Claims for Patent: 10,335,486

Summary for Patent: 10,335,486

Title:	MRNA combination therapy for the treatment of cancer
Abstract:	The present disclosure relates to the use of nucleic acid (e.g., mRNA) combination therapies for the treatment of cancer. The disclosure provides compositions, and methods for their preparation, manufacture, and therapeutic use, wherein those compositions comprise at least two polynucleotides (e.g., mRNAs) in combination wherein the at least two polynucleotides are selected from the group consisting of (i) a polynucleotide encoding an immune response primer (e.g., IL23), (ii) a polynucleotide encoding an immune response co-stimulatory signal (e.g., OX40L), (iii) a polynucleotide encoding a checkpoint inhibitor (e.g., an anti CTLA-4 antibody), and, (iv) a combination thereof. The therapeutic methods disclosed herein comprise, e.g., the administration of a combination therapy disclosed herein for the treatment of cancer, e.g., by reducing the size of a tumor or inhibiting the growth of a tumor, in a subject in need thereof. In some aspects, the combination therapies disclosed herein disclosed are administered intratumorally.
Inventor(s):	Frederick; Joshua P. (Boston, MA), Hewitt; Susannah (Jamaica Plain, MA), Bai; Ailin (Newton, MA), Hoge; Stephen G. (Brookline, MA), Presnyak; Vladimir (Cambridge, MA), McFadyen; Iain (Arlington, MA), Benenato; Kerry (Sudbury, MA), Kumarasinghe; Ellalahewage Sathyajith (Harvard, MA)
Assignee:	ModernaTX, Inc. (Cambridge, MA)
Application Number:	15/996,146
Patent Claims:	1. A method for treating cancer in a subject by inducing or enhancing an anti-tumor immune response, comprising administering to the subject a first messenger RNA (mRNA) encoding an IL-23 polypeptide comprising an IL-12p40 polypeptide operably linked, with or without a linker, to an IL-23p19 polypeptide, a second mRNA encoding an IL-18 polypeptide, and a third mRNA encoding an OX40L polypeptide, thereby treating cancer in the subject by inducing or enhancing an anti-tumor immune response. 2. The method of claim 1, wherein the IL-23 polypeptide comprises an IL-12p40 polypeptide operably linked via a linker to an IL-23p19 polypeptide, and wherein the linker is a Gly/Ser linker. 3. The method of claim 1, wherein the IL-23 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 983, wherein the IL-18 polypeptide comprises the amino acid sequence as set forth in SEQ ID NO: 581, and wherein the OX40L polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1160 and 1161. 4. The method of claim 1, wherein (i) the first mRNA encoding an IL-23 polypeptide comprises an open reading frame, wherein the open reading frame comprises a nucleotide sequence at least 90% identical to the nucleotide sequence as set forth in SEQ ID NO: 984; (ii) the second mRNA encoding an IL-18 polypeptide comprises an open reading frame, wherein the open reading frame comprises a nucleotide sequence at least 90% identical to the nucleotide sequence set forth in SEQ ID NO: 582; and (iii) the third mRNA encoding an OX40L polypeptide comprises an open reading frame, wherein the open reading frame comprises a nucleotide sequence at least 90% identical to the nucleotide sequence as set forth in SEQ ID NO: 1163. 5. The method of claim 4, wherein the first mRNA, second mRNA and third mRNA each comprise a 3' untranslated region (UTR) comprising at least one microRNA-122 (miR-122) binding site. 6. The method of claim 5, wherein the miR-122 binding site is a miR-122-5p binding site, and wherein the miR-122-5p binding site comprises the nucleotide sequence as set forth in SEQ ID NO: 26. 7. The method of claim 4, wherein the first, second and third mRNA comprise a 5'UTR comprising the nucleotide sequence set forth in SEQ ID NO: 1216 and a 3'UTR comprising the nucleotide sequence as set forth in SEQ ID NO: 1253. 8. The method of claim 1, wherein the first, second and third mRNAs are chemically modified. 9. The method of claim 8, wherein the first, second and third mRNAs are fully modified with chemically-modified uridines. 10. The method of claim 8, wherein the first, second and third mRNAs are fully modified with N1-methylpseudouridine. 11. The method of claim 1, wherein the first, second and third mRNAs are formulated in separate lipid nanoparticles. 12. The method of claim 11, wherein the lipid nanoparticles are administered simultaneously or sequentially. 13. The method of claim 1, wherein the first, second and third mRNAs are formulated in the same lipid nanoparticle. 14. The method of claim 1, comprising administering a checkpoint inhibitor polypeptide, wherein the checkpoint inhibitor polypeptide inhibits PD1, PD-L1, CTLA4, or a combination thereof, and wherein the checkpoint inhibitor polypeptide is an antibody or antigen-binding fragment thereof. 