Agonistic anti-IL-2R antibodies and methods of use
Inventors
Trinklein, Nathan • Harris, Katherine • Lorentsen, Kyle • MALIK CHAUDHRY, Harbani Kaur • Loughlin, Kaitlyn
Assignees
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Publication Number
US-11884735-B2
Publication Date
2024-01-30
Expiration Date
Abstract
Anti-IL2R (e.g., anti-IL2RB, anti-IL2RG, anti-IL2RB/G) antibodies are disclosed, along with methods of making such antibodies, compositions, including pharmaceutical compositions, comprising such antibodies, and use of such antibodies and compositions in the treatment of diseases and disorders that are mediated by the IL2/IL2R signaling pathway.
Core Innovation
The invention describes engineered heavy chain-only antibodies that include a first heavy chain variable region binding IL2RB and a second heavy chain variable region binding IL2RG. Each variable region is defined by specific CDR1, CDR2, and CDR3 sequence motifs with allowed substitutions and SEQ ID-defined CDR sequence identities for binding to the respective IL2 receptor subunits. The architecture therefore targets IL2RB and IL2RG through distinct heavy-chain variable regions within a heavy chain-only format.
The heavy chain-only antibodies further specify constant-region structures lacking CH1, consisting of hinge/CH2/CH3 and variants in the context of IgG4 Fc, including heterodimerizing knobs-and-holes substitutions, disulfide-bridge-forming substitutions, charge pair substitutions, and silenced or effector-less Fc variants with glycosylation-disrupting mutations. The document also describes heavy-chain-only multispecific antibody configurations and stated binding and quality attributes through Kd and Tm/Tagg ranges, together with characterization concepts such as internalization and functional evaluation.
Claims Coverage
The independent claim coverage centers on a heavy chain-only antibody with two heavy-chain variable regions that specifically bind IL2RB and IL2RG, where each CDR1, CDR2, and CDR3 region is defined by motif sequence formulas with allowed amino-acid substitutions and specific SEQ ID NOs. The claim set also includes sequence-identity constraints, absence of CH1, and pharmaceutical composition coverage.
Heavy chain-only IL2RB and IL2RG binding via defined CDR motifs
A heavy chain-only antibody comprising a first heavy chain variable region that binds to IL2RB, with CDR1, CDR2, and CDR3 sequences defined by specified formulas and allowed substitutions, and a second heavy chain variable region that binds to IL2RG, with CDR1, CDR2, and CDR3 sequences defined by specified formulas and allowed substitutions.
Sequence-identity constrained heavy chain variable regions
The heavy chain-only antibody where the first heavy chain variable region and the second heavy chain variable region each have at least 95% sequence identity to specified SEQ ID sequences.
No CH1 in heavy chain constant region
A heavy chain-only antibody including a heavy chain constant region with a hinge region, CH2 domain, and CH3 domain, but lacking a CH1 sequence in its heavy chain constant region.
Pharmaceutical composition with excipient
A pharmaceutical composition comprising the heavy chain-only antibody and a pharmaceutically acceptable excipient.
Overall, the claim coverage focuses on a heavy chain-only antibody format with IL2RB- and IL2RG-binding defined by specific CDR sequence motifs and sequence identity constraints, with narrower formats specifying absence of CH1 and a pharmaceutical composition including an excipient.
Stated Advantages
Avoids preferential Treg activation and associated IL-2 toxicities by binding IL2RB/IL2RG rather than IL2RA (CD25).
Retains potent stimulation of other T-cell subsets and NK cells while using agonistic anti-IL2R antibodies.
Documented Applications
Cancer treatment, including solid tumors and liquid cancers, using agonistic IL2R signaling stimulation as described in the document.
IL2R signaling stimulation using the described agonistic anti-IL2R antibodies.
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