# US 12,599,660 B2 · Therapeutic RNA for HPV-positive cancer

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- Number: US 12,599,660 B2
- Document ID: US12599660B2
- Status: Granted
- Kind: B2
- Application number: 18/012,366
- Filed: 2021-07-06
- Published: 2025-08-21
- Granted: 2026-04-14
- Earliest claimed: 2020-07-07
- Assignees: BioNTech SE; TRON-Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg-Universität Mainz gGmbH
- Applicants: BioNTech SE; TRON-Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg-Universität Mainz Gemeinnützige GMBH
- Inventors: Ugur Sahin; Sebastian Kreiter; Mustafa Diken; Fulvia Vascotto; Nadja Salomon; Christian Grunwitz
- Web page: https://patentgrep.com/patent/US12599660B2

## CPC

- A61K 39/12: Viral antigens
- A61K 33/243: Platinum; Compounds thereof
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 31/20: for DNA viruses
- A61P 35/00: Antineoplastic agents
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/53: {DNA (RNA) vaccination}
- A61K 2039/54: {characterised by the route of administration}
- A61K 2039/55555: {Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers}
- A61K 2039/605: {MHC molecules or ligands thereof}
- C12N 2710/20034: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

This disclosure relates to the field of therapeutic RNA to treat HPV-positive cancer, in particular anogenital, cervical and penile cancers and cancer in the head and neck region such as cancer in the genital region and head and neck squamous cell carcinoma (HNSCC). Disclosed herein are compositions, uses, and methods for treatment of HPV-positive cancers. Administration of therapeutic RNAs to a patient having HPV-positive cancer disclosed herein can reduce tumor size, prolong time to progressive disease, and/or protect against metastasis and/or recurrence of the tumor and ultimately extend survival time.

## Claims

### Claim 1

A composition or medical preparation comprising at least one RNA, wherein the at least one RNA encodes:
(i) an amino acid sequence comprising human papillomavirus (HPV) E6 protein, an immunogenic variant thereof, or an immunogenic fragment of the HPV E6 protein or the immunogenic variant thereof; and
(ii) an amino acid sequence comprising HPV E7 protein, an immunogenic variant thereof, or an immunogenic fragment of the HPV E7 protein or the immunogenic variant thereof;
wherein (a) the RNA encoding the amino acid sequence under (i) comprises at least one of: the nucleotide sequence of SEQ ID NO: 2, a nucleotide sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identity to the nucleotide sequence of SEQ ID NO: 2,
a nucleotide sequence encoding the amino acid sequence of amino acids 37 to 194 of SEQ ID NO: 1, and a nucleotide sequence encoding an amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identity to the amino acid sequence of amino acids 37 to 194 of SEQ ID NO: 1; or
(b) the RNA encoding the amino acid sequence under (ii) comprises at least one of: the nucleotide sequence of SEQ ID NO: 4, a nucleotide sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identity to the nucleotide sequence of SEQ ID NO: 4,
a nucleotide sequence encoding the amino acid sequence of amino acids 37 to 134 of SEQ ID NO: 3, and a nucleotide sequence encoding an amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identity to the amino acid sequence of amino acids 37 to 134 of SEQ ID NO: 3.

### Claim 2 (depends on 1)

The composition or medical preparation of claim 1, wherein each of the amino acid sequences under (i), or (ii) is encoded by a separate RNA.

### Claim 3 (depends on 1)

The composition or medical preparation of claim 1, wherein at least one amino acid sequence under (i), or (ii) comprises an amino acid sequence enhancing at least one of: antigen processing, and presentation.

### Claim 4 (depends on 3)

The composition or medical preparation of claim 3, wherein the amino acid sequence enhancing at least one of: antigen processing, and presentation comprises an amino acid sequence corresponding to the transmembrane and cytoplasmic domain of a MHC molecule, preferably a MHC class I molecule comprising the amino acid sequence of SEQ ID NO: 26, or an amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identity to the amino acid sequence of SEQ ID NO: 26.

### Claim 5 (depends on 1)

The composition or medical preparation of claim 1, wherein at least one amino acid sequence under (i), or (ii) comprises an amino acid sequence which breaks immunological tolerance or at least one RNA is co-administered with RNA encoding an amino acid sequence which breaks immunological tolerance.

### Claim 6 (depends on 5)

The composition or medical preparation of claim 5, wherein the amino acid sequence which breaks immunological tolerance comprises helper epitopes, preferably tetanus toxoid-derived helper epitopes comprising the amino acid sequence of SEQ ID NO: 27, or an amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identity to the amino acid sequence of SEQ ID NO: 27.

