embodiments, the composition comprising the anti-ILlRl antibody appears clear upon storage at 40 °C for at least 25 days. In some embodiments, the composition comprising the anti-ILlRl antibody appears clear upon storage at 40 °C for at least 28 days.ATTORNEY DOCKET NO.: KPL-080W01

[0219] In some embodiments, the composition comprising the anti-ILlRl antibody appears slightly cloudy with very little settled precipitation upon storage at 40 °C for at least 15 days. In some embodiments, the composition comprising the anti-ILlRl antibody appears slightly cloudy with very little settled precipitation upon storage at 40 °C for at least 20 days. In some embodiments, the composition comprising the anti-ILlRl antibody appears slightly cloudy with very little settled precipitation upon storage at 40 °C for at least 25 days. In some embodiments, the composition comprising the anti-ILlRl antibody appears slightly cloudy with very little settled precipitation upon storage at 40 °C for at least 28 days.

[0220] In some embodiments, the stability is measured by antibody aggregation and fragmentation (e.g., %HMW, %Main, and / or %LMW) in the composition. In some embodiments, the change in overall charge variants (e.g., %Main, %Acidic, and / or %Basic) can be used to monitor chemical modification in the antibody composition.

[0221] In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 25%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 24%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 23%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 22%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 21%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 20%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 19%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 18%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 17%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 16%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 15%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 14%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 13%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days isATTORNEY DOCKET NO.: KPL-080W01less than 12%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 11%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 10%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 9%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 8%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 7%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 6%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 5%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 4%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 3.5%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 3.2%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 3%. In some embodiments, % decrease in main peak of the anti-ILlRl antibody upon storage at 40 °C for at least 28 days is less than 2%. In some embodiments % decrease in main peak is assessed by size exclusion chromatography (SEC). In some embodiments % decrease in main peak is assessed by capillary isoelectric focusing (icIEF).

[0222] Fragmentation is a well-characterized degradation pathway of therapeutic antibodies and is usually monitored by capillary electrophoresis-sodium dodecyl sulfate (CE-SDS). In some embodiments, stability of an antibody formulation is assessed by nonreducing CE-SDS (NR-CD-SDS).

[0223] In some embodiments, less than 20% of an anti-ILlRl antibody exists as fragments upon storage at 40 °C for at least 28 days. In some embodiments, less than 18% of an anti-ILlRl antibody exists as fragments upon storage at 40 °C for at least 28 days. In some embodiments, less than 16% of an anti-ILlRl antibody exists as fragments upon storage at 40 °C for at least 28 days. In some embodiments, less than 15% of an anti-ILlRl antibody exists as fragments upon storage at 40 °C for at least 28 days. In some embodiments, less than 14% of an anti-ILlRl antibody exists as fragments upon storage at 40 °C for at least 28 days. In some embodiments, less than 13% of an anti-ILlRl antibodyATTORNEY DOCKET NO.: KPL-080W01exists as fragments upon storage at 40 °C for at least 28 days. In some embodiments, less than 12% of an anti-ILlRl antibody exists as fragments upon storage at 40 °C for at least 28 days. In some embodiments, less than 11% of an anti-ILlRl antibody exists as fragments upon storage at 10 °C for at least 28 days. In some embodiments, less than 9% of an anti-IL1R1 antibody exists as fragments upon storage at 40 °C for at least 28 days. In some embodiments, less than 8% of an anti-ILlRl antibody exists as fragments upon storage at 40 °C for at least 28 days. In some embodiments, less than 7% of an anti-ILlRl antibody exists as fragments upon storage at 40 °C for at least 28 days. In some embodiments, less than 6% of an anti-ILlRl antibody exists as fragments upon storage at 40 °C for at least 28 days. In some embodiments, less than 5% of an anti-ILlRl antibody exists as fragments upon storage at 40 °C for at least 28 days. In some embodiments, less than 4% of an anti-ILlRl antibody exists as fragments upon storage at 40 °C for at least 28 days. In some embodiments, less than 3% of an anti-ILlRl antibody exists as fragments upon storage at 40 °C for at least 28 days. In some embodiments, less than 2% of an anti-ILlRl antibody exists as fragments upon storage at 40 °C for at least 28 days. In some embodiments, less than 1% of an anti-IL1R1 antibody exists as fragments upon storage at 40 °C for at least 28 days.IL1R1 Binding Characteristics

[0224] Binding characteristics to an antigen is an important feature of an antibody. Modifications to an antibody have to be carefully designed such that the modifications do not adversely affect the antibody’s binding affinity to its target. The present inventors have unexpectedly found that certain mutations in the Fc domain increased the anti-ILlRl antibody’s binding affinity to IL1R1.

