Method of manufacturing bispecific antibodies, bispecific antibodies and therapeutic use of such antibodies
Inventors
Bardroff, Michael Otto • BUCH, Tina • Graf, Christian • Heitmann, Daniel • Jostock, Thomas • Knopf, Hans-Peter • KOEHLER, Rolf • Kovarik, Jiri • Oliver, Stephen John • Patel, Dhavalkumar • Woisetschlaeger, Maximilian
Assignees
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Publication Number
US-11987644-B2
Publication Date
2024-05-21
Expiration Date
Abstract
The invention relates to bivalent bispecific monoclonal antibodies (bbmAb) or variants thereof, and methods of manufacturing such antibodies by co-expressing modified Fc-mutated derivatives of two different monoclonal antibodies in mammalian cell lines.
Core Innovation
The invention relates to a knob-into-hole (KiH) Fc-mutated bivalent bispecific monoclonal antibody that binds to IL-18 and IL-1β and comprises defined immunoglobulin heavy and light chains. The specific chain amino acid sequences are provided, including a first immunoglobulin heavy chain comprising SEQ ID NO. 87, a first immunoglobulin light chain comprising SEQ ID NO. 103, a second immunoglobulin heavy chain comprising SEQ ID NO. 55, and a second immunoglobulin light chain comprising SEQ ID NO. 71. The document further characterizes knob-in-hole IL-18/IL-1β bispecific antibodies.
A key aspect is the framework that avoids shared light chains and/or heavy chains to support higher yield/purity and to reduce anti-drug antibody risk. The disclosed approach describes mismatched fragment removal and other purification concepts to achieve high purity of the intended heterodimer, with reported impurities identified as light-chain mispairing and/or hole-knob mismatches. Product purity and aggregation levels are assessed using SEC, CZE, and CE-SDS.
The document further describes Fc effector-silencing mutations and KiH knob/hole Fc mutations within the immunoglobulin chain definitions, including example mutation combinations and optional additional disulfide stabilization. It also reports binding and neutralization data for bbmAb1 showing high-affinity binding to human and marmoset IL-18 and IL-1β, simultaneous dual neutralization, and additive inhibitory effects of combined IL-1β/IL-18 blockade in cell-based assays and transcriptomics.
Claims Coverage
The independent claims define a bispecific antibody by specified IL-18 and IL-1β binding and by four specified immunoglobulin chain amino-acid sequences, with additional coverage for a pharmaceutical composition and for treatment of inflammasome-related disorders via administration of an effective amount. Four inventive features are identified.
Bispecific antibody with defined IL-18 and IL-1β binding sequences
A bispecific antibody that binds to IL-18 and IL-1β and comprises a first immunoglobulin heavy chain comprising SEQ ID NO. 87, a first immunoglobulin light chain comprising SEQ ID NO. 103, a second immunoglobulin heavy chain comprising SEQ ID NO. 55, and a second immunoglobulin light chain comprising SEQ ID NO. 71.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising the bispecific antibody together with a pharmaceutically acceptable carrier.
Method of treating an inflammasome-related disorder by administering an effective amount
A method for treating an inflammasome-related disorder by administering to a subject an effective amount of the bispecific antibody.
Treatment of specified inflammasome-related disorders
The method covering inflammasome-related disorders including sickle cell disease, vasculopathy, ischemia-reperfusion injury, cardiovascular disease, peripheral artery disease, atherosclerosis, vascular dysfunction, skeletal muscle ischemia, pulmonary sarcoidosis, fibrosis, malaria, hemodialysis-dependent chronic kidney disease, and Crohn’s disease.
Overall, the claim coverage centers on a sequence-defined IL-18/IL-1β bispecific antibody, with dependent coverage directed to a pharmaceutical composition and therapeutic treatment of inflammasome-related disorders by administering an effective amount, including specific disorder examples.
Stated Advantages
higher yield/purity
reduce anti-drug antibody risk
high purity of the intended heterodimer
dual neutralization in simultaneous cell-based assays
Simultaneous dual neutralization outperforming single mAbs.
Additive inhibitory effects of combined IL-1β/IL-18 blockade, including inhibition of IFNγ.
Additively downregulated genes including IL-26.
Documented Applications
therapeutic use in inflammasome-related diseases
treatment of inflammasome-related disorders
treatment of sickle cell disease, vasculopathy, ischemia-reperfusion injury, cardiovascular disease, peripheral artery disease, atherosclerosis, vascular dysfunction, skeletal muscle ischemia, pulmonary sarcoidosis, fibrosis, malaria, hemodialysis-dependent chronic kidney disease, or Crohn’s disease
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