### Claim 7 (depends on 1)

The composition or medical preparation of claim 1, wherein at least one of the amino acid sequences under (i), or (ii) is encoded by a coding sequence which modified by at least one of: codon-optimization and increase of the G/C content compared to wild type coding sequence, wherein the codon-optimization and the increase in the G/C content preferably does not change the sequence of the encoded amino acid sequence.

### Claim 8 (depends on 1)

The composition or medical preparation of claim 1, wherein at least one RNA comprises at least one of:
(a) the 5′ cap m27,2′-OGppsp (5′) G,
(b) a 5′ UTR comprising the nucleotide sequence of SEQ ID NO: 30, or a nucleotide sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identity to the nucleotide sequence of SEQ ID NO: 30,
(c) a 3′ UTR comprising the nucleotide sequence of SEQ ID NO: 31, or a nucleotide sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identity to the nucleotide sequence of SEQ ID NO: 31, and
(d) a poly-A sequence, wherein the poly-A sequence comprises at least 100 nucleotides, wherein further the poly-A sequence comprises the nucleotide sequence of SEQ ID NO: 32.

### Claim 9 (depends on 1)

The composition or medical preparation of claim 1, wherein the RNA is formulated as a liquid, formulated as a solid, or a combination thereof wherein the RNA is formulated for injection, wherein further the RNA is formulated for intravenous administration.

### Claim 10 (depends on 1)

The composition or medical preparation of claim 1, wherein the RNA is formulated as lipoplex particles, wherein the RNA lipoplex particles are obtainable by mixing the RNA with liposomes.

### Claim 11 (depends on 1)

The composition or medical preparation of claim 1, which further comprises an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is selected from
a) a PD-1 inhibitor,
b) a PD-L1 inhibitor,
c) an anti-PD-1 antibody,
d) an anti-PD-L1 antibody,
(e) an anti-PD-1 antibody selected from: pembrolizumab (KEYTRUDA; MK-3475), nivolumab (OPDIVO; BMS-936558), pidilizumab (CT-011), cemiplimab (LIBTAYO, REGN2810), spartalizumab (PDR001), MEDI0680 (AMP-514), dostarlimab (TSR-042), cetrelimab (JNJ 63723283), toripalimab (JS001), AMP-224 (GSK-2661380), PF-06801591, tislelizumab (BGB-A317), ABBV-181, BI 754091, and SHR-1210, and
(f) an anti-PD-L1 antibody selected from: atezolizumab (TECENTRIQ; RG7446; MPDL3280A; R05541267), durvalumab (MEDI4736), BMS-936559, avelumab (bavencio), lodapolimab (LY3300054), CX-072 (Proclaim-CX-072), FAZ053, KN035, and MDX-1105.

### Claim 12 (depends on 1)

The composition or medical preparation of claim 1, which further comprises a platinum compound, wherein the platinum compound comprises cisplatin.

### Claim 13 (depends on 1)

The composition or medical preparation of claim 1, which comprises an immune checkpoint inhibitor and a platinum compound.

### Claim 14 (depends on 1)

The composition or medical preparation of claim 1, which is a pharmaceutical composition, wherein the pharmaceutical composition further comprises one or more compounds selected from pharmaceutically acceptable carriers, diluents and excipients.

### Claim 15 (depends on 1)

The composition or medical preparation of claim 1, wherein the medical preparation is a kit.

### Claim 16 (depends on 1)

The composition or medical preparation of claim 1 for pharmaceutical use.

### Claim 17 (depends on 16)

The composition or medical preparation of claim 16, wherein the pharmaceutical use comprises a therapeutic or prophylactic treatment of a disease or disorder.

### Claim 18 (depends on 17)

The composition or medical preparation of claim 17, wherein the therapeutic or prophylactic treatment of a disease or disorder comprises treating or preventing HPV-positive cancer.

### Claim 19 (depends on 1)

The composition or medical preparation of claim 1, which is for administration to a human.

### Claim 20 (depends on 17)

The composition or medical preparation of claim 17, wherein the therapeutic or prophylactic treatment of a disease or disorder further comprises administering radiotherapy, preferably local radiotherapy.

### Claim 21 (depends on 1)

A method of treating HPV-positive cancer in a subject comprising administering the composition or medical preparation of claim 1.

### Claim 22 (depends on 21)

The method of claim 21, wherein the RNA is administered by intravenous injection.

### Claim 23 (depends on 21)

The method of claim 21, which further comprises administering to the subject an immune checkpoint inhibitor.

### Claim 24 (depends on 21)

The method of claim 21, which further comprises administering to the subject a platinum compound.

### Claim 25 (depends on 21)

The method of claim 21, which comprises administering to the subject an immune checkpoint inhibitor and a platinum compound.

### Claim 26 (depends on 21)

The method of claim 21, wherein the subject is a human.

### Claim 27 (depends on 21)

The method of claim 21, which further comprises administering to the subject radiotherapy, preferably local radiotherapy.