Cytotoxic immunoglobulin
Inventors
Himmler, Gottfried • Mudde, Geert • Bauer, Anton • Redl, Gerda • Woisetschlager, Maximillian
Assignees
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Publication Number
US-8859738-B2
Publication Date
2014-10-14
Expiration Date
Abstract
The invention relates to a cytotoxic modular antibody with a molecular weight of up to 6 OkD, specifically binding to a cell surface target with a binding affinity of Kd<10−8 M, a method of producing such antibody and its use as a therapeutic.
Core Innovation
The invention relates to small cytotoxic modular antibodies in which a molecular scaffold is engineered to provide high-affinity binding to a cell-surface target, including erbB receptors such as Her2. The modular antibodies include cytotoxic effector functions associated with ADCC, ADCP, CDC, and apoptosis, and are described with a molecular weight up to about 60 kD and binding affinity on the order of Kd<10^-8 M and IC50<10^-8 M.
The disclosed subject matter provides an Fcab that binds to Her2. The Fcab comprises a CH3 domain in which the CH3 domain includes an AB loop comprising the amino acid sequence of SEQ ID NO: 191, a CD loop comprising SEQ ID NO: 241, and an EF loop comprising the amino acid sequence of SEQ ID NO: 370.
A modular immunoglobulin scaffold framework is defined, including Fcab formats and immunoglobulin structural loops versus CDR loops. The invention specifies modular library design in which randomized structural loop regions within a CH3 domain, including structural loop regions identified as AB, CD, and EF loop positions, are used to generate Fcab libraries, including non-focused and focused Fcab libraries.
Claims Coverage
The claim set provided includes two independent claims. Across these independent claims, the inventive features focus on Her2-binding via an Fcab CH3 domain defined by AB/CD/EF loop sequences, and on a cytotoxic modular antibody defined by molecular weight and Her2 binding affinity that includes such an Fcab.
Her2-binding Fcab with CH3 AB/CD/EF loop sequences
An Fcab that binds to Her2, wherein the Fcab comprises a CH3 domain, wherein said CH3 domain comprises an AB loop comprising the amino acid sequence of SEQ ID NO: 191, a CD loop comprising SEQ ID NO: 241, and an EF loop comprising the amino acid sequence of SEQ ID NO: 370.
Cytotoxic modular antibody with Her2 affinity and CH3 AB/CD/EF loop sequences
A cytotoxic modular antibody with a molecular weight of up to 60 kD, wherein the modular antibody specifically binds to Her2 with a binding affinity of Kd<10^-8 M, and wherein the modular antibody comprises an Fcab comprising a CH3 domain, wherein said CH3 domain comprises an antigen binding site which specifically binds Her2, wherein said antigen binding site of said CH3 domain comprises an AB loop comprising the amino acid sequence of SEQ ID NO: 191, a CD loop comprising SEQ ID NO: 241, and an EF loop comprising the amino acid sequence of SEQ ID NO: 370.
Claim coverage is centered on Her2-binding through an Fcab CH3 domain whose antigen-binding-relevant loops are specified by AB (SEQ ID NO: 191), CD (SEQ ID NO: 241), and EF (SEQ ID NO: 370), and on a cytotoxic modular antibody form that specifies molecular weight up to 60 kD and Her2 binding affinity of Kd<10^-8 M while including that defined Fcab.
Stated Advantages
Provides an Fcab and a cytotoxic modular antibody that specifically bind to Her2 using defined AB/CD/EF loop sequences within a CH3 domain.
For the cytotoxic modular antibody, provides a specified binding affinity to Her2 of Kd<10^-8 M and a molecular weight of up to 60 kD.
Achieves high-affinity binding to Her2 with cytotoxic effector functions (ADCC, ADCP, CDC, and apoptosis).
Documented Applications
Characterization and validation of Her2-specific binding and cytotoxicity for selected Fcabs/Fcab fragments, including antigen binding assessment and cytotoxicity (ADCC) with measured EC50 values, as described in the provided partial content.
Assessment of Fc receptor/Protein A integrity and antigen binding specificity, including noted weak cross-reactivity to other Her family members, as described in the provided partial content.
Selection and enrichment of Her2-binding Fcab variants using FACS with biotinylated Her2 and Protein A/CD64 co-selection.
Use of CH3-based modular Fcab library designs, including non-focused and focused Fcab libraries, incorporating randomized structural loop regions (AB/CD/EF loop positions) for Her2-binding.
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