Single-chain Knobs-in-holes Bispecific Antibody Construction

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Unmet Need: In the United States, 40% of males and 38% of females will develop cancer in their lifetimes. Additionally, as of 2015, the annual direct medical costs of cancer stood at $80.2 billion. Targeted therapies, such as monoclonal antibody drugs, show great promise in cancer treatment, but these therapies still have many important limitations including acquired resistance, in which tumor cells can circumvent susceptibility to the antibody by mutating the target antigen or utilizing alternative escape pathways. Consequently, novel therapies with superior selectivity, specificity, and robustness against resistance are needed to improve cancer care and patient survival rates. One potential strategy to overcome current limitations is through development of bispecific antibodies (BsAbs) that engage two different target receptors to recruit multiple anti-cancer mechanisms with a single drug. However, high-yield and compact formats for BsAb production are needed to realize the full potential of this strategy.

Technology Overview: Johns Hopkins researchers have developed a new format to express a bivalent, bispecific antibody that combines the previously established knob-in holes strategy and single-chain Fab strategy to produce a more versatile and compact BsAb format that leads to equivalent or superior recombinant protein expression levels compared to monoclonal antibodies. This format has been used to express BsAbs with dual specificity for the IL-6 and IL-8 receptors to selectively target the synergistic IL-6/IL-8 pathway that drives the migration of tumorigenic, metastatic cells. The inventors have also used this format to express multispecific antibodies targeting other tumor-associated antigens for a variety of applications in cancer therapy. The bispecific strategy allows for enhanced binding to both cell surface targets, resulting in synergetic suppression of disease, while minimizing off-target effects by favoring interactions with only tumor cells that express both receptors. The bispecific approach also reduces the likelihood of acquired resistance through mutational escape, and addresses important downstream manufacturing concerns by eliminating the need for optimizing dosing ratios, which would be required for mixed-agent therapy. The initial formulations are designed for oncology, but the bispecific approach can be readily extended to a vast scope of other diseases, such as autoimmune disorders, infectious diseases, neurodegenerative conditions, and cardiovascular diseases.

Stage of Development: The inventors have generated BsAbs using their novel bivalent, bispecific format and demonstrated yields equivalent to or greater than those of monoclonal antibodies. In vitro binding studies revealed that bispecific antibodies targeting the IL-6 and IL-8 receptors bind both receptors independently. Moreover, these BsAbs reduced 3D cell migration and inhibited tumor metastasis in mice, even more effectively than monoclonal antibody therapy or antibody/small molecule combination treatments. Further in vivo research on a variety of antibodies that employ this versatile, compact antibody format will be required to advance this technology into clinical studies for a range of biomedical applications.
Patent Information:
Title App Type Country Serial No. Patent No. File Date Issued Date Expire Date Patent Status
BISPECIFIC BINDING AGENTS PCT: Patent Cooperation Treaty United Kingdom 2118101.1   5/29/2020     Pending
BISPECIFIC BINDING AGENTS PCT: Patent Cooperation Treaty United States 17/614,864   11/29/2021     Pending
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