Bispecific antibody
Inventors
Shibayama, Shiro • TEZUKA, Tomoya • Throsby, Mark • De Kruif, Cornelis Adriaan • VAN LOO, Pieter Fokko • KLOOSTER, Rinse • ROOVERS, Robertus Cornelis
Assignees
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Publication Number
US-12325746-B2
Publication Date
2025-06-10
Expiration Date
Abstract
An agent for preventing, suppressing the progression of symptoms of, suppressing the recurrence of or treating autoimmune diseases, comprising a bispecific antibody or an antibody fragment thereof, having a first arm specifically binding to PD-1 and a second arm specifically binding to CD19, as described herein.
Core Innovation
The invention relates to PD-1/CD19 bispecific antibodies and to a bispecific antibody having a first arm specifically binding to PD-1 and a second arm specifically binding to CD19. The first arm includes a heavy chain variable region and a light chain variable region, and the second arm includes a heavy chain variable region and a light chain variable region, with binding mediated through specified PD-1- and CD19-recognizing antibody variable-region sequences defined by SEQ ID NOs.
The document further describes increasing the isoelectric point of the CD19-binding second-arm heavy chain/light chain complex to improve separation during cation exchange purification. This is achieved using C-terminal peptide adducts and VH substitutions in the CD19-binding arm, including glutamine-114 to arginine, with preferred pI ranges of about 8.3 to 8.9 and clone-specific purification and retention behaviors on cation exchange.
The patent also characterizes structural and functional aspects of the PD-1/CD19 bispecific antibodies, including PD-1/PD-L1 interaction capability, reduced cytokine production such as IL-2, IFN-gamma, and TNF-alpha, and suppression of T-cell activation and memory T-cell activation. It further discusses constant-region/isotype options, including IgG1 and IgG4 variants with engineered Fc/hinge substitutions, and a common light chain approach across the arms.
Claims Coverage
Across the independent claims, the inventive coverage centers on a PD-1/CD19 bispecific antibody defined by specified VH/VL sequences. One independent claim specifies the variable-region sequences for the PD-1-binding arm and the CD19-binding arm, while the other independent claim further restricts the antibody by specifying heavy-chain and light-chain constant-region sequences for the respective arms.
PD-1 and CD19 binding arms defined by variable-region sequences
A bispecific antibody having a first arm specifically binding to PD-1 and a second arm specifically binding to CD19, wherein the first arm has a VH comprising SEQ ID NO: 5 and a VL comprising SEQ ID NO: 25, and the second arm has a VH comprising SEQ ID NO: 62 and a VL comprising SEQ ID NO: 25.
Variable-region and constant-region sequences for both arms
A bispecific antibody comprising a PD-1-binding first arm with a heavy chain VH comprising SEQ ID NO: 5 and a heavy chain constant region comprising SEQ ID NO: 23, and a light chain VL comprising SEQ ID NO: 25 and a light chain constant region comprising SEQ ID NO: 29, and a CD19-binding second arm with a heavy chain VH comprising SEQ ID NO: 62 and a heavy chain constant region comprising SEQ ID NO: 24, and a light chain VL comprising SEQ ID NO: 25 and a light chain constant region comprising SEQ ID NO: 29.
The independent claims cover PD-1/CD19 bispecific antibodies defined by specific amino acid sequences for the variable regions of the PD-1-binding arm and the CD19-binding arm. One independent claim further specifies heavy-chain and light-chain constant-region sequences using SEQ ID NOs: 23, 24, and 29.
Stated Advantages
Improved separation of PD-1/CD19 bispecific antibodies from by-products including homodimers and separate arm complexes during cation exchange purification.
Reduced cytokine production such as IL-2, IFN-gamma, and TNF-alpha.
Suppression of T-cell activation and memory T-cell activation.
Suppresses B-cell activation and (memory) T-cell activation.
Maintains PD-1-PD-L1 interaction.
Prevents, suppresses progression, prevents recurrence, and treats autoimmune diseases and related conditions.
Documented Applications
Cation exchange purification of PD-1/CD19 bispecific antibodies using clones or variants with increased isoelectric point to improve separation from by-products.
Production and purification overview of PD-1/CD19 bispecific antibodies with desirable functional properties including PD-1-PD-L1 interaction and reduced cytokine production.
Preventing, suppressing progression, preventing recurrence, and treating autoimmune diseases and related conditions, including GVHD and type I diabetes mellitus.
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