Compositions and methods for the treatment of HER2-expressing solid tumors
Inventors
Wood, Lauren V. • Roberson, Brenda D. • Berzofsky, Jay A. • Morris, John C. • Steel, Jason C. • Terabe, Masaki • Brenner, Malcolm K.
Assignees
Baylor College of Medicine • US Department of Health and Human Services
Publication Number
US-11266726-B2
Publication Date
2022-03-08
Expiration Date
2036-10-31
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Abstract
Recombinant adenoviruses expressing the extracellular (EC) and transmembrane (TM) domains of human HER2 (HER2ECTM) are described. The recombinant adenoviruses express a chimeric fiber protein having the adenovirus type 35 (Ad5) shaft and knob domains, which facilitates transduction of human dendritic cells by the recombinant HER2ECTM expressing adenovirus. Compositions that include dendritic cells transduced by the recombinant adenovirus and their use for treating HER-positive tumors is described.
Core Innovation
The invention disclosed is a recombinant adenovirus type 5 vector encoding the extracellular (EC) and transmembrane (TM) domains of human HER2 (HER2ECTM) and an adenovirus type 35 fiber protein, specifically a chimeric fiber protein having an Ad5 tail domain and Ad35 shaft and knob domains. This vector, referred to as Ad5f35HER2ECTM or AdHER2, efficiently transduces human dendritic cells due to the Ad35 fiber protein enhancing infection capacity. The transduced dendritic cells express HER2ECTM, which elicits a HER2-specific immune response when administered to a subject. Compositions comprise isolated dendritic cells transduced with this recombinant adenovirus, often cultured with AB allogeneic plasma, pharmaceutically acceptable carriers, and optionally adjuvants.
The problem addressed is the limitation of existing FDA-approved monoclonal antibody therapies (trastuzumab, pertuzumab, and ado-trastuzumab emtansine) for HER2-expressing cancers. These therapies target small portions of the HER2 extracellular domain, require repeated administration every three weeks, may stop working over time, have significant inconvenience and cost, and have known adverse effects such as cardiac toxicity. No current therapy induces a patient to produce their own polyclonal antibodies targeting multiple epitopes of HER2. Therefore, there is a need for new therapies that induce durable, polyclonal immune responses against HER2-positive tumors to overcome treatment resistance, improve efficacy, and reduce treatment burden.
The invention presents a safer and potentially more effective therapeutic vaccine platform. By expressing only the EC and TM domains of human HER2, excluding the intracellular domain responsible for oncogenic activity, the adenoviral vector focuses immune responses on relevant tumor antigenic sites while minimizing safety risks. The use of a chimeric adenovirus fiber enhances transduction efficiency of dendritic cells, which serve as antigen-presenting cells to elicit potent HER2-specific immunity. This approach circumvents limitations of monoclonal antibodies by inducing polyclonal antibody and T cell responses, potentially overcoming resistance observed with current therapies, and reduces the treatment frequency burden by active immune induction.
Claims Coverage
The independent claims cover a recombinant adenovirus nucleic acid molecule, the recombinant adenovirus produced from it, and methods employing adenovirus-transduced dendritic cells for treatment. Three main inventive features are identified.
Recombinant adenovirus encoding HER2 EC and TM domains and Ad35 fiber protein
A nucleic acid molecule encoding the extracellular and transmembrane domains of human HER2 along with an adenovirus type 35 fiber protein, comprising the specific nucleotide sequence SEQ ID NO: 1.
Recombinant adenovirus produced in isolated cells
A recombinant adenovirus generated by transforming isolated cells with the recombinant adenovirus nucleic acid molecule that encodes HER2 EC and TM domains and the Ad35 fiber protein.
Therapeutic method employing autologous dendritic cells transduced with recombinant adenovirus
A method of treating HER2-positive cancer in a subject by administering a composition comprising autologous dendritic cells transduced with the recombinant adenovirus in a pharmaceutically acceptable carrier. The method may include specific fiber protein sequences, adjuvants, cancer types treated, and co-administration of additional therapies such as checkpoint inhibitors, antibodies against immune-inhibitory cytokines, oncolytic viruses, or chemotherapies.
The claims encompass the recombinant adenovirus vector and virus expressing human HER2 EC and TM domains with an Ad35 fiber protein, dendritic cells transduced with this adenovirus, and methods using these cells for treating HER2-positive cancers including various combination therapies.
Stated Advantages
The vaccine induces a polyclonal anti-tumor immune response producing antibodies against multiple HER2 epitopes, potentially overcoming limitations of monoclonal antibodies that target only small extracellular domains.
The recombinant adenovirus displays improved transduction efficiency of human dendritic cells via the chimeric Ad5/Ad35 fiber protein, enhancing immune response elicitation.
Vaccination potentially reduces the need for repeated administration associated with conventional monoclonal antibody therapies, which are inconvenient and costly.
Exclusion of the intracellular domain of HER2, which mediates oncogenic activity, improves safety by minimizing risk of stimulating tumor growth.
Use of AB allogeneic plasma in dendritic cell culture enhances transduction efficiency and expression of HER2, and may augment immune responses through a 'danger signal.'
The vaccine is well tolerated with no significant cardiac toxicity observed in clinical trials, unlike some existing HER2-targeted antibodies.
Documented Applications
Treatment of HER2-positive cancers in subjects, including breast, ovarian, colorectal, prostate, renal cell, bladder, gastroesophageal, non-small cell lung cancers, sarcoma, and ependymoma.
Use as adjuvant therapy following surgery to reduce disease recurrence, and as neoadjuvant therapy before surgery.
Therapeutic vaccination in patients resistant to currently approved HER2-targeted therapies such as trastuzumab, pertuzumab, and ado-trastuzumab emtansine.
Combination therapies with checkpoint inhibitors, antibodies to immune-inhibitory cytokines, oncolytic viruses, other tumor antigen vaccines, chemotherapy, radiation, surgical resection, or β-mannosylceramide.
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