# US 2019/0169266 A1 · Constructs having a sirp-alpha domain or variant thereof

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- Number: US 2019/0169266 A1
- Document ID: US20190169266A1
- Status: Published application
- Kind: A1
- Application number: 16/153,404
- Filed: 2018-10-05
- Published: 2019-06-06
- Earliest claimed: 2015-08-07
- Assignees: ALX Oncology Inc.
- Applicants: ALX Oncology Inc.
- Inventors: Jaume PONS; Laura DEMING; Corey GOODMAN; Bang Janet SIM; Steven Elliot KAUDER; Hong WAN; Tracy Chia-Chien KUO
- Web page: https://patentgrep.com/patent/US20190169266A1

## CPC

- C07K 14/70596: {Molecules with a "CD"-designation not provided for elsewhere}
- A61K 38/177: {Receptors; Cell surface antigens; Cell surface determinants}
- 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}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/6811: {the drug being a protein or peptide, e.g. transferrin or bleomycin}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07K 14/70503: {Immunoglobulin superfamily}
- C07K 16/00: Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
- C07K 16/2803: {against the immunoglobulin superfamily}
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 38/1709: {from mammals}
- A61K 2039/505: {comprising antibodies}
- C07K 14/4703: {Inhibitors; Suppressors}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/524: CH2 domain
- C07K 2317/526: CH3 domain
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- 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)
- 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

## Abstract

The present disclosure features signal-regulatory protein a (SIRPα) polypeptides and constructs that are useful, e.g., to target a cell (e.g., a cancer cell or a cell of the immune system), to increase phagocytosis of the target cell, to eliminate immune cells such as regulatory T-cells, to kill cancer cells, to treat a disease (e.g., cancer) in a subject, or any combinations thereof. The SIRP-α constructs include a high affinity SIRP-α D1 domain or variant thereof that binds CD47 with higher affinity than a wild-type SIRP-α. The SIRP-α polypeptides or constructs include a SIRP-α D1 variant fused to an Fc domain monomer, a human serum albumin (HSA), an albumin-binding peptide, or a polyethylene glycol (PEG) polymer. Compositions provided herein include (i) a polypeptide including a signal-regulatory protein a (SIRP-α) D1 variant and (ii) an antibody.

## Claims

### Claim at position 1

1-156. (canceled)

### Claim 157

A polypeptide, comprising:
(a) a signal-regulatory protein a (SIRP-α) D1 variant comprising SEQ ID NO: 85; and
(b) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index,
wherein the C-terminus of the SIRP-α D1 variant is linked to the N-terminus of the human IgG1 Fc region.

### Claim 158 (depends on 157)

A nucleic acid encoding the polypeptide of claim 157.

### Claim 159 (depends on 158)

A vector comprising the nucleic acid of claim 158.

### Claim 160 (depends on 158)

A host cell comprising the nucleic acid of claim 158.

### Claim 161 (depends on 160)

A method of producing a polypeptide, comprising culturing the host cell of claim 160 under appropriate conditions to cause expression of the polypeptide and recovering the polypeptide.

### Claim 162 (depends on 157)

A pharmaceutical composition comprising the polypeptide of claim 157 and a pharmaceutically acceptable excipient.

### Claim 163

A pharmaceutical composition comprising
(a) a dimer comprising a polypeptide that comprises
(i) a signal-regulatory protein a (SIRP-α) D1 variant comprising SEQ ID NO: 85; and
(ii) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index,
wherein the C-terminus of the SIRP-α D1 variant is linked to the N-terminus of the human IgG1 Fc region, and
(b) a pharmaceutically acceptable excipient.

### Claim 164 (depends on 163)

The pharmaceutical composition of claim 163, wherein each monomer in the dimer comprises a polypeptide that comprises
(i) a signal-regulatory protein a (SIRP-α) D1 variant comprising SEQ ID NO: 85; and
(ii) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index,
wherein the C-terminus of the SIRP-α D1 variant is linked to the N-terminus of the human IgG1 Fc region.

### Claim 165

A method of treating an individual having cancer, the method comprising administering to the individual a pharmaceutical composition comprising a polypeptide and a pharmaceutically acceptable excipient, wherein the polypeptide comprises
(a) a signal-regulatory protein a (SIRP-α) D1 variant comprising SEQ ID NO: 85; and
(b) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index,
wherein the C-terminus of the SIRP-α D1 variant is linked to the N-terminus of the human IgG1 Fc region.

