Methods of treatment of cancer with antibody-IL-2 engrafted proteins
The present disclosure provides for IL2 engrafted into the CDR sequences of an antibody having preferred therapeutic profiles over molecules known and used in the clinic. In particular, the provided antibody cytokine engrafted protein compositions increase or maintain CD8+ T effector cells while reducing the activity of Treg cells. Additionally, provided compositions convey improved half-life, stability and produceability over recombinant human IL2 formulations such as Proleukin®.
1 . A method of treating cancer in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an antibody cytokine engrafted protein, wherein the antibody cytokine engrafted protein comprises:
an IgG class heavy chain comprising an IgG class heavy chain variable region (VH) comprising a Complementarity Determining Region (CDR) HCDR1 engrafted with a mutated Interleukin 2 (IL2) molecule, a HCDR2, and a HCDR3; and
an IgG class light chain comprising an IgG class light chain variable region (VL) comprising a LCDR1, a LCDR2, and a LCDR3,
and wherein
(a) the HCDR1 comprises SEQ ID NO:7, the HCDR2 comprises SEQ ID NO:8, the HCDR3 comprises SEQ ID NO:9, the LCDRI comprises SEQ ID NO:23, the LCDR2 comprises SEQ ID NO:24, and the LCDR3 comprises SEQ ID NO:25, wherein the HCDRs and the LCDRs comprise between 0 to 1 substitution;
(b) the HCDR1 comprises SEQ ID NO:10, the HCDR2 comprises SEQ ID NO:11, the HCDR3 comprises SEQ ID NO:12, the LCDRI comprises SEQ ID NO:26, the LCDR2 comprises SEQ ID NO:27, and the LCDR3 comprises SEQ ID NO:28, wherein the HCDRs and the LCDRs comprise between 0 to 1 substitution;
(c) the HCDR 1 comprises SEQ ID NO:13, the HCDR2 comprises SEQ ID NO:14, the HCDR3 comprises SEQ ID NO:15, the LCDRI comprises SEQ ID NO:29, the LCDR2 comprises SEQ ID NO:30, and the LCDR3 comprises SEQ ID NO:31, wherein the HCDRs and the LCDRs comprise between 0 to 1 substitution;
(d) the HCDR1 comprises SEQ ID NO:16, the HCDR2 comprises SEQ ID NO:17, the HCDR3 comprises SEQ ID NO:18, the LCDR1 comprises SEQ ID NO:32, the LCDR2 comprises SEQ ID NO:33, and the LCDR3 comprises SEQ ID NO:34, wherein the HCDRs and the LCDRs comprise between 0 to 1 substitution;
(e) the HCDR 1 comprises SEQ ID NO:39, the HCDR2 comprises SEQ ID NO:40, the HCDR3 comprises SEQ ID NO:41, the LCDRI comprises SEQ ID NO:55, the LCDR2 comprises SEQ ID NO:56, and the LCDR3 comprises SEQ ID NO:57, wherein the HCDRs and the LCDRs comprise between 0 to 1 substitution;
(f) the HCDR1 comprises SEQ ID NO:42, the HCDR2 comprises SEQ ID NO:43, the HCDR3 comprises SEQ ID NO: 44, the LCDRI comprises SEQ ID NO: 58, the LCDR2 comprises SEQ ID NO:59, and the LCDR3 comprises SEQ ID NO:60, wherein the HCDRs and the LCDRs comprise between 0 to 1 substitution;
(g) the HCDR 1 comprises SEQ ID NO:45, the HCDR2 comprises SEQ ID NO:46, the HCDR3 comprises SEQ ID NO:47, the LCDRI comprises SEQ ID NO:61, the LCDR2 comprises SEQ ID NO:62, and the LCDR3 comprises SEQ ID NO:63, wherein the HCDRs and the LCDRs comprise between 0 to 1 substitution; or
(h) the HCDR1 comprises SEQ ID NO:48, the HCDR2 comprises SEQ ID NO:49, the HCDR3 comprises SEQ ID NO:50, the LCDRI comprises SEQ ID NO:64, the LCDR2 comprises SEQ ID NO:65, and the LCDR3 comprises SEQ ID NO:66, wherein the HCDRs and the LCDRs comprise between 0 to 1 substitution.
2 . The method of claim 1 , wherein the cancer is selected from the group consisting of melanoma, lung cancer, colorectal cancer, prostate cancer, breast cancer, and lymphoma.
3 . The method of claim 1 , wherein the antibody cytokine engrafted protein is administered in combination with a therapeutic agent.
4 . The method of claim 3 , wherein the therapeutic agent is a second antibody cytokine engrafted protein.
5 . The method of claim 3 , wherein the therapeutic agent is a tyrosine kinase inhibitor.
6 . The method of claim 3 , wherein the therapeutic agent is an immune checkpoint inhibitor.
7 . The method of claim 6 , wherein the immune checkpoint inhibitor is an inhibitor of an immune checkpoint molecule selected from the group consisting of: PD-1, PD-L1, PD-L2, TIM3, CTLA-4, LAG-3, CEACAM-1, CEACAM-5, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and TGFR.
8 . The method of claim 1 , wherein the antibody cytokine engrafted protein specifically binds to a low affinity IL2 receptor.
9 . The method of claim 1 , wherein the antibody cytokine engrafted protein preferentially expands T effector cells over regulatory T cells.
10 . The method of claim 1 , wherein the antibody cytokine engrafted protein stimulates one or more of CD8+ T effector cell proliferation, natural killer (NK) cell proliferation or combination thereof, greater than recombinant IL2 or aldesleukin.
11 . The method of claim 1 , wherein the VH comprises the amino acid sequence of SEQ ID NO:19 or SEQ ID NO:51.
12 . The method of claim 1 , wherein the IgG class heavy chain is selected from IgG 1 , IgG2, and IgG4.
13 . The method of claim 1 , wherein the IgG class heavy chain comprises the amino acid sequence of SEQ ID NO:21 or SEQ ID NO:53.
14 . The method of claim 1 , wherein the VL comprises the amino acid sequence of SEQ ID NO: 35 or SEQ ID NO: 67.
15 . The method of claim 1 , wherein the IgG class light chain comprises the amino acid sequence of SEQ ID NO:37 or SEQ ID NO:69.
16 . The method of claim 1 , wherein the IgG class light chain comprises an amino acid sequence having 95% or more sequence identity with SEQ ID NO:37 and the IgG class heavy chain comprises an amino acid sequence having 95% or more sequence identity with SEQ ID NO:21.
17 . The method of claim 16 , wherein the IgG class light chain comprises the amino acid sequence of SEQ ID NO:37 and the IgG class heavy chain comprises the amino acid sequence of SEQ ID NO:21.
18 . The method of claim 1 , wherein the IgG class light chain comprises an amino acid sequence having 95% or more sequence identity with SEQ ID NO:69 and the IgG class heavy chain comprises an amino acid sequence having 95% or more sequence identity with SEQ ID NO:53.
19 . The method of claim 18 , wherein the IgG class light chain comprises the amino sequence of SEQ ID NO:69 and the IgG class heavy chain comprises the amino sequence of SEQ ID NO:53.