Methods and compositions for inhibiting polyomavirus-associated pathology
Inventors
Buck, Christopher B. • Pastrana, Diana V.
Assignees
US Department of Health and Human Services
Publication Number
US-9764022-B2
Publication Date
2017-09-19
Expiration Date
2032-07-17
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Abstract
Disclosed herein are methods of eliciting an immune response against a polyomavirus (for example, BKV serotype I (BKV-I), BKV serotype II (BKV-II), BKV serotype III (BKV-III) and/or BKV serotype IV (BKV-IV)) and methods of treating or inhibiting polyomavirus-associated pathology (such as polyomavirus-associated nephropathy, BKV-associated hemorrhagic cystitis, or JC virus-associated progressive multifocal leukoencephalopathy; PML). Further disclosed are immunogenic compositions of use in the disclosed methods. Also disclosed are methods of selecting an organ transplant donor and/or recipient including detecting whether the prospective donor and/or recipient has BKV serotype-specific (such as BKV serotype IV-specific) neutralizing antibodies.
Core Innovation
The invention provides methods of eliciting an immune response against polyomaviruses, particularly BK polyomavirus (BKV) serotypes I, II, III, and IV, by administering immunogenic compositions comprising capsid polypeptides or nucleic acids encoding such polypeptides from multiple BKV serotypes. These methods also extend to treating, inhibiting, or preventing polyomavirus-associated pathologies such as polyomavirus-associated nephropathy (PVAN), BKV-associated hemorrhagic cystitis, and JC virus-associated progressive multifocal leukoencephalopathy (PML). Furthermore, the invention includes methods for selecting organ transplant donors and recipients based on detection of BKV serotype-specific neutralizing antibodies.
The problem addressed arises from the limitations in current understanding and management of BKV infections, particularly in immunocompromised individuals such as organ transplant recipients. While nearly all adults are believed to be seropositive for BKV, earlier assumptions that seropositivity to one BKV serotype confers protection against others have been challenged. The invention recognizes the need for improved diagnostic and immunization strategies due to the existence of multiple BKV serotypes with limited cross-reactivity, which can lead to transplantation complications like PVAN and graft loss. Current treatments and monitoring strategies inadequately prevent or address infection by less common BKV serotypes, and intravenous immunoglobulin (IVIG) therapy's role in treating PVAN remains unclear.
The invention thus discloses compositions including one or more capsid polypeptides (VP1, VP2, VP3) from multiple BKV serotypes or subtypes to elicit genotype-specific neutralizing antibodies. It highlights the lack of cross-neutralization between BKV serotypes and the distinct immunogenic profiles of subtypes, indicating that vaccination with a single serotype polypeptide is insufficient for full protection. The methods cover the detection of serotype-specific neutralizing antibodies in donors and recipients to improve transplant selection and personalize immunization approaches, thereby aiming to reduce morbidity and mortality associated with polyomavirus infections in immunocompromised individuals.
Claims Coverage
The patent features two independent claims focusing on eliciting genotype-specific neutralizing antibody responses to BK polyomaviruses by administering isolated capsid polypeptides or nucleic acids encoding them. The main inventive features include specific combinations of BKV serotype polypeptides and their modes of administration to achieve targeted immune responses.
Administering BKV-Ib2 and BKV-IV capsid polypeptides to elicit type-specific neutralizing antibodies
A method of eliciting neutralizing antibody responses in a subject seropositive for BKV-Ia but not BKV-Ib2, by administering therapeutically effective amounts of isolated BKV-Ib2 capsid polypeptide or encoding nucleic acid, and at least one isolated BKV genotype IV capsid polypeptide or encoding nucleic acid, thereby producing both BKV-Ib2- and BKV-IV-specific neutralizing antibodies.
Concurrent or sequential administration of BKV-Ib2 and BKV-IV capsid polypeptides as virus-like particles
The administration of the BKV-Ib2 and BKV-IV capsid polypeptides can be carried out concurrently or sequentially, with at least one polypeptide administered as a virus-like particle (VLP) comprising the respective capsid proteins.
Inclusion of BKV genotype II and III capsid polypeptides for broader immunization
Methods further encompass administering therapeutically effective amounts of isolated BKV-II and/or BKV-III capsid polypeptides or encoding nucleic acids distinct from each other and from BKV-Ib2 and BKV-IV polypeptides to elicit neutralizing antibodies against these genotypes.
Incorporation of JC polyomavirus capsid polypeptides to elicit immune responses
Methods optionally include administering JC polyomavirus (JCV) capsid polypeptides or encoding nucleic acids along with BKV polypeptides to induce neutralizing antibodies against JCV.
Use of adjuvants and treatment of immunocompromised or transplant subjects
The methods may comprise co-administration of adjuvants and are designed particularly for immunocompromised subjects, subjects treated with or candidates for immunosuppressants, or organ transplant recipients or candidates.
Specific amino acid sequences defining capsid polypeptides for use in immunization
The BKV-Ib2 and BKV-IV capsid polypeptides utilized have defined amino acid sequences (e.g., SEQ ID NOs: 14, 75-93 for BKV-Ib2; SEQ ID NOs: 4-6, 16, 110-125 for BKV-IV), ensuring precise immunogenic targets for eliciting neutralizing antibodies.
The independent claims cover methods of eliciting genotype-specific neutralizing antibodies against various BKV serotypes by administering isolated capsid polypeptides or nucleic acids encoding them, alone or in combinations, including JC polyomavirus capsid proteins, with administration in VLP form and optionally with adjuvants, targeting immunocompromised or transplant recipients to improve immune protection against polyomavirus-associated pathologies.
Stated Advantages
Induces genotype-specific neutralizing antibodies that overcome limited cross-reactivity among BKV serotypes, enhancing protective immunity.
Improves prevention and treatment of polyomavirus-associated diseases such as PVAN and PML in immunocompromised subjects and transplant recipients.
Allows selection of organ transplant donors and recipients based on serotype-specific neutralizing antibody status, reducing risk of infection or reinfection by different BKV serotypes.
Documented Applications
Eliciting immune responses to multiple BKV serotypes to prevent or treat BKV infections and associated diseases like polyomavirus-associated nephropathy and hemorrhagic cystitis.
Treating or inhibiting JC virus-associated progressive multifocal leukoencephalopathy (PML) through immunization with JCV capsid polypeptides.
Screening and selecting renal transplant donors and recipients by detecting BKV serotype-specific neutralizing antibodies to improve transplant success and reduce viral complications.
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