Modified yeast-brachyury immunotherapeutic compositions
Inventors
King, Thomas H. • Guo, Zhimin • Schlom, Jeffrey • Palena, Claudia
Assignees
GlobeImmune Inc • US Department of Health and Human Services
Publication Number
US-11065313-B2
Publication Date
2021-07-20
Expiration Date
2036-08-01
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Disclosed are improved yeast-based immunotherapeutic compositions comprising modified Brachyury antigens, and methods for the prevention and/or treatment of cancers characterized by the expression or overexpression of Brachyury.
Core Innovation
The invention relates to improved yeast-Brachyury immunotherapeutic compositions and methods for prevention and/or treatment of cancers characterized by the expression or overexpression of Brachyury. These compositions comprise a yeast vehicle and at least one modified Brachyury antigen with reduced or abolished DNA binding activity compared to wild-type Brachyury, achieved by mutation such as deletion or substitution within the DNA binding region. The invention also covers uses of these compositions to treat or prevent such cancers and methods to improve manufacture and use of these immunotherapeutic compositions.
The problem being addressed is that Brachyury is a transcription factor involved in early development and metastatic progression of cancer, expressed in many human tumors including chordomas and metastatic cancers. While Brachyury is a newly recognized target for cancer immunotherapy, existing yeast-Brachyury immunotherapeutic products that contain unmodified Brachyury antigen retain DNA binding activity and have manufacturing challenges, including a robust yeast flocculation phenotype leading to cell aggregation during production. There remains a need for new immunotherapeutic products that effectively treat or prevent cancers associated with Brachyury expression, with improved manufacturability and immunogenicity.
Claims Coverage
The patent includes seven main inventive features centered on yeast-based immunotherapeutic compositions and methods related to modified Brachyury antigens.
Yeast-Brachyury immunotherapeutic composition with modified Brachyury antigen
A composition comprising a yeast and at least one modified Brachyury antigen expressed by the yeast, where the modified antigen comprises specified sequences (SEQ ID NO:10 or SEQ ID NO:13 or their partial sequences) differing from wild-type by deletion of amino acid positions 198-222, resulting in disrupted DNA binding.
Reduced yeast flocculation phenotype
The yeast expressing the modified Brachyury antigen have a reduced flocculation phenotype compared to yeast expressing wild-type Brachyury, improving manufacturability.
Fusion protein incorporation
The modified Brachyury antigen can be expressed as a fusion protein comprising amino acid sequences SEQ ID NO:12 or SEQ ID NO:15, which include stabilizing peptides and tags.
Pharmaceutical formulation compatibility
The immunotherapeutic composition can be formulated in a pharmaceutically acceptable excipient suitable for administration to a subject.
Whole inactivated yeast expressing fusion protein
A composition comprising whole, inactivated yeast expressing a Brachyury fusion protein of positions 2-410 of SEQ ID NO:10 that elicits a Brachyury-specific T cell response.
Whole inactivated yeast expressing alternative fusion protein
A composition comprising whole, inactivated yeast expressing a Brachyury fusion protein of positions 2-410 of SEQ ID NO:13 that elicits a Brachyury-specific T cell response.
Methods for treating cancer and related conditions
Methods of treating Brachyury-expressing cancer, metastatic cancer progression, chemotherapy- or radiation-resistance, or EBV-associated B-cell lymphoma by administering the yeast-Brachyury immunotherapeutic compositions as described.
The claims cover yeast-based immunotherapeutic compositions expressing modified Brachyury antigens with disrupted DNA binding and reduced yeast flocculation, fusion protein embodiments, pharmaceutical formulations, and methods to treat Brachyury-related cancers and conditions, highlighting improved immunogenicity and manufacturability.
Stated Advantages
Modified Brachyury antigens disrupt DNA binding activity while retaining immunogenicity.
Yeast expressing modified Brachyury antigens exhibit reduced flocculation phenotype, simplifying manufacturing.
Enhanced expression levels of Brachyury antigen in yeast compared to unmodified antigens.
Compositions elicit Brachyury-specific T cell responses without exogenous adjuvants or immunostimulatory molecules.
Potential to prevent or delay metastatic progression and chemotherapy or radiation resistance in cancers.
Documented Applications
Use of yeast-Brachyury immunotherapeutic compositions for prevention and treatment of cancers expressing Brachyury, including breast cancer, chordoma, metastatic and late-stage cancers, and B cell tumors such as CLL and lymphomas.
Treatment to reduce, arrest, reverse, or delay metastatic progression of cancer.
Use as adjunct to chemotherapy and/or radiation therapy to reduce therapy resistance.
Treatment of chordoma, a Brachyury-expressing rare bone cancer.
Treatment of diseases associated with Epstein Barr Virus infection, including EBV-associated B-cell lymphoma.
Interested in licensing this patent?