[0225] In some embodiments, an anti-ILlRl antibody with a modified Fc domain binds to IL1R1 with a dissociation constant (KD) that is at least 1.5-fold less than that of the anti-ILlRl antibody with a parent Fc domain. In some embodiments, an anti-ILlRl antibody with a modified Fc domain binds to IL1R1 with a dissociation constant (KD) that is at least 1.8-fold less than that of the anti-ILlRl antibody with a parent Fc domain. In some embodiments, an anti-ILlRl antibody with a modified Fc domain binds to IL1R1 with a dissociation constant (KD) that is at least 2.0-fold less than that of the anti-ILlRl antibody with a parent Fc domain. In some embodiments, an anti-ILlRl antibody with a modified Fc domain binds to IL1R1 with a dissociation constant (KD) of about 1.5-fold less, about 1.8-fold less, or about 2.0-fold less than that of the anti-ILlRl antibody with a parent Fc domain.ATTORNEY DOCKET NO.: KPL-080W01

[0226] In some embodiments, an anti-ILlRl antibody with a modified Fc domain comprising amino acid substitutions M428L and N434S binds to IL1R1 with a dissociation constant (KD) that is at least 1.5-fold less than that of the anti-ILlRl antibody with a parent Fc domain. In some embodiments, an anti-ILlRl antibody with a modified Fc domain comprising amino acid substitutions M428L and N434S binds to IL1R1 with a dissociation constant (KD) that is at least 1.8-fold less than that of the anti-ILlRl antibody with a parent Fc domain. In some embodiments, an anti-ILlRl antibody with a modified Fc domain comprising amino acid substitutions M428L and N434S binds to IL1R1 with a dissociation constant (KD) that is at least 2.0-fold less than that of the anti-ILlRl antibody with a parent Fc domain. In some embodiments, an anti-ILlRl antibody with a modified Fc domain comprising amino acid substitutions M428L and N434S binds to IL1R1 with a dissociation constant (KD) of about 1.5-fold less, about 1.8-fold less, or about 2.0-fold less than that of the anti-ILlRl antibody with a parent Fc domain.

[0227] In some embodiments, an anti-ILlRl antibody with a modified Fc domain comprising amino acid substitutions amino acid substitutions V / L309D, Q311H, andN434S binds to IL1R1 with a dissociation constant (KD) that is at least 1.5-fold less than that of the anti-ILlRl antibody with a parent Fc domain. In some embodiments, an anti-ILlRl antibody with a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, and N434S binds to IL1R1 with a dissociation constant (KD) that is at least 1.8-fold less than that of the anti-ILlRl antibody with a parent Fc domain. In some embodiments, an anti-ILlRl antibody with a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, and N434S binds to IL1R1 with a dissociation constant (KD) that is at least 2.0-fold less than that of the anti-ILlRl antibody with a parent Fc domain. In some embodiments, an anti-IL1R1 antibody with a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, and N434S binds to IL1R1 with a dissociation constant (KD) of about 1.5-fold less, about 1.8-fold less, or about 2.0-fold less than that of the anti-ILlRl antibody with a parent Fc domain.

[0228] In some embodiments, an anti-ILlRl antibody with a modified Fc domain binds to IL1R1 with a dissociation constant (KD) that is at least 1.5-fold less than that of the anti-ILlRl antibody with a wild-type IgG2 Fc domain. In some embodiments, an anti-ILlRl antibody with a modified Fc domain binds to IL1R1 with a dissociation constant (KD) that is at least 1.8-fold less than that of the anti-ILlRl antibody with a wild-type IgG2 Fc domain. In some embodiments, an anti-ILlRl antibody with a modified Fc domain binds to IL1R1ATTORNEY DOCKET NO.: KPL-080W01with a dissociation constant (KD) that is at least 2.0-fold less than that of the anti-ILlRl antibody with a wild-type IgG2 Fc domain. In some embodiments, an anti-ILlRl antibody with a modified Fc domain binds to IL1R1 with a dissociation constant (KD) of about 1.5-fold less, about 1.8-fold less, or about 2.0-fold less than that of the anti-ILlRl antibody with a wild-type IgG2 Fc domain.

