Fusion constructs and methods of using thereof
Inventors
Sabzevari, Helen • METENOU, Simon • Chen, ChangHung • SHAH, Rutul R.
Assignees
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Publication Number
US-11535669-B2
Publication Date
2022-12-27
Expiration Date
Abstract
Provided herein is a composition comprising a fusion protein or a fragment or a variant thereof comprising an anti-PD1 antibody or a fragment/variant thereof and a TGF-β trap. Provided herein is a composition comprising a fusion protein or a fragment thereof or a variant thereof comprising an anti-PD1 antibody or a fragment/variant thereof and a ADA2 polypeptide. Also provided herein are methods of using the composition in treating cancer.
Core Innovation
The invention relates to anti-PD1 fusion proteins for cancer therapy, including anti-PD-1 or variants or fragments fused to adenosine deaminase ADA2. The fusion construct concurrently blocks PD-1/PD-L1 signaling and reduces extracellular adenosine in the tumor microenvironment, and this fusion is described in connection with anti-tumor treatment contexts and Methods of Treating Cancer.
The fusion protein design specifies an IgG4 antibody provided as multiple polypeptides with sequence-identity relationships to defined SEQ ID sequences, including a third polypeptide comprising SEQ ID NO: 146 with a mutation at position 108, including an S108P mutation in the sequence context. The IgG4 antibody additionally includes a fourth polypeptide with sequence identity to a specified SEQ ID sequence and at least one linker connecting one or more polypeptides.
The disclosure further describes antibody format options including VH/VL, Fab, Fab2, (Fab')2, Fv, scFv, Fc, diabody, triabody, minibody, and VBAR, together with flexible, rigid, and cleavable linkers. The broader disclosure also references combination therapy concepts, TGF-β-related immunobiology, extracellular adenosine and A2AR pathway effects, and optional use with engineered CAR/exogenous-receptor T cells, polynucleotides, expression vectors, pharmaceutical compositions, RHEOSWITCH, and ecdysone receptor (EcR).
Claims Coverage
Independent claim coverage centers on an IgG4-based multi-polypeptide anti-PD1 fusion protein design with defined sequence-identity constraints to specific SEQ ID sequences, a mutation at position 108, and at least one linker connecting polypeptides. Across the independent claims and referenced dependents, there are four inventive features.
IgG4 antibody formed from multiple SEQ-ID constrained polypeptides with position 108 mutation
A fusion protein in which an IgG4 antibody comprises a first polypeptide at least 95% identical to SEQ ID NO: 6 or 7, a second polypeptide at least 95% identical to SEQ ID NO: 12 or 13, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 146 but with a mutation at position 108 thereof.
Additional polypeptide sequence-identity requirement
The fusion protein further comprises a fourth polypeptide at least 95% identical to SEQ ID NO: 14.
Linker connecting one or more polypeptides
One or more polypeptides of the fusion protein are connected by a linker.
Linker and sequence refinements
Dependent claims further narrow linker sequence and specify tighter sequence instances.
The claim coverage is directed to a multi-polypeptide IgG4 antibody construct with sequence-identity constraints, a position 108 mutation, and a linker connecting polypeptides, with dependent claims further constraining linker and polypeptide sequences.
Stated Advantages
Achieves synergistic anti-tumor activity by concurrently blocking PD-1/PD-L1 signaling and reducing extracellular adenosine in the tumor microenvironment.
Documented Applications
Methods of Treating Cancer.
Combination therapy concepts.
Treatment where PD-1/CTLA-4 responses are non-responsive.
Gene-switch/intracellular regulation systems including RHEOSWITCH and ecdysone receptor (EcR).
CAR/TCR platforms.
Optional use with engineered CAR/exogenous-receptor T cells.
Polynucleotides, expression vectors, and pharmaceutical compositions.
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