# US 11,897,959 B2 · Anti-AXL antibodies, antibody fragments and their immunoconjugates and uses thereof

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- Number: US 11,897,959 B2
- Document ID: US11897959B2
- Status: Granted
- Kind: B2
- Application number: 17/465,968
- Filed: 2021-09-03
- Published: 2021-12-30
- Granted: 2024-02-13
- Earliest claimed: 2016-04-15
- Assignees: BioAtla, Inc.
- Applicants: BioAtla, Inc.
- Inventors: Jay M. Short; Hwai Wen Chang; Gerhard Frey
- Web page: https://patentgrep.com/patent/US11897959B2

## CPC

- C07K 16/2863: {against receptors for growth factors, growth regulators}
- A61K 47/65: Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
- A61K 47/6803: {Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates}
- A61K 47/68031: {the drug being an auristatin}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61P 35/00: Antineoplastic agents
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- 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: 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

An antibody or antibody fragment having a heavy chain variable region and/or light chain variable region that specifically binds to Axl protein. Immuoconjugages, pharmaceutical compositions and kits comprising the antibodies and antibody fragments are also provided. Also disclosed are methods of treating Axl-expressing cancers using the antibodies, antibody fragments, immunoconjugates and pharmaceutical compositions of the present invention.

## Claims

### Claim 1

An antibody or antibody fragment that specifically binds to Axl protein, said antibody or antibody fragment comprising a heavy chain variable region including three complementarity determining regions having H1, H2, and H3 sequences, and a light chain variable region including three complementarity determining regions having L1, L2, and L3 sequences, wherein:
(a) the H1 sequence is X1GX2X3MX4 (SEQ ID NO: 1);
(b) the H2 sequence is LIKX5SNGGTX6YNQKFKG (SEQ ID NO: 2); and
(c) the H3 sequence is GX7X8X9X10X11X12X13X14DYX15X16 (SEQ ID NO: 3),
wherein
X1 is T or A or W,
X2 is H or A,
X3 is T,
X4 is N,
X5 is P,
X6 is S,
X7 is H,
X8 is Y,
X9 is E,
X10 is S,
X11 is Y,
X12 is E,
X13 is A,
X14 is M,
X15 is W, and
X16 is G, and
(d) the L1 sequence is KASQDX17X18SX19VX20 (SEQ ID NO: 4);
(e) the L2 sequence is X21X22X23TRX24T (SEQ ID NO: 5); and
(f) the L3 sequence is QEX25X26SX27X28X29X30 (SEQ ID NO: 6),
wherein
X17 is V,
X18 is S or V,
X19 is A,
X20 is A,
X21 is W,
X22 is Q,
X23 is D,
X24 is H,
X25 is H,
X26 is F,
X27 is T or P,
X28 is P,
X29 is L, and
X30 is T or R;
wherein the isolated antibody or antibody fragment has a higher binding affinity to human Axl protein in a tumor microenvironment of pH 5.8 to 7.0 in comparison with a non-tumor microenvironment of pH 7.2 to 7.8; and
the antibody or antibody fragment has a ratio of binding affinity to the human Axl protein in the tumor microenvironment to a binding affinity to the human Axl protein in the non-tumor microenvironment of at least 1.5:1.

### Claim 2 (depends on 1)

The antibody or antibody fragment of claim 1, wherein the antibody or antibody fragment is a chimeric antibody, a multispecific antibody, or a humanized antibody.

### Claim 3 (depends on 1)

The antibody or antibody fragment of claim 1, wherein X1 is W, X2 is A, X18 is V, X27 is P, and X30 is T.

### Claim 4 (depends on 1)

The antibody or antibody fragment of claim 1, wherein X1 is T, X2 is H, X18 is V, X27 is T, and X30 is T.

### Claim 5 (depends on 1)

The antibody or antibody fragment of claim 1, wherein X1 is T, X2 is A, X18 is S, X27 is T, and X30 is T.

### Claim 6 (depends on 1)

The antibody or antibody fragment of claim 1, wherein X1 is W, X2 is A, X18 is S, X27 is P, and X30 is T.

### Claim 7 (depends on 1)

The antibody or antibody fragment of claim 1, wherein the antibody or antibody fragment has a ratio of binding affinity to the Axl protein at a value of a condition in a tumor microenvironment and a binding affinity to the Axl protein at a different value of the same condition in a non-tumor microenvironment of at least about 2:1, at least about 3:1, at least about 4:1, at least about 5:1, at least about 6:1, at least about 7:1, at least about 8:1, at least about 9:1, at least about 10:1, at least about 20:1, at least about 30:1, at least about 50:1, at least about 70:1, or at least about 100:1.

### Claim 8 (depends on 1)

An immunoconjugate comprising the antibody or antibody fragment of claim 1.

### Claim 9 (depends on 8)

The immunoconjugate of claim 8, wherein the immunoconjugate comprises at least one agent selected from a chemotherapeutic agent, a radioactive atom, a cytostatic agent and a cytotoxic agent.

### Claim 10 (depends on 9)

The immunoconjugate of claim 9, comprising at least two of said agents.

### Claim 11 (depends on 9)

The immunoconjugate of claim 9, wherein the antibody or antibody fragment and the at least one agent are covalently bonded to a linker molecule.

### Claim 12 (depends on 9)

The immunoconjugate of claim 9, wherein the at least one agent is selected from maytansinoids, auristatins, dolastatins, calicheamicin, pyrrolobenzodiazepines, and anthracyclines.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising the antibody or antibody fragment of claim 1 and a pharmaceutically acceptable carrier.

### Claim 14 (depends on 13)

The pharmaceutical composition of claim 13, further comprising a tonicity agent.

### Claim 15 (depends on 13)

A method of treating cancer comprising a step of administering the pharmaceutical composition of claim 13 to a patient with an Axl-expressing cancer.

### Claim 16 (depends on 9)

A pharmaceutical composition comprising the immunoconjugate of claim 9 and a pharmaceutically acceptable carrier.

### Claim 17 (depends on 16)

The pharmaceutical composition of claim 16, further comprising a tonicity agent.

### Claim 18 (depends on 16)

A method of treating cancer comprising a step of administering the pharmaceutical composition of claim 16 to a patient with an Axl-expressing cancer.

### Claim 19 (depends on 1)

A method of treating cancer comprising a step of administering the antibody or antibody fragment of claim 1 to a patient with an Axl-expressing cancer.

### Claim 20 (depends on 8)

A method of treating cancer comprising a step of administering the immunoconjugate of claim 8 to a patient with an Axl-expressing cancer.