Modified antibodies and related compounds, compositions and methods of use
Inventors
Jackson, David Y. • Ha, Edward
Assignees
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Publication Number
US-11932695-B2
Publication Date
2024-03-19
Expiration Date
Abstract
Provided herein are modified antibodies, compounds used to make them, and intermediates in their synthesis; compositions; formulations and methods, including methods of treating diseases, disorders or conditions, for example, cancer, in humans.
Core Innovation
The invention relates to modified antibodies represented by formula (IIa), where A is an antibody or antibody fragment. The two depicted cysteine residues are taken from at least one reduced interchain cysteine-cysteine disulfide bond in A, and the structure includes an integer n from 1 to 13 with a bond that can be single or a double bond between the residues.
Each R and R′ is independently hydrogen or C1-6 alkyl, with optional substitution on one or more carbons by an oxo, a thio, an imine, or a substituted imine. Related structural variants are described with parameterized forms for k, k′, X, and X′, together with embodiments in which Ra and Ra′ are H, C1-3 alkyl, or absent.
The disclosed subject matter describes producing the modified antibody by reacting reduced interchain cysteine-cysteine disulfide thiols with a bifunctional electrophile. The resulting homogeneous modified antibody contains cysteine residues linked via a thioester or related attachment and is characterized by structural formulas (II and subclasses (IIa-IIe)), with a stability rationale directed to avoiding reformation of interchain disulfides relative to monofunctional maleimide approaches.
Claims Coverage
The independent claim is directed to a modified antibody defined by formula (IIa), with core structural limitations expressed through the cysteine origin from reduced interchain disulfide bonds, the integer n (1-13), the single/double bond option, and the R/R′ substituent constraints. Dependent claims further refine the depicted bond type, narrow substituent selections, and restrict the antibody target to cancer-antigen-specific antibodies including enumerated named monoclonal antibodies, for a total of 8 inventive features.
Modified antibody defined by formula IIa with cysteine residues from reduced interchain disulfide
A modified antibody represented by formula (IIa) in which A is an antibody or antibody fragment; the two depicted cysteine residues are from at least one reduced interchain cysteine-cysteine disulfide bond in A; n is an integer from 1 to 13; and the depicted bond represents a single or a double bond.
Substituent constraints on R and R′ in the modified antibody
In the modified antibody of formula (IIa), each R and R′ is independently hydrogen or C1-6 alkyl, wherein one or more carbons in the C1-6 alkyl are optionally substituted by a group selected from an oxo, a thio, an imine, and a substituted imine.
Single depicted bond variant
The modified antibody is defined such that the specified depicted bond is a single bond.
n set to 4
The modified antibody has the parameter n set to 4.
Substituent narrowing for Ra and Ra′ under a refined structure
In the modified antibody of formula (IId), Ra and Ra′ are each independently hydrogen, C1-3 alkyl, or absent.
Cancer-antigen-specific antibody as A
The modified antibody has A as an antibody that is specific to a cancer antigen.
A selected from a listed set of named monoclonal antibodies
The antibody or antibody fragment A is selected from a listed set of monoclonal antibody names including alemtuzumab, anitumumab, bevacizumab, brentuximab, cetuximab, gemtuzumab, glembatumumab, inotuzumab, ipilimumab, lovortuzumab, milatuzumab, ofatumumab, rituximab, tositumomab, and trastuzumab.
Across the independent claim and its dependencies, the coverage centers on modified antibodies of formula (IIa) defined by the origin of cysteine residues from reduced interchain cysteine-cysteine disulfide bonds, linkage characterization through n and a single/double bond, and substituent constraints on R/R′. Dependent claims narrow bond type, fix n, restrict substituent classes, and limit A to cancer-antigen-specific antibodies including enumerated named monoclonal antibodies.
Stated Advantages
Enhanced stability via a covalent staple/snap linkage of the homogeneous modified antibody conjugate.
Improved homogeneity.
Comparable potency/binding in vitro.
Comparable potency/binding in vivo.
Improving stability and avoiding reformation of interchain disulfides relative to monofunctional maleimide approaches.
Documented Applications
Treatment of cancer, tumor, and cell proliferative disorder using a therapeutically effective amount framework.
Assessment of improved homogeneity and comparable potency/binding using Ellman’s colorimetric assay, cell ELISA, ATP Lite, and murine xenograft models.
Cancer treatment formulations in humans, including use of the disclosed modified antibodies in such contexts.
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