[0229] In some embodiments, an anti-ILlRl antibody with a modified Fc domain comprising amino acid substitutions M428L and N434S binds to IL1R1 with a dissociation constant (KD) that is at least 1.5-fold less than that of the anti-ILlRl antibody with a wildtype IgG2 Fc domain. In some embodiments, an anti-ILlRl antibody with a modified Fc domain comprising amino acid substitutions M428L and N434S binds to IL1R1 with a dissociation constant (KD) that is at least 1.8-fold less than that of the anti-ILlRl antibody with a wild-type IgG2 Fc domain. In some embodiments, an anti-ILlRl antibody with a modified Fc domain comprising amino acid substitutions M428L and N434S binds to IL1R1 with a dissociation constant (KD) that is at least 2.0-fold less than that of the anti-ILlRl antibody with a wild-type IgG2 Fc domain. In some embodiments, an anti-ILlRl antibody with a modified Fc domain comprising amino acid substitutions M428L and N434S binds to IL1R1 with a dissociation constant (KD) of about 1.5-fold less, about 1.8-fold less, or about 2.0-fold less than that of the anti-ILlRl antibody with a wild-type IgG2 Fc domain.

[0230] In some embodiments, an anti-ILlRl antibody with a modified Fc domain comprising amino acid substitutions amino acid substitutions V / L309D, Q311H, andN434S binds to IL1R1 with a dissociation constant (KD) that is at least 1.5-fold less than that of the anti-ILlRl antibody with a wild-type IgG2 Fc domain. In some embodiments, an anti-ILlRl antibody with a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, and N434S binds to IL1R1 with a dissociation constant (KD) that is at least 1.8-fold less than that of the anti-ILlRl antibody with a wild-type IgG2 Fc domain. In some embodiments, an anti-ILlRl antibody with a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, and N434S binds to IL1R1 with a dissociation constant (KD) that is at least 2.0-fold less than that of the anti-ILlRl antibody with a wild-type IgG2 Fc domain. In some embodiments, an anti-ILlRl antibody with a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, and N434S binds to IL1R1 with a dissociation constant (KD) of about 1.5-fold less, about 1.8-fold less, or about 2.0-fold less than that of the anti-IL1R1 antibody with a wild-type IgG2 Fc domain.ATTORNEY DOCKET NO.: KPL-080W01Therapeutic Use

[0231] In some embodiments, the present invention further provides, among other things, compositions comprising the anti-ILlRl antibody described herein. In some embodiments, the composition comprising the anti-ILlRl antibody further comprises a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are determined in part by the particular composition being administered, as well as by the particular method used to administer the compositions. Accordingly, there is a wide variety of suitable formulations of pharmaceutical compositions available.

[0232] In some embodiments, the present invention provides, among other things, a nucleic acid encoding the anti-ILlRl antibody described herein. In some embodiments, the composition comprises the nucleic acid. In some embodiments, the composition comprises the nucleic acid and a pharmaceutically acceptable carrier.

[0233] In some embodiments, the present invention provides, among other things, a host cell comprising the nucleic acid. In some embodiments, the composition comprises the host cell. In some embodiments, the composition comprises the host cell and a pharmaceutically acceptable carrier.

[0234] In some embodiments, the present invention provides, among other things, a method of producing the anti-ILlRl antibody described herein comprising culturing the host cell under conditions sufficient to produce the anti-ILlRl antibody. In some embodiments, the method further comprises purifying the anti-ILlRl antibody.

[0235] In some embodiments, the present invention provides, among other things, a method of treating a disease or disorder associated with IL-1 or IL1R1, comprising administering to a subject in need thereof the anti-ILlRl antibody described herein. In some embodiments, the present invention provides, among other things, a method of treating an inflammatory disease associated with IL-1 or IL1R1, comprising administering to a subject in need thereof the anti-ILlRl antibody described herein.

[0236] In some embodiments, the inflammatory disease comprises post-cardiac injury syndrome (PCIS), pericarditis, recurrent pericarditis, refractory pericarditis, idiopathic pericarditis, idiopathic recurrent pericarditis, non-idiopathic pericarditis, myocardial infarction pericarditis, posttraumatic pericarditis, post-pericardiotomy syndrome (PPS), early post-myocardial infarct-associated pericarditis, late post- myocardial infarction pericarditis, non-iatrogenic trauma, iatrogenic trauma, deficiency of interleukin- 1 receptor antagonistATTORNEY DOCKET NO.: KPL-080W01(DIRA), rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndromes (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), hidradenitis suppurativa, ankylosing spondylitis (AS), gout (e.g., acute gout, acute gout flares and preventative gout), hyperimmunoglobulin D syndrome (HIDS), mevalonate kinase deficiency (MKD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), familial mediterranean fever (FMF), atherosclerotic cardiovascular disease (ASCVD), acute respiratory distress syndrome (ARDS), Type 2 diabetes, sterile pancreatitis, sterile prostatitis, myocarditis, inflammatory bowel disease (IBD), cardiac sarcoidosis, VEXAS syndrome, interstitial cystitis, Periodic Fever Syndromes (PFS), Adult-onset Still’s disease (AOSD), endometriosis or macrophage activation syndrome (MAS). In some embodiments, the inflammatory disease comprises PCIS. In some embodiments, the inflammatory disease comprises pericarditis. In some embodiments, the inflammatory disease comprises recurrent pericarditis. In some embodiments, the inflammatory disease comprises refractory pericarditis. In some embodiments, the inflammatory disease comprises idiopathic pericarditis. In some embodiments, the disease is idiopathic recurrent pericarditis. In some embodiments, the inflammatory disease comprises non-idiopathic pericarditis. In some embodiments, the inflammatory disease comprises myocardial infarction pericarditis. In some embodiments, the inflammatory disease comprises posttraumatic pericarditis. In some embodiments, the inflammatory disease comprises postpericardiotomy syndrome (PPS). In some embodiments, the inflammatory disease comprises early post-myocardial infarct-associated pericarditis. In some embodiments, the inflammatory disease comprises late post-myocardial infarction pericarditis. In some embodiments, the inflammatory disease comprises non-iatrogenic trauma. In some embodiments, the disease is deficiency of interleukin- 1 receptor antagonist (DIRA). In some embodiments, the inflammatory disease comprises iatrogenic trauma.