### Claim 166 (depends on 165)

The method of claim 165, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody, a tumor associated antigen, or a non-antibody therapeutic.

### Claim 167

A method of treating an individual having cancer, the method comprising administering to the individual a pharmaceutical composition comprising a dimer and a pharmaceutically acceptable excipient, wherein the dimer comprises a polypeptide that comprises:
(a) a signal-regulatory protein a (SIRP-α) D1 variant comprising SEQ ID NO: 85; and
(b) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index,
wherein the C-terminus of the SIRP-α D1 variant is linked to the N-terminus of the human IgG1 Fc region.

### Claim 168 (depends on 167)

The method of claim 167, wherein each monomer in the dimer comprises a polypeptide that comprises:
(a) a signal-regulatory protein a (SIRP-α) D1 variant comprising SEQ ID NO: 85; and
(b) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index,
wherein the C-terminus of the SIRP-α D1 variant is linked to the N-terminus of the human IgG1 Fc region.

### Claim 169 (depends on 167)

The method of claim 167, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody, a tumor associated antigen, or a non-antibody therapeutic.

### Claim 170

A dimer comprising a polypeptide that comprises the amino acid sequence set forth in SEQ ID NO: 136.

### Claim 171 (depends on 170)

The dimer of claim 170, wherein each monomer in the dimer comprises a polypeptide that comprises the amino acid sequence set forth in SEQ ID NO: 136.

### Claim 172

A nucleic acid encoding a polypeptide that comprises the amino acid sequence set forth in SEQ ID NO: 136.

### Claim 173 (depends on 172)

A vector comprising the nucleic acid of claim 172.

### Claim 174 (depends on 172)

A host cell comprising the nucleic acid of claim 172.

### Claim 175 (depends on 174)

A method of producing a polypeptide, comprising culturing the host cell of claim 174 under appropriate conditions to cause expression of the polypeptide and recovering the polypeptide.

### Claim 176

A pharmaceutical composition comprising a polypeptide that comprises the amino acid sequence set forth in SEQ ID NO: 136 and a pharmaceutically acceptable excipient.

### Claim 177

A pharmaceutical composition comprising (a) a dimer that comprises a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 136 and (b) a pharmaceutically acceptable excipient.

### Claim 178 (depends on 177)

The pharmaceutical composition of claim 177, wherein each monomer in the dimer comprises a polypeptide that comprises the amino acid sequence set forth in SEQ ID NO: 136.

### Claim 179

A method of treating an individual having cancer, the method comprising administering to the individual a pharmaceutical composition comprising a polypeptide that comprises the amino acid sequence set forth in SEQ ID NO: 136 and pharmaceutically acceptable excipient.

### Claim 180 (depends on 179)

The method of claim 179, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody, a tumor associated antigen, or a non-antibody therapeutic.

### Claim 181

A method of treating an individual having cancer, the method comprising administering to the individual a pharmaceutical composition comprising a dimer and a pharmaceutically acceptable excipient, wherein the dimer comprises a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 136.

### Claim 182 (depends on 181)

The method of claim 181, wherein each monomer in the dimer comprises a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 136.

### Claim 183 (depends on 181)

The method of claim 181, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody, a tumor associated antigen, or a non-antibody therapeutic.

### Claim 184

A polypeptide, comprising:
(a) a signal-regulatory protein a (SIRP-α) D1 variant comprising SEQ ID NO: 81; and
(b) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index,
wherein the C-terminus of the SIRP-α D1 variant is linked to the N-terminus of the human IgG1 Fc region.

### Claim 185 (depends on 184)

A nucleic acid encoding the polypeptide of claim 184.

### Claim 186 (depends on 185)

A vector comprising the nucleic acid of claim 185.

### Claim 187 (depends on 185)

A host cell comprising the nucleic acid of claim 185.

### Claim 188 (depends on 187)

A method of producing a polypeptide, comprising culturing the host cell of claim 187 under appropriate conditions to cause expression of the polypeptide and recovering the polypeptide.

### Claim 189 (depends on 184)

A pharmaceutical composition comprising the polypeptide of claim 184 and a pharmaceutically acceptable excipient.

