Composition comprising antibody that binds to domain II of HER2 and acidic variants thereof
Patent No. US9181346 (titled "Composition comprising antibody that binds to domain II of HER2 and acidic variants thereof") on Jan 23, 2014. The application was issued on Nov 10, 2015.
What is this patent about?
’346 is related to the field of targeted cancer immunotherapy, specifically focusing on the production and therapeutic use of antibody compositions that target the HER2 receptor. The invention addresses the technical challenge of managing protein heterogeneity in monoclonal antibodies, such as Pertuzumab, which naturally form various chemical isomers and variants during cell culture and manufacturing processes.
The underlying idea behind ’346 is that a therapeutic HER2 antibody composition can remain clinically effective and safe even when it contains a specific profile of acidic variants. The inventor discovered that these variants—which differ from the primary antibody species due to chemical modifications like glycation or disulfide bond changes—exhibit pharmacokinetics and biological potency equivalent to the main antibody, provided their total concentration is controlled.
The claims of ’346 focus on methods of treating HER2-positive cancers using pharmaceutical formulations that contain a main species antibody defined by specific variable light and heavy chain sequences (SEQ ID Nos. 3 and 4) alongside a defined set of acidic variants. These independent claims specifically protect the use of compositions where the main antibody is accompanied by variants such as non-reducible, disulfide-reduced, glycated, deamidated, or sialylated forms.
In practice, the invention works by administering a formulation where the antibody binds to Domain II of the HER2 receptor, thereby sterically hindering the receptor's ability to dimerize with other HER family members like EGFR or HER3. This mechanism effectively shuts down the downstream signaling pathways, such as MAPK and Akt, that drive tumor cell proliferation. The composition is typically produced in CHO cells and purified to ensure the variant distribution matches the specified therapeutic profile.
This approach differs from prior solutions by providing a precise characterization of the heterogeneous landscape of the antibody product rather than treating variants simply as impurities to be removed. By identifying that these specific acidic modifications do not compromise the drug’s behavior in the body, the invention allows for a more robust manufacturing process that ensures consistent therapeutic performance across different production batches.
How does this patent fit in bigger picture?
Technical Landscape
In the late 2000s when ’346 was filed, the production of therapeutic monoclonal antibodies was typically implemented using large-scale mammalian cell culture systems that inherently generated a heterogeneous mixture of protein products. At a time when systems commonly relied on standard ion-exchange chromatography for purity assessment, the characterization of antibody heterogeneity was often limited to broad categories of charge variants. Engineering constraints made the precise identification and quantification of specific molecular species—such as those resulting from glycation, deamidation, or incomplete disulfide bond formation—non-trivial, particularly when attempting to maintain batch-to-batch consistency for complex antibodies targeting specific receptor domains.
Prosecution Position
The disclosed invention represents a technical advancement in the stabilization and characterization of HER2 antibody compositions, specifically those binding to domain II. The solution is rooted in an architectural refinement of the antibody composition itself, where the total amount of specific acidic variants—including glycated, disulfide reduced, and non-reducible species—is strictly controlled to remain below a defined threshold. This integration of specific variant monitoring, such as the identification of sialylated and deamidated forms alongside main species antibodies, enables a technical capability to ensure consistent pharmacokinetics between the predominant antibody and its variants. By defining and limiting these specific structural heterogeneities, the invention overcomes the technical constraint of functional variability in complex biologics, ensuring that the therapeutic composition maintains a uniform biological profile.
Claims
The patent contains a total of 26 claims, with claims 1, 11, and 16 serving as the independent claims. These independent claims focus on methods for treating HER2 positive cancers, specifically breast cancer, by administering pharmaceutical formulations that contain a primary HER2 antibody species along with specific acidic variants, such as disulfide reduced and non-reducible variants. The dependent claims serve to further refine the therapeutic methods by specifying additional antibody variants, defining pharmacokinetic properties, limiting the percentage of acidic variants within the composition, identifying specific amino acid sequences, and incorporating the administration of secondary HER2 antibodies like Trastuzumab.
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US9181346
- Application Number
- US14162208A
- Filing Date
- Jan 23, 2014
- Publication Date
- Nov 10, 2015
- External Links
- Slate, USPTO , Google Patents