[0237] In some embodiments, the inflammatory disease comprises rheumatoid arthritis. In some embodiments, the inflammatory disease comprises systemic juvenile idiopathic arthritis (SJIA). In some embodiments, the inflammatory disease comprises cryopyrin-associated periodic syndromes (CAPS). In some embodiments, the disease is familial cold autoinflammatory syndrome (FCAS). In some embodiments, the disease is Muckle-Wells syndrome (MWS). In some embodiments, the disease is hidradenitis suppurativa. In some embodiments, the inflammatory disease comprises ankylosing spondylitis (AS). In some embodiments, the inflammatory disease comprises gout (e.g., acuteATTORNEY DOCKET NO.: KPL-080W01gout, acute gout flares and preventative gout). In some embodiments, the disease is hyperimmunoglobulin D syndrome (HIDS). In some embodiments, the disease is mevalonate kinase deficiency (MKD). In some embodiments, the disease is tumor necrosis factor receptor-associated periodic syndrome (TRAPS). In some embodiments, the disease is familial mediterranean fever (FMF). In some embodiments, the disease is atherosclerotic cardiovascular disease (ASCVD). In some embodiments, the disease is acute respiratory distress syndrome (ARDS). In some embodiments, the disease is Type 2 diabetes. In some embodiments, the disease is sterile pancreatitis. In some embodiments, the disease is sterile prostatitis. In some embodiments, the disease is myocarditis. In some embodiments, the inflammatory disease comprises inflammatory bowel disease (IBD). In some embodiments, the disease is cardiac sarcoidosis. In some embodiments, the disease is VEXAS syndrome. In some embodiments, the disease is interstitial cystitis. In some embodiments, the disease is Periodic Fever Syndromes (PFS). In some embodiments, the disease is Adult-onset Still’s disease (AOSD). In some embodiments, the disease is endometriosis. In some embodiments, the inflammatory disease comprises macrophage activation syndrome (MAS).EXAMPLES

[0238] Various aspects of the invention are described in further detail in the following Examples. The following examples describe some of the exemplary modes of making and practicing the present invention. However, it should be understood that these examples are for illustrative purposes only and are not meant to limit the scope of the invention.Example 1. FcRn Binding Characteristics of Anti-ILIRI Antibodies Engineered with Fc Mutations

[0239] This example illustrates that engineering Fc mutations into an anti-ILlRl antibody (hereinafter referred to as “WT”), increased the binding affinity to FcRn at acidic pH (e.g., pH 5.8) by at least 3-fold to 50-fold relative to the parent Fc domain. The WT antibody referenced in this and the following examples has the wild-type IgG2 Fc domain.

[0240] The Fc region of antibodies binds to FcRn, a receptor that helps protect antibodies from degradation. When an antibody binds to FcRn at acidic pH (found in endosomes), the antibody-FcRn complex is internalized and recycled back into the bloodstream rather than being degraded in lysosomes. This recycling process increases the antibody’s half-life. At neutral pH, the primary goal is to release the antibody from FcRnATTORNEY DOCKET NO.: KPL-080W01after it has been recycled back to the cell surface. At neutral pH, a high dissociation rate constant (KOff) and high dissociation constant (KD) values are desired to ensure the antibody doesn't stay bound to FcRn and can be free to circulate and exert its therapeutic effect.

[0241] 10 Fc mutants were engineered into WT as shown in Table 7. Unless indicated otherwise, the Fc position numbering is according to EU index in Kabat. Notably, all Fc mutants have preserved target (IL1R1) binding and IL1R1 functional activity.Table 7. Exemplary Fc Mutants Engineered into WT.

