# US 11,110,178 B2 · Antibody adjuvant conjugates

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- Number: US 11,110,178 B2
- Document ID: US11110178B2
- Status: Granted
- Kind: B2
- Application number: 16/817,864
- Filed: 2020-03-13
- Published: 2020-07-02
- Granted: 2021-09-07
- Earliest claimed: 2016-07-07
- Assignees: The Board of Trustees of the Leland Standford Junior University; Bolt Biotherapeutics, Inc.
- Applicants: The Board of Trustees of the Leland Stanford Junior University; Bolt Biotherapeutics, Inc.
- Inventors: Michael Nathaniel Alonso; Edgar George Engleman; Shelley Erin Ackerman; Justin Kenkel; Arthur Lee; David Y. Jackson
- Web page: https://patentgrep.com/patent/US11110178B2

## CPC

- A61K 47/68: the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K 47/6801: {Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 47/6855: {the tumour determinant being from breast cancer cell}
- A61P 35/00: Antineoplastic agents
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2851: {against the lectin superfamily, e.g. CD23, CD72}
- C07K 16/3053: {Skin, nerves, brain}
- C07K 16/44: against material not provided for elsewhere {, e.g. haptens, metals, DNA, RNA, amino acids}
- A61K 2039/55511: {Organic adjuvants}
- A61K 2039/55516: {Proteins; Peptides}
- A61K 2039/5555: {Muramyl dipeptides}
- A61K 2039/55561: {CpG containing adjuvants; Oligonucleotide containing adjuvants}
- A61K 2039/55572: {Lipopolysaccharides; Lipid A; Monophosphoryl lipid A}
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C07K 16/2887: {against CD20}
- C07K 16/30: from tumour cells
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/74: Inducing cell proliferation
- 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)

## Abstract

The invention provides an immunoconjugate comprising an antibody construct which includes an antigen binding domain and an Fc domain, an adjuvant moiety, and a linker, wherein each adjuvant moiety is covalently bonded to the antibody via the linker. Methods for treating cancer with the immunoconjugates of the invention are also described.

## Claims

### Claim 1

An immunoconjugate comprising
(a) an antibody construct comprising (i) an antigen binding domain and (ii) an Fc domain,
(b) an adjuvant moiety of formula:
wherein each J independently is hydrogen, OR4, or R4, each R4 independently is hydrogen, or an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl group comprising from 1 to 8 carbons, each U independently is CH or N wherein at least one U is N, each subscript t independently is an integer from 1 to 3, Q is optionally present and is an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl group comprising from 1 to 8 carbons, and the dashed line (“”) represents the point of attachment of the adjuvant, and
(c) a linker,
wherein the adjuvant moiety is covalently bonded to the antibody construct via the linker.

### Claim 2 (depends on 1)

The immunoconjugate of claim 1, wherein the antigen binding domain binds to an antigen selected from the group consisting of CDH1, CD19, CD20, CD29, CD30, CD38, CD40, CD47, EpCAM, MUC1, MUC16, EGFR, VEGF, HER2, SLAMF7, PDGFRa, gp75, CTLA4, PD-1, PD-L1, PD-L2, LAG-3, B7-H4, KIR, TNFRSF4, OX4OL, IDO-1, IDO-2, CEACAM1, BTLA, TIM3, A2Ar, VISTA, CLEC4C (BDCA-2, DLEC, CD303, CLECSF7), CLEC4D (MCL, CLECSF8), CLEC4E (Mincle), CLEC6A (Dectin-2), CLEC5A (MDL-1, CLECSF5), CLEC1B (CLEC-2), CLEC9A (DNGR-1), and CLEC7A (Dectin-1).

### Claim 3 (depends on 1)

The immunoconjugate of claim 1, wherein the antigen binding domain binds to EGFR, HER2, or PD-L1.

### Claim 4 (depends on 1)

The immunoconjugate of claim 1, wherein the antibody construct is an antibody.

### Claim 5 (depends on 4)

The immunoconjugate of claim 4, wherein the antibody is selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, avelumab, ipilimumab, obinutuzumab, trastuzumab, cetuximab, rituximab, pertuzumab, bevacizumab, daratumumab, etanercept, olaratumab, elotuzumab, margetuximab, and biosimilars thereof.

### Claim 6 (depends on 4)

The immunoconjugate of claim 4, wherein the antibody comprises a modified Fc region.

### Claim 7 (depends on 4)

The immunoconjugate of claim 4, wherein immunoconjugate has a structure according to Formula I:
or a pharmaceutically acceptable salt thereof, wherein
Ab is the antibody with
being an amino acid residue of the antibody, wherein A is a modified or unmodified sidechain of the amino acid residue,
Z is the linker,
Adj is the adjuvant moiety, and
subscript r is an integer from 1 to 10.