15. The method of claim 14, wherein the antibody is an anti-CTLA4 antibody or antigen-binding fragment thereof that specifically binds CTLA4, an anti-PD1 antibody or antigen-binding fragment thereof that specifically binds PD1, an anti-PD-L1 antibody or antigen-binding fragment thereof that specifically binds PD-L1, or a combination thereof. 16. The method of claim 15, wherein the anti-PD-L1 antibody is atezolizumab, avelumab, or durvalumab, wherein the anti-CTLA-4 antibody is tremelimumab or ipilimumab, and wherein the anti-PD1 antibody is nivolumab or pembrolizumab. 17. The method of claim 3, wherein (i) the first mRNA encoding an IL-23 polypeptide comprises an open reading frame, wherein the open reading frame comprises a nucleotide sequence at least 90% identical to the nucleotide sequence as set forth in SEQ ID NO: 984; (ii) the second mRNA encoding an IL-18 polypeptide comprises an open reading frame, wherein the open reading frame comprises a nucleotide sequence at least 90% identical to the nucleotide sequence set forth in SEQ ID NO: 582; and (iii) the third mRNA encoding an OX40L polypeptide comprises an open reading frame, wherein the open reading frame comprises a nucleotide sequence at least 90% identical to the nucleotide sequence as set forth in SEQ ID NO: 1163. 18. A method for treating cancer in a subject by inducing or enhancing an anti-tumor immune response, comprising administering to the subject a lipid nanoparticle comprising a first messenger RNA (mRNA) encoding an IL-23 polypeptide comprising an IL-12p40 polypeptide operably linked, with or without a linker, to an IL-23p19 polypeptide, a second mRNA encoding an IL-18 polypeptide, and a third mRNA encoding an OX40L polypeptide, thereby treating cancer in the subject by inducing or enhancing an anti-tumor immune response. 19. The method of claim 18, wherein the IL-23 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 983, wherein the IL-18 polypeptide comprises the amino acid sequence as set forth in SEQ ID NO: 581, and wherein the OX40L polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1160 and 1161. 20. The method of claim 18, wherein, (i) the first mRNA encoding an IL-23 polypeptide comprises an open reading frame, wherein the open reading frame comprises a nucleotide sequence at least 90% identical to the nucleotide sequence as set forth in SEQ ID NO: 984; (ii) the second mRNA encoding an IL-18 polypeptide comprises an open reading frame, wherein the open reading frame comprises a nucleotide sequence at least 90% identical to the nucleotide sequence set forth in SEQ ID NO: 582; and (iii) the third mRNA encoding an OX40L polypeptide comprises an open reading frame, wherein the open reading frame comprises a nucleotide sequence at least 90% identical to the nucleotide sequence as set forth in SEQ ID NO: 1163. 21. The method of claim 20, wherein the first, second and third mRNAs comprise a 5'UTR comprising the nucleotide sequence set forth in SEQ ID NO: 1216 and a 3'UTR comprising the nucleotide sequence as set forth in SEQ ID NO: 1253. 22. The method of claim 21, wherein the first, second and third mRNAs are fully modified with N1-methylpseudouridine. 23. The method of claim 19, wherein, (i) the first mRNA encoding an IL-23 polypeptide comprises an open reading frame, wherein the open reading frame comprises a nucleotide sequence at least 90% identical to the nucleotide sequence as set forth in SEQ ID NO: 984; (ii) the second mRNA encoding an IL-18 polypeptide comprises an open reading frame, wherein the open reading frame comprises a nucleotide sequence at least 90% identical to the nucleotide sequence set forth in SEQ ID NO: 582; and (iii) the third mRNA encoding an OX40L polypeptide comprises an open reading frame, wherein the open reading frame comprises a nucleotide sequence at least 90% identical to the nucleotide sequence as set forth in SEQ ID NO: 1163.

Details for Patent 10,335,486

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bristol-myers Squibb Company	YERVOY	ipilimumab	Injection	125377	03/25/2011		2036-05-18
Merck Sharp & Dohme Corp.	KEYTRUDA	pembrolizumab	For Injection	125514	09/04/2014		2036-05-18
Merck Sharp & Dohme Corp.	KEYTRUDA	pembrolizumab	Injection	125514	01/15/2015		2036-05-18
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	12/22/2014		2036-05-18
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	10/04/2017		2036-05-18
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	08/27/2021		2036-05-18
Genentech, Inc.	TECENTRIQ	atezolizumab	Injection	761034	05/18/2016		2036-05-18