[0242] Dissociation constant (KD), dissociation rate constant (KOff), and association rate constant (Kon) to FcRn at both acidic pH (e.g., pH 5.8) and neutral pH (e.g., pH 7.4) were determined for WT with engineered Fc mutations listed in Table 7. Table 8 shows the results, and FIG. 1A-1C show exemplary binding curves of WT and antibodies engineered with Fc mutations.Table 8. Binding Affinities of Anti-ILIRI Antibodies to FcRn at Acidic and Neutral pHs.> > > >ATTORNEY DOCKET NO.: KPL-080W01Example 2. Pharmacokinetics (PK) of Anti-ILIRI Antibodies Engineered with Fc Mutations

[0243] This example demonstrates that Fc-engineered anti-ILlRl antibodies show significantly improved pharmacokinetics (PK) properties as compared to WT, including increased half-life and volume of distribution in vivo.

[0244] In this study, two mouse models were used, Tg32 model and Tg276 model, which are humanized transgenic mice that are engineered to express human FcRn. Typically, Tg32 (homozygous) mouse model provides more accurate prediction of human PK, but is less sensitive to differences between antibodies. On the other hand, Tg276 (hemizygous) allows for detection of subtle differences between PK of antibodies with Fc mutations, but it is less predictive of human PK parameters. Fc-engineered anti-ILlRl antibodies shown in Table 7 and the WT antibody were tested according to study design shown in Table 9.Table 9. Study Design of Anti-ILlRl Antibodies Engineered with Fc Mutants in Tg32 and Tg276 Mouse Models.

[0245] FIG. 2A-2B show the percentage of anti-ILlRl antibodies in the Tg276 mouse model remaining in serum after collection at various time points, normalized to the serum concentration of the respective antibody at Day 1. (WT, which does not have any Fc mutations, was used as a control). Notably, LS and DHS Fc mutants, among other mutants, showed significantly increased % antibody remaining as compared to the WT control (FIG.2B) FIG. 2C-2D show the percentage of anti-ILlRl antibodies in the Tg32 mouse model remaining in serum after collection at various time points, normalized to the serum concentration of the respective antibody at Day 1. Although the Tg32 mouse model is known to be less sensitive to variations between different antibodies, data shows that % antibody remaining of Fc-engineered anti-ILlRl antibodies (e.g., LS and DHS mutants) is much higher than that of the WT control, and is thus predictive of improved PK in humans compared to WT.

[0246] Next, PK parameters were determined based on the Tg32 mouse model. The results are shown in Table 10. In particular, DHS and LS Fc mutants increased the half-life of WT by more than 2-fold, and significantly increased volume of distribution in vivo.ATTORNEY DOCKET NO.: KPL-080W01Table 10. Summary of PK Parameters from Tg32 Mouse Model.*SEM = standard error of the mean

[0247] Additionally, PK parameters determined based on the Tg276 mouse are shown in Table 11. Similar to the trend observed in Tg32 mouse model, DHS and LS Fc mutants increased the half-life of WT by more than 2-fold, and significantly increased volume of distribution in vivo.Table 11. Summary of PK Parameters from Tg276 Mouse Model.ATTORNEY DOCKET NO.: KPL-080W01*SEM = standard error of the meanExample 3. Stability and Manufacturability of Anti-ILIRI Antibody Engineered with Fc Mutations

[0248] The study in this example assesses developability and manufacturability of the WT and Fc-engineered anti-ILlRl antibodies.

[0249] Manufacturability CMC developability are other important factors that are considered in the development of therapeutic drugs. Manufacturability can be assessed by numerous parameters, including conformational and colloidal stability, feasibility of high antibody concentration, viscosity, aggregation, fragmentation, change in charge variants, and / or chemical stability at peptide / amino acid level.

[0250] The characterizations for CMC developability assessment of the WT and Fc- engineered anti-ILlRl antibodies were conducted using a control buffer condition (25 mM sodium acetate with 25.9 mg / mL proline, pH 4.9), as shown in Table 12.Table 12. Summary of CMC Developability Assessment.ATTORNEY DOCKET NO.: KPL-080W01< < < < < < <

[0251] As alluded above, development of an antibody therapeutics is a complex and multifaceted process, with several factors influencing efficacy, safety, and manufacturability of the product. Balancing such factors is important for developing a successful antibodybased therapy. Below is a summary table of certain characteristics of Fc-engineered anti- IL1R1 antibodies (Table 13).Table 13. Summary of Favorable Characteristics of WT and Fc-Engineered Anti-ILIRI Antibodies.&n.d. = not determinedATTORNEY DOCKET NO.: KPL-080W01Example 4. IL1R1 Binding Characteristics of Anti-ILIRI Antibodies Engineered with Fc Mutations

[0252] The study in this example evaluates binding kinetics of the wild-type Fc parent anti-ILlRl antibody (WT) and Fc-engineered anti-ILlRl antibodies (LS and DHS) using surface plasmon resonance (SPR).

