NK cells with an increased antibody-dependent cellular toxicity (ADCC) against tumors
Inventors
Childs, Richard W. • Carlsten, Mattias C. V.
Assignees
US Department of Health and Human Services
Publication Number
US-12188005-B2
Publication Date
2025-01-07
Expiration Date
2035-11-13
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Abstract
Disclosed herein are modified NK cells, compositions comprising modified NK cells, and methods for treating a tumor or hyperproliferative disease in a subject. In some embodiments, the modified NK cells include NK cells including a heterologous nucleic acid molecule encoding a CD16 protein comprising a valine at amino acid position 158 (CD16-V158), a heterologous nucleic acid molecule encoding a CCR7 protein, or both. In some embodiments, methods include treating a subject with a tumor by administering a composition comprising an anti-cancer monoclonal antibody and administering a composition comprising the modified NK cells to the subject. Also disclosed are methods of making modified NK cells by obtaining a population of NK cells from a subject and transfecting the population of NK cells with a heterologous nucleic acid molecule encoding CD16-V158, a heterologous nucleic acid molecule encoding a CCR7 protein, or both.
Core Innovation
Natural killer (NK) cells are immune cells involved in the defense against cancer and can induce strong anti-tumor responses in hematopoietic stem cell transplantation and adoptive NK cell transfer. However, long-term culturing of NK cells causes undesirable phenotypic changes that compromise their homing capacity, cytotoxic function, and in vivo longevity. Genetic manipulation of NK cells via viral transduction is challenging due to reduced viability and low transduction efficiency. Therefore, a need exists for methods to modify NK cells to enhance NK cell-based immunity.
The invention provides modified NK cells, compositions comprising these modified NK cells, and methods for treating tumors or hyperproliferative diseases by administering the modified NK cells to subjects. The modified NK cells include those expressing a heterologous nucleic acid encoding a CD16 protein with valine at amino acid position 158 (CD16-V158), a CCR7 protein, or both. Methods involve obtaining NK cells from a subject or donor, transfecting them with nucleic acids encoding CD16-V158, CCR7, or both, expanding the cells in vitro, and administering them with an anti-cancer monoclonal antibody that binds tumor cells. The electroporation method for transfection is performed using GMP-compliant platforms to maintain viability and function of NK cells.
Claims Coverage
The claims disclose two independent methods of treating subjects with cancers using modified NK cells and therapeutic monoclonal antibodies, presenting four main inventive features related to NK cell modification and administration.
NK cell modification to co-express high-affinity CD16-V158 and CCR7
Obtaining NK cells from a subject or donor and transfecting them with heterologous nucleic acids encoding a CD16 protein comprising valine at position 158 of the mature protein and a CCR7 protein to create modified NK cells.
Blocking CD38 surface antigen on modified NK cells
Treating the modified NK cells with Fab or F(ab)2 fragments of an anti-CD38 monoclonal antibody to produce CD38-blocked modified NK cells before administration.
Administering monoclonal antibody targeting cancer cell antigens prior to modified NK cells
Administering a monoclonal antibody composition that binds to cancer cells expressing a target antigen (e.g., CD38 for multiple myeloma or CD20 for lymphoma) prior to administering the modified NK cells composition.
Administering modified NK cells after monoclonal antibody infusion within a defined time
Administering the composition comprising modified NK cells after administration of the monoclonal antibody to the subject, for example approximately 1-8 hours later.
The claims focus on methods for treating multiple myeloma or lymphoma by using NK cells genetically modified to express CD16-V158 and CCR7, optionally with CD38 blockade, combined with therapeutic monoclonal antibodies administered in a defined sequence to enhance anti-tumor activity.
Stated Advantages
mRNA electroporation provides a rapid, efficient, and non-toxic method to genetically modify ex vivo expanded NK cells without using viral vectors, avoiding associated regulatory and safety issues.
Modified NK cells expressing the high-affinity CD16-V158 receptor enhance antibody-dependent cellular cytotoxicity (ADCC) against tumor cells, including multiple myeloma and lymphoma.
Modified NK cells expressing CCR7 improve homing capacity and migration to lymphoid tissues, targeting hematological malignancies in lymph nodes.
Transfection of NK cells does not significantly decrease viability, proliferation, or cytotoxic function compared to non-transfected controls.
Documented Applications
Treating tumors or hyperproliferative diseases through adoptive transfer of genetically modified NK cells expressing CD16-V158 and/or CCR7 in combination with therapeutic monoclonal antibodies.
Treatment of multiple myeloma by administering CD38-targeting monoclonal antibodies (e.g., daratumumab) along with CD38-blocked, CD16-V158-expressing modified NK cells.
Treatment of lymphomas by administering CD20-targeting monoclonal antibodies (e.g., rituximab or ofatumumab) with modified NK cells expressing CD16-V158 and CCR7.
Use of mRNA electroporation methods for clinical-grade production of modified NK cells for immunotherapy.
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