Genetically modified NK-92 cells and monoclonal antibodies for the treatment of cancer
This invention is directed to treatment of a subject having or suspected of having a cancer comprising administering to the subject a monoclonal antibody and NK-92 expressing Fc receptor.
1. A pharmaceutical composition comprising a population of engineered NK-92 cells and a monoclonal antibody having a cytotoxic effect, wherein the engineered NK-92 cells are genetically modified to express a nucleic acid construct comprising a polynucleotide that encodes a CD16 polypeptide having a valine at position 158 of the mature form of the CD16 polypeptide, and a polynucleotide that encodes an interleukin-2 (IL-2) targeted to the endoplasmic reticulum (ER), wherein the nucleic acid construct is a bicistronic construct comprising the polynucleotide that encodes the CD16 polypeptide and the polynucleotide that encodes the IL-2 targeted to the ER.
2. The pharmaceutical composition of claim 1 , wherein the bicistronic construct comprises, in the 5′ to 3′ direction: the polynucleotide encoding the CD16 polypeptide, an IRES, and the polynucleotide encoding the IL-2 targeted to the ER.
3. The pharmaceutical composition of claim 1 , wherein the CD16 polypeptide comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:2 and comprises valine at position 158.
4. The pharmaceutical composition of claim 1 , wherein the CD16 polypeptide comprises the amino acid sequence of SEQ ID NO:2.
5. The pharmaceutical composition of claim 1 , wherein the population of genetically modified NK-92 cells is further modified to express a suicide gene.
6. The pharmaceutical composition of claim 5 , wherein the population of NK-92 cells is genetically modified to express an inducible caspase 9 suicide gene.
7. The pharmaceutical composition of claim 1 , formulated for administration to a human subject.
8. The pharmaceutical composition of claim 1 , formulated for administration of the population of genetically modified NK-92 cells in a number of up to 10 billion per infusion.
9. The pharmaceutical composition of claim 1 , formulated for intravenous administration to a subject.
10. The pharmaceutical composition of claim 1 , formulated for injection into the bone marrow of a subject.
11. The pharmaceutical composition of claim 1 , wherein the monoclonal antibody is a naked monoclonal antibody of an IgG subtype that induces ADCC.
12. The pharmaceutical composition of claim 11 , wherein the monoclonal antibody is alemtuzumab, rituximab, trastuzumab, avelumab, daratumumab or elotuzumab.