[0253] SPR was performed with each of the three antibodies run in triplicate.Specifically, the antibody was captured on chip using anti-IgG, and extracellular domain of human IL1R1 was used as an analyte, run on a Sierra SPR-32 Pro by Bruker. Each mAb was measured at seven analyte concentrations optimized for the entire dataset. KD was determined by Global fit using a 1 : 1 Langmuir binding model. As shown in Table 14, an anti-ILlRl antibody with DHS mutations had the lowest KD value.Table 14. Summary of Dissociation Constants (KD).Example 5. Functional Characterization of Anti-ILlRl Antibodies Engineered with Fc Mutations

[0254] The study in this example evaluates the functional inhibitory activity of the wild-type Fc parent anti-ILRl antibody (WT) with Fc-engineered anti-ILlRl antibodies (LS and DHS) using a cell-based IL-1 HEK-Blue reporter assay.

[0255] To test whether the increased affinity of Fc-engineered mutants LS and DHS is translated to functional inhibitory activity, each antibody (WT, LS, and DHS) was titrated in IL-1 HEK-Blue cells, a reporter cell line for measuring IL-1 receptor activity, in the presence of the IL-1R1 activating cytokine, IL-1B. Table 15 shows the IC50 values, which are indicative of inhibitory capacity of the anti-ILlRl antibodies.Table 15. Exemplary ICso Values of WT and Fc-Engineered Anti-ILlRl Antibodies.

[0256] The results showed that LS and DHS mutations demonstrated lower IC50 values as compared to WT.ATTORNEY DOCKET NO.: KPL-080W01Example 6. Pharmacokinetics (PK) of Anti-ILIRI Antibodies Engineered with Fc Mutations in a Cynomolgus Monkey Model

[0257] This example shows the PK profiles of WT and Fc-engineered anti-ILlRl antibodies (LS and DHS) in cynomolgus monkeys.

[0258] Cynomolgus monkeys were administered a single dose of a WT, DHS, or LS anti-ILlRl antibody at a dose level of 10 mg / kg intravenously. Antibody concentration was monitored for 22 weeks and PK parameters were determined. PK parameters are shown in Table 16. As shown, the LS-engineered anti-ILlRl antibody had 1.29-fold increase in halflife as compared to WT, and the DHS-engineered anti-ILlRl antibody had 2.01-fold increase in half-life as compared to WT. Additionally, DHS-engineered anti-ILlRl antibody continued to show the slowest clearance with the most extended half-life, thus substantially increasing AUC and duration of therapeutic exposure relative to WT.Table 16. Summary of Fold-Changes in PK Parameters at a Dose of 10 mg / kg in Cynomolgus Monkeys at Week 22.EQUIVALENTS AND SCOPE

[0259] The present embodiments are not to be limited in scope by the specific embodiments described herein. Indeed, various modifications in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the embodiments and any appended claims.

[0260] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods andATTORNEY DOCKET NO.: KPL-080W01materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described herein.

Claims

ATTORNEY DOCKET NO.: KPL-080W01CLAIMS1. An anti-interleukin- 1 receptor type- 1 (IL1R1) antibody comprising:a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3;a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; anda modified Fc domain comprising amino acid substitutions M428L and N434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

2. An anti-interleukin- 1 receptor type- 1 (IL1R1) antibody comprising:a variable heavy chain (VH) comprising a HCDR1, a HCDR2, and a HCDR3 in the variable heavy chain (VH) of SEQ ID NO: 7;a variable light chain (VL) comprising a LCDR1, a LCDR2, and a LCDR3 in the variable light chain (VL) of SEQ ID NO: 8; anda modified Fc domain comprising amino acid substitutions M428L and N434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

3. An anti-interleukin- 1 receptor type- 1 (IL1R1) antibody comprising:a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3;a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; anda modified Fc domain comprising amino acid substitutions V / L309D, Q311H, and N434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

4. An anti-interleukin- 1 receptor type- 1 (IL1R1) antibody comprising:a variable heavy chain (VH) comprising a HCDR1, a HCDR2, and a HCDR3 in the variable heavy chain (VH) of SEQ ID NO: 7;a variable light chain (VL) comprising a LCDR1, a LCDR2, and a LCDR3 in the variable light chain (VL) of SEQ ID NO: 8; andATTORNEY DOCKET NO.: KPL-080W01a modified Fc domain comprising amino acid substitutions V / L309D, Q311H, and N434S as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