### Claim 190

A pharmaceutical composition comprising
(a) a dimer comprising a polypeptide that comprises
(i) a signal-regulatory protein a (SIRP-α) D1 variant comprising SEQ ID NO: 81; and
(ii) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index,
wherein the C-terminus of the SIRP-α D1 variant is linked to the N-terminus of the human IgG1 Fc region, and
(b) a pharmaceutically acceptable excipient.

### Claim 191 (depends on 190)

The pharmaceutical composition of claim 190, wherein each monomer in the dimer comprises a polypeptide that comprises
(i) a signal-regulatory protein a (SIRP-α) D1 variant comprising SEQ ID NO: 81; and
(ii) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index,
wherein the C-terminus of the SIRP-α D1 variant is linked to the N-terminus of the human IgG1 Fc region.

### Claim 192

A method of treating an individual having cancer, the method comprising administering to the individual a pharmaceutical composition comprising a polypeptide and a pharmaceutical excipient, wherein the polypeptide comprises
(a) a signal-regulatory protein a (SIRP-α) D1 variant comprising SEQ ID NO: 81; and
(b) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index,
wherein the C-terminus of the SIRP-α D1 variant is linked to the N-terminus of the human IgG1 Fc region.

### Claim 193 (depends on 192)

The method of claim 192, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody, a tumor associated antigen, or a non-antibody therapeutic.

### Claim 194

A method of treating an individual having cancer, the method comprising administering to the individual a pharmaceutical composition comprising a dimer and a pharmaceutically acceptable excipient, wherein the dimer comprises a polypeptide that comprises
(a) a signal-regulatory protein a (SIRP-α) D1 variant comprising SEQ ID NO: 81; and
(b) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index,
wherein the C-terminus of the SIRP-α D1 variant is linked to the N-terminus of the human IgG1 Fc region.

### Claim 195 (depends on 194)

The method of claim 194, wherein each monomer in the dimer comprises a polypeptide comprising:
(a) a signal-regulatory protein a (SIRP-α) D1 variant comprising SEQ ID NO: 81; and
(b) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index, wherein the C-terminus of the SIRP-α D1 variant is linked to the N-terminus of the human IgG1 Fc region.

### Claim 196 (depends on 194)

The method of claim 194, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody, a tumor associated antigen, or a non-antibody therapeutic.

### Claim 197

A dimer comprising a polypeptide that comprises the amino acid sequence set forth in SEQ ID NO: 135.

### Claim 198 (depends on 197)

The dimer of claim 197, wherein each monomer in the dimer comprises a polypeptide that comprises the amino acid sequence set forth in SEQ ID NO: 135.

### Claim 199

A nucleic acid encoding a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 135.

### Claim 200 (depends on 199)

A vector comprising the nucleic acid of claim 199.

### Claim 201 (depends on 199)

A host cell comprising the nucleic acid of claim 199.

### Claim 202 (depends on 201)

A method of producing a polypeptide, comprising culturing the host cell of claim 201 under appropriate conditions to cause expression of the polypeptide and recovering the polypeptide.

### Claim 203

A pharmaceutical composition comprising a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 135 and a pharmaceutically acceptable excipient.

### Claim 204

A pharmaceutical composition comprising (a) a dimer that comprises a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 135 and (b) a pharmaceutically acceptable excipient.

### Claim 205 (depends on 204)

The pharmaceutical composition of claim 204, wherein each monomer in the dimer comprises a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 135.

### Claim 206

A method of treating an individual having cancer, the method comprising administering to the individual a pharmaceutical composition comprising a polypeptide that comprises the amino acid sequence of SEQ ID NO: 135 and pharmaceutically acceptable excipient.

### Claim 207 (depends on 206)

The method of claim 206, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody, a tumor associated antigen, or a non-antibody therapeutic.

### Claim 208

A method of treating an individual having cancer, the method comprising administering to the individual a pharmaceutical composition comprising a dimer and a pharmaceutically acceptable excipient, wherein the dimer comprises a polypeptide comprising the amino acid sequence of SEQ ID NO: 135.

### Claim 209 (depends on 208)

The method of claim 208, wherein each monomer in the dimer comprises a comprising the amino acid sequence set forth in SEQ ID NO: 135.

### Claim 210 (depends on 208)

The method of claim 208, further comprising administering at least one additional agent to the individual, wherein the at least one additional agent is an antibody, a tumor associated antigen, or a non-antibody therapeutic.