### Claim 8 (depends on 4)

The immunoconjugate of claim 4, wherein the immunoconjugate has a structure according to Formula II:
or a pharmaceutically acceptable salt thereof, wherein
Ab is the antibody with
being an amino acid residue of the antibody, wherein A is a lysine sidechain, thiol-modified lysine sidechain, or cysteine sidechain of the amino acid residue,
Adj is the adjuvant moiety,
subscript r is an integer 1 to 10,
Z1 is selected from —C(O)—, —C(O)NH—, and —CH2—,
Z2 and Z4 are each independently selected from a bond, C1-30 alkylene, and 3- to 30-membered heteroalkylene, wherein
one or more groupings of adjacent atoms in the C1-30 alkylene and 3- to 30-membered heteroalkylene are optionally and independently replaced by —C(O)—, —NRaC(O)—, or C(O)NRa—, wherein each Ra is independently selected from H and C1-6 alkyl,
one or more groupings of adjacent atoms in the C1-30 alkylene and 3- to 30-membered heteroalkylene are optionally and independently replaced by a 4- to 8-membered divalent carbocycle, and
one or more groupings of adjacent atoms in the C1-30 alkylene and 3- to 30-membered heteroalkylene are optionally and independently replaced by a 4- to 8-membered divalent heterocycle having one to four heteroatoms selected from O, S, and N,
Z3 is a bond, a divalent peptide moiety, or a divalent polymer moiety, and
Z5 is selected from an amine-bonded moiety and a thiol-bonded moiety.

### Claim 9 (depends on 4)

The immunoconjugate of claim 4, wherein the immunoconjugate has a structure according to Formula III:
or a pharmaceutically acceptable salt thereof, wherein
Ab is the antibody with
being a lysine residue of the antibody,
Adj is the adjuvant moiety,
G is CH2, C═O, or a bond,
L is a linking moiety, and
subscript r is an integer from 1 to 10.

### Claim 10 (depends on 9)

The immunoconjugate of claim 9, wherein L is selected from:
wherein R is optionally present and is a linear or branched, cyclic or straight, saturated or unsaturated alkyl, heteroalkyl, aryl, or heteroaryl chain comprising from 1 to 8 carbons, a is an integer from 1 to 40, each A is independently selected from any amino acid, subscript c is an integer from 1 to 20, the dashed line (“″) represents the point of attachment to
and the wavy line (“”) represents the point of attachment to

### Claim 11 (depends on 9)

The immunoconjugate of claim 9, wherein L is:
a is an integer from 1 to 40; the dashed line (“”) represents the point of attachment to
and the wavy line (“”) represents the point of attachment to
wherein each adjuvant moiety is covalently bonded to the antibody via the linker.

### Claim 12 (depends on 11)

The immunoconjugate of claim 11, wherein G is a bond.

### Claim 13 (depends on 12)

The immunoconjugate of claim 12, wherein a is an integer from 1 to 10.

### Claim 14 (depends on 13)

The immunoconjugate of claim 13, wherein is r is an integer from 1 to 5.

### Claim 15 (depends on 1)

The immunoconjugate of claim 1, wherein Q is not present.

### Claim 16 (depends on 15)

The immunoconjugate of claim 15, wherein each U is N and each subscript t is 2.

### Claim 17 (depends on 1)

The immunoconjugate of claim 1, wherein each U is N and each subscript t is 2.

### Claim 18 (depends on 1)

The immunoconjugate of claim 1, wherein the adjuvant moiety is of formula:

### Claim 19 (depends on 4)

The immunoconjugate of claim 4, wherein the antibody is trastuzumab or a biosimilar thereof.

### Claim 20 (depends on 19)

The immunoconjugate of claim 19, wherein Q is not present.

### Claim 21 (depends on 20)

The immunoconjugate of claim 20, wherein each U is N and each subscript t is 2.

### Claim 22 (depends on 19)

The immunoconjugate of claim 19, wherein each U is N and each subscript t is 2.

### Claim 23 (depends on 19)

The immunoconjugate of claim 19, wherein the adjuvant moiety is of formula:

### Claim 24 (depends on 6)

The immunoconjugate of claim 6, wherein (i) the modified Fc region contains at least one amino acid insertion, deletion, or substitution and/or (ii) the modified Fc region is deglycosylated or afucosylated.

### Claim 25 (depends on 1)

The immunoconjugate of claim 1, wherein immunoconjugate has a structure according to Formula I:
or a pharmaceutically acceptable salt thereof, wherein
Ab is the antibody construct with
being an amino acid residue of the antibody construct, wherein A is a modified or unmodified sidechain of the amino acid residue,
Z is the linker,
Adj is the adjuvant moiety, and
subscript r is an integer from 1 to 10.

### Claim 26 (depends on 1)

The immunoconjugate of claim 1, wherein the immunoconjugate has a structure according to Formula III:
or a pharmaceutically acceptable salt thereof, wherein
Ab is the antibody construct with
being a lysine residue of the antibody construct,
Adj is the adjuvant moiety,
G is CH2, C═O, or a bond,
L is a linking moiety, and
subscript r is an integer from 1 to 10.

### Claim 27 (depends on 26)

The immunoconjugate of claim 26, wherein L is:
a is an integer from 1 to 40; the dashed line (“”) represents the point of attachment to
and the wavy line (“”) represents the point of attachment to
wherein each adjuvant moiety is covalently bonded to the antibody construct via the linker.

### Claim 28 (depends on 27)

The immunoconjugate of claim 27, wherein G is a bond.

### Claim 29 (depends on 28)

The immunoconjugate of claim 28, wherein a is an integer from 1 to 10.

### Claim 30 (depends on 29)

The immunoconjugate of claim 29, wherein is r is an integer from 1 to 5.