5. An anti-interleukin- 1 receptor type- 1 (IL1R1) antibody comprising:a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3;a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; anda modified Fc domain comprising amino acid substitutions:a) M428L and N434S;b) V / L309D, Q311H, and N434S / Y;c) M428L;d) T307A, E380A, and N434A;e) V / L309D, Q311H, M428L, and N434S / Y;f) T250Q and M428L; org) M252Y, S254T, T256E, V / L309D, Q311H, andN434S / Y,as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

6. An anti-interleukin- 1 receptor type- 1 (IL1R1) antibody comprising:a variable heavy chain (VH) comprising a HCDR1, a HCDR2, and a HCDR3 in the variable heavy chain (VH) of SEQ ID NO: 7;a variable light chain (VL) comprising a LCDR1, a LCDR2, and a LCDR3 in the variable light chain (VL) of SEQ ID NO: 8; anda modified Fc domain comprising amino acid substitutions:a) M428L and N434S;b) V / L309D, Q311H, and N434S / Y;c) M428L;d) T307A, E380A, and N434A;e) V / L309D, Q311H, M428L, and N434S / Y;f) T250Q and M428L; org) M252Y, S254T, T256E, V / L309D, Q311H, andN434S / Y,ATTORNEY DOCKET NO.: KPL-080W01as compared to a parent Fc domain, wherein numbering is according to the EU index in Kabat.

7. The anti-ILlRl antibody of any one of the preceding claims, wherein the modified Fc domain is derived from IgGl, IgG2, IgG3, or IgG4.

8. The anti-ILlRl antibody of claim 7, wherein the modified Fc domain is derived from IgG2.

9. The anti-ILlRl antibody of claim 8, wherein the modified Fc domain does not comprise amino acid substitutions M252Y, S254T, and T256E wherein numbering is according to the EU index in Kabat.

10. An anti-interleukin- 1 receptor type- 1 (IL1R1) antibody comprising:a variable heavy chain (VH) comprising a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3;a variable light chain (VL) comprising a LCDR1 of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; andan Fc domain means for increasing binding affinity of the anti-ILlRl antibody to FcRn at acidic pH by at least 5 -fold.

11. An anti-interleukin- 1 receptor type-1 (IL1R1) antibody comprising:a variable heavy chain (VH) comprising a HCDR1, a HCDR2, and a HCDR3 in the variable heavy chain (VH) of SEQ ID NO: 7;a variable light chain (VL) comprising a LCDR1, a LCDR2, and a LCDR3 in the variable light chain (VL) of SEQ ID NO: 8; andan Fc domain means for increasing binding affinity of the anti-ILlRl antibody to FcRn at acidic pH by at least 5 -fold.

12. The anti-ILlRl antibody of claim 10 or 11, wherein the increased binding affinity of the anti-ILlRl antibody to FcRn at acidic pH is by at least 7-fold, at least 10-fold, at least 15-fold, at least 30-fold, at least 50-fold, at least 60-fold, or at least 70-fold.ATTORNEY DOCKET NO.: KPL-080W0113. The anti-ILlRl antibody of any one of the preceding claims, wherein the anti-ILlRl antibody has a dissociation constant (KD) to FcRn at acidic pH that is at least 5-fold, at least 7-fold, at least 10-fold, at least 15-fold, at least 30-fold, at least 50-fold, at least 60-fold, or at least 70 fold greater than the KD to FcRn at acidic pH of an anti-ILlRl antibody with the parent Fc domain.

14. The anti-ILlRl antibody of any one of the preceding claims, wherein the anti-ILlRl antibody has a dissociation rate constant (KOff) to FcRn at neutral pH that is greater than 0.01 s'1.

15. The anti-IL-lRl antibody of claim 14, wherein the anti-ILlRl antibody has a dissociation rate constant (KOff) to FcRn at neutral pH that is greater than 0.02 s'1or 0.04 s'1.

16. The anti-ILlRl antibody of any one of the preceding claims, wherein the anti-ILlRl antibody has a dissociation constant (KD) to FcRn at acidic pH that is below 20 nM, and a dissociation rate constant (KOff) to FcRn a neutral pH that is greater than 0.005 s'1.

17. The anti-ILlRl antibody of claim 16, wherein the anti-ILlRl antibody has a dissociation constant (KD) to FcRn at acidic pH that is below 5 nM, and a dissociation rate constant (Koa) to FcRn a neutral pH that is greater than 0.02 s'1.

