Engineered anti-il-2 antibodies
Inventors
AMIT, Inbar • Levin, Itay • NIMROD, Guy • FISCHMAN, Sharon • BARAK FUCHS, Reut • STRAJBL, Marek • WYANT, Timothy • ZHENIN, Michael • BLUVSHTEIN YERMOLAEV, Olga • SASSON, Yehezkel • GROSSMAN, Noam • LEVITIN, Natalia • OFRAN, Yanay
Assignees
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Publication Number
US-12312400-B2
Publication Date
2025-05-27
Expiration Date
Abstract
Described herein are engineered anti-IL-2 antibodies with modified amino acid sequences. The engineered antibodies confer modified receptor binding specificity to an lL-2-anti-IL-2 antibody complies inhibiting the binding of IL-2 to CD25. This allows for the binding of an IL-2 antibody complex to the dimeric IL-2 receptor (CD122/CD132) present on effector T cells and NK cells but prevents the binding of human IL-2 to non-immune cells expressing high levels of CD25, e.g., lung endothelium and vascular endothelium, or to immune cells expressing the high affinity trimeric IL-2 receptor (CD25/CD122/CD132), e.g., Treg cells and CD25+ short lived cytotoxic effector T cells The engineered anti-IL-2 antibodies would facilitate expansion of subsets of effector immune cells and decrease undesirable effects caused by IL-2. Thus the engineered anti-IL-2 antibodies would be useful in treating disease such as cancer and infection.
Core Innovation
The invention relates to anti-IL-2 antibodies and antibody/hIL-2 immune complexes that bind IL-2 with high affinity and selectively discriminate between CD25 and CD122 on antibody/IL-2 complexes. The antibodies are epitope-specific, including BDG17.023 and humanized clones including BDG17.038/043/053/054/066/067/069, and are described as binding human IL-2 and cynomolgus IL-2.
The anti-IL-2 antibodies spare IL-2 binding to the signaling beta/gamma dimer while blocking IL-2 interaction with the high-affinity IL-2 receptor alpha chain, thereby engaging the IL-2 receptor dimer rather than the full trimer. This selective receptor engagement preferentially stimulates effector immune cells, including CD8+ memory phenotype and NK/NKT cells, while limiting regulatory T-cell expansion.
The disclosure includes antibody formats such as IgG and antibody fragments including Fv, scFv, Fab, F(ab′)2, minibody, diabody, and triabody, together with pharmaceutical compositions comprising pharmaceutically acceptable carriers, formulations and excipients. The antibodies and complexes are further characterized by binding kinetics and affinity, aggregation and folding, and formulation stability under stress testing.
Claims Coverage
The consolidated claim set covers four independent claim themes: an isolated anti-IL-2 antibody, isolated polynucleotides encoding the antibody VH/VL or related variable regions, an isolated polynucleotide encoding an anti-IL-2 scFv, and treatment methods using the anti-IL-2 antibody composition. Across these claims, the inventive features focus on defined VH/VL complementarity determining regions tied to specific SEQ ID NO variants and on therapeutic use for specified diseases or conditions, including combination timing with immune checkpoint inhibitors.
Defined anti-IL-2 antibody VH and VL HCDRs and LCDRs by SEQ ID NO variants
An isolated anti-IL-2 antibody comprising a VH and VL in which the HCDRs and LCDRs contain amino-acid ranges mapped to SEQ ID NO: 10, 12, 14, 16, or 18 for VH and SEQ ID NO: 11, 13, 15, 17, or 19 for VL.
Isolated polynucleotide encoding anti-IL-2 VH and/or VL with specified HCDRs and LCDRs
An isolated polynucleotide sequence encoding a VH and/or a VL of an anti-IL-2 antibody, wherein the HCDRs and LCDRs comprise specified amino-acid ranges mapped to SEQ ID NO: 10, 12, 14, 16, or 18 for VH and SEQ ID NO: 11, 13, 15, 17, or 19 for VL, including encoding a VH and a VL with defined HCDR and LCDR combinations.
Isolated polynucleotide encoding an anti-IL-2 scFv
An isolated polynucleotide sequence encoding an anti-IL-2 scFv, wherein the polynucleotide sequence is set forth in SEQ ID NO: 1, 2, 3, 4, or 5.
Treatment of disease or condition with the anti-IL-2 antibody and combination timing with immune checkpoint inhibitors
A method for treating a disease or condition in a subject by administering an anti-IL-2 antibody composition for diseases or conditions including cancer, melanoma, metastatic renal cell carcinoma, viral infection, SARS-CoV-2, and IL-2-induced conditions including pulmonary edema, pneumonia, or vascular leak syndrome, and further treating with immune checkpoint inhibitors with inhibitor treatment occurring concurrently with, before, or after anti-IL-2 antibody treatment.
The independent claims are directed to isolated anti-IL-2 antibodies defined by specific VH/VL HCDR/LCDR amino-acid ranges tied to SEQ ID NO variants, isolated polynucleotides encoding the corresponding VH and/or VL or anti-IL-2 scFv variants, and therapeutic treatment methods using the anti-IL-2 antibody composition for specified diseases or conditions, including combination therapy with immune checkpoint inhibitors with specified timing.
Stated Advantages
Preferential stimulation of effector immune cells, including CD8+ memory phenotype and NK/NKT cells.
Limitation of regulatory T-cell expansion.
Limitation of IL-2-driven toxicities associated with CD25 expression on pulmonary/vascular endothelium, including pulmonary edema and vascular leak syndrome.
Shift immune responses toward effector CD8+/NK expansion with reduced Treg expansion.
Demonstrate tolerability in melanoma xenograft and syngeneic models.
Identify a most stable formulation (F4) for BDG17.069 under formulation-stability stress testing.
Documented Applications
Treatment of viral infections, notably SARS-CoV-2.
Treatment of cancer, including melanoma and metastatic renal cell carcinoma.
Treatment of IL-2-induced conditions including pulmonary edema, pneumonia, and vascular leak syndrome.
Combination therapy with immune checkpoint inhibitors administered concurrently with, before, or after anti-IL-2 antibody treatment.
Bacterial infections are mentioned as therapeutic indications in the provided document summary.
Melanoma xenograft models using antibody/hIL-2 immune complexes.
Melanoma syngeneic models using antibody/hIL-2 immune complexes.
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