18. The anti-ILlRl antibody of any one of claims 10-17, wherein the acidic pH is below 7.0.

19. The anti-ILlRl antibody of claim 18, wherein the acidic pH is 5.8.

20. The anti-ILlRl antibody of any one of claims 10-19, wherein the neutral pH is between 7.0 and 8.0.

21. The anti-ILlRl antibody of claim 20, wherein the neutral pH is 7.4.

22. The anti-ILlRl antibody of any one of the preceding claims, wherein EC50 value for inhibition of IL-6 production is less than 100 nM, less than 80 nM, or less than 60 nM.

23. The anti-ILlRl antibody of any one of the preceding claims, wherein the anti-ILlRl antibody has a half-life (ti / 2 value) that is at least greater than 10 days.ATTORNEY DOCKET NO.: KPL-080W0124. The anti-ILlRl antibody of claim 23, wherein the anti-ILlRl antibody has a half-life (ti / 2 value) that is at least greater than 15 days.

25. The anti-ILlRl antibody of any one of the preceding claims, wherein the anti-ILlRl antibody with a modified Fc domain binds to IL1R1 with a dissociation constant (KD) that is at least 1.5-fold less, at least 1.8-fold less, or at least 2.0-fold less than that of the anti-ILlRl antibody with a parent Fc domain.

26. The anti-ILlRl antibody of any one of the preceding claims, wherein the parent Fc domain is a wild-type Fc domain derived from IgGl, IgG2, IgG3, or IgG4.

27. The anti-ILlRl antibody of claim 26, wherein the parent Fc domain is a wild-type IgG2 Fc domain.

28. The anti-ILlRl antibody of claim 27, wherein the parent Fc domain comprises an amino acid sequence of SEQ ID NO: 9.

29. The anti-ILlRl antibody of any one of the preceding claims, wherein the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 7.

30. The anti-ILlRl antibody of claim 29, wherein the VH comprises an amino acid sequence of SEQ ID NO: 7.

31. The anti-ILlRl antibody of any one of the preceding claims, wherein the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 8.

32. The anti-ILlRl antibody of claim 31, wherein the VL comprises an amino acid sequence of SEQ ID NO: 8.

33. The anti-ILlRl antibody of any one of the preceding claims, wherein the anti-ILlRl antibody comprises the VH of SEQ ID NO: 7 and the VL of SEQ ID NO: 8.

34. The anti-ILlRl antibody of any one of the preceding claims, wherein the modified Fc domain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 23.ATTORNEY DOCKET NO.: KPL-080W0135. The anti-ILlRl antibody of claim 34, wherein the modified Fc domain comprises an amino acid sequence of SEQ ID NO: 23.

36. The anti-ILlRl antibody of any one of claims 1-33, wherein the modified Fc domain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 21.

37. The anti-ILlRl antibody of claim 36, wherein the modified Fc domain comprises an amino acid sequence of SEQ ID NO: 21.

38. The anti-ILlRl antibody of claim 35, wherein the anti-ILlRl antibody comprises a heavy chain of SEQ ID NO: 33 and a light chain of SEQ ID NO: 11.

39. The anti-ILlRl antibody of claim 37, wherein the anti-ILlRl antibody comprises a heavy chain of SEQ ID NO: 31 and a light chain of SEQ ID NO: 11.

40. A method of treating an inflammatory disease associated with IL1 or IL1R1, comprising administering the anti-ILlRl antibody of any one of the preceding claims to a subject in need thereof.

41. The method of claim 40, wherein the disease is post-cardiac injury syndrome (PCIS), pericarditis, recurrent pericarditis, refractory pericarditis, idiopathic pericarditis, idiopathic recurrent pericarditis, non-idiopathic pericarditis, myocardial infarction pericarditis, posttraumatic pericarditis, post-pericardiotomy syndrome (PPS), early post-myocardial infarct-associated pericarditis, late post- myocardial infarction pericarditis, non-iatrogenic trauma, iatrogenic trauma, deficiency of interleukin- 1 receptor antagonist (DIRA), rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndromes (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), hi dradenitis suppurativa, ankylosing spondylitis (AS), gout, acute gout, acute gout flares, preventative gout, hyperimmunoglobulin D syndrome (HIDS), mevalonate kinase deficiency (MKD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), familial mediterranean fever (FMF), atherosclerotic cardiovascular disease (ASCVD), acute respiratory distress syndrome (ARDS), Type 2 diabetes, sterile pancreatitis, sterile prostatitis, myocarditis, inflammatory bowel disease (IBD), cardiacATTORNEY DOCKET NO.: KPL-080W01sarcoidosis, VEXAS syndrome, interstitial cystitis, Periodic Fever Syndromes (PFS), Adultonset Still’s disease (AOSD), endometriosis or macrophage activation syndrome (MAS).

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