# US 2020/0399391 A1 · Anti-cd38 antibodies and formulations

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- Number: US 2020/0399391 A1
- Document ID: US20200399391A1
- Status: Published application
- Kind: A1
- Application number: 16/896,784
- Filed: 2020-06-09
- Published: 2020-12-24
- Earliest claimed: 2019-06-10
- Assignees: Sanofi
- Applicants: Sanofi
- Inventors: Marielle CHIRON BLONDEL; Cendrine LEMOINE; Angela VIRONE-ODDOS; Béatrice CAMERON; Jacques DUMAS; Alain FOURNIER; Jonathan KINGSBURY; Brian MURRAY; Nathan OSTBERG; Sanket PATKE; Zichuan ZHANG
- Web page: https://patentgrep.com/patent/US20200399391A1

## CPC

- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- C07K 2317/72: Increased effector function due to an Fc-modification
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- 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)

## Abstract

Provided herein are antibodies that specifically bind human CD38, formulations and unit dosage forms comprising the antibodies, methods of preparing the antibodies and methods of using the antibodies.

## Claims

### Claim 1

An antibody that specifically binds human CD38, wherein the antibody comprises
a) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 2 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
b) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 3 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
c) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 4 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
d) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 5 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 8, or
e) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 5 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 9, or
f) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 6 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 8, or
g) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 6 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 9.

### Claim 2

A pharmaceutical composition comprising a formulated antibody, wherein the formulated antibody comprises an antibody, sucrose, L-histidine, and polysorbate 80 (PS80), wherein the antibody specifically binds human CD38 and is present at a concentration of 50 mg/mL, the sucrose is present at a concentration of 8% (w/v), the L-histidine is present at a concentration of 10 mM, and the PS80 is present at a concentration of 0.05% (v/v), wherein the formulation has a pH of 6.2, and wherein the antibody comprises
a) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 2 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
b) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 3 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
c) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 4 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
d) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 5 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 8, or
e) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 5 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 9, or
f) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 6 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 8, or
g) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 6 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 9.

### Claim 3

A unit dosage form of a formulated antibody that specifically binds human CD38, wherein the formulated antibody comprises 215 mg of the antibody, 6.21 mg L-histidine, 344 mg sucrose, and 2.15 mg polysorbate 80, wherein the formulated antibody is lyophilized, and wherein the antibody comprises
a) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 2 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
b) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 3 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
c) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 4 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
d) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 5 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 8, or
e) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 5 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 9, or
f) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 6 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 8, or
g) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 6 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 9.

### Claim 4 (depends on 2)

The pharmaceutical composition of claim 2, wherein the formulated antibody is lyophilized.

### Claim 5 (depends on 2)

The pharmaceutical composition of claim 2, wherein amino acid at position 1 of the HC amino acid sequence is pyroglutamine.

### Claim 6 (depends on 2)

The pharmaceutical composition of claim 2, wherein the antibody has an isoelectric point (pI) of 5.8 to 9.0 when measured by capillary isoelectric focusing (cIEF).

### Claim 7 (depends on 2)

The pharmaceutical composition of claim 2, wherein the antibody comprises a main charge variant and at least one acidic charge variant and wherein the antibody has at least one of
a) the HC of the at least one charge variant comprises at least one deamidated asparagine selected from the group consisting of N289, N318, N387, and N392 as numbered according to SEQ ID NO: 1, or
b) the antibody comprises a main charge variant and least one acidic charge variant, wherein the main charge variant comprises at least 71% of the antibody and the acidic charge variant comprises no more than 30% of the antibody, or
c) the main charge variant has an isoelectric point (pI) of 7.5 and wherein the one or more acidic charge variant has pI of 5.8 when measured by capillary isoelectric focusing (cIEF).

### Claim 8 (depends on 2)

The pharmaceutical composition of claim 2, wherein the antibody comprises at least one basic charge variant, and wherein the antibody has at least one of
a) the basic charge variant comprises no more than 4% of the antibody, or
b) the one or more basic charge variants has a pI of 9.0 when measured by capillary isoelectric focusing (cIEF).

### Claim 9 (depends on 2)

The pharmaceutical composition of claim 2, wherein the antibody
a) is capable of killing a CD38-expressing cell by Antibody Dependent Cellular Cytotoxicity (ADCC), wherein the cell has a CD38 receptor density of ≤13,000 CD38 sites on the surface of the cell in the presence of Natural Killer cells expressing the 158F, 158V, or both 158F and 158V variants CD16a (FcγRIIIa), and/or
b) binds CD16a (FcγRIIIa) having phenylalanine at amino acid position 158 (158F) with a KD of 59 nM as measured by Surface Plasmon Resonance (SPR) and wherein the antibody binds CD16a having valine at amino acid position 158 (158V) with a KD of 75 nM as measured by SPR, and/or
c) binds CD16a (FcγRIIIa) having phenylalanine at amino acid position 158 (158F) with a KD of 96 nM as measured by binding to FcγRIIIa 158F-expressing HEK cells and wherein the antibody binds FcγRIIIa having valine at amino acid position 158 (158V) with a KD of 40 nM as measured by binding to FcγRIIIa 158V-expressing HEK cells, and/or
d) binds CD32a (FcγRIIa) having arginine at amino acid position 131 (131R) with a KD of 94 nM as measured by binding to FcγRIIa 131R-expressing HEK cells and wherein the antibody binds FcγRIIa having histidine at amino acid position 131 (131H) with a KD of 222 nM as measured by binding to FcγRIIa 131H-expressing HEK cells.

### Claim 10 (depends on 2)

The pharmaceutical composition of claim 2, wherein
a) the antibody is capable of killing a CD38-expressing cell by ADCC wherein the cell has a CD38 receptor density of >400,000 on the surface of the cell, and is capable of killing a CD38-expressing cell by ADCC wherein the cell has a CD38 receptor density of ≥100,000 on the surface of the cell, and is capable of killing a CD38-expressing cell by ADCC wherein the cell has a CD38 receptor density of ≤13,000 on the surface of the cell, in the presence of Natural Killer cells expressing the 158F, 158V, or both 158F and 158V variants of CD16a (FcγRIIIa) and/or
b) the antibody is capable of killing a CD38-expressing cell by Antibody Dependent Cellular Phagocytosis (ADCP) in the presence of human peripheral blood mononuclear cells (PMBCs), wherein the cell has a CD38 receptor density of >400,000 on the surface of the cell.

### Claim 11 (depends on 10)

The pharmaceutical composition of claim 10, wherein
a) in the presence of Natural Killer cells expressing the higher affinity variant (158V) of CD16a (FcγRIIIa), the antibody is capable of killing KMS-12BM cells by ADCC with an EC 50 of about 0.6 ng/mL and/or
b) in the presence of Natural Killer cells expressing the lower affinity variant (158F) of CD16a (FcγRIIIa), the antibody is capable of killing KMS-12BM cells by ADCC with an EC 50 of about 0.65 ng/mL and/or
c) in the presence of Natural Killer cells expressing the higher affinity variant (158V) of CD16a (FcγRIIIa), the antibody is capable of killing RPMI-8226 cells by ADCC with an EC 50 of about 0.09 ng/mL and/or
d) in the presence of Natural Killer cells expressing the lower affinity variant (158F) of CD16a (FcγRIIIa), the antibody is capable of killing RPMI-8226 cells by ADCC with an EC 50 of about 0.09 ng/mL and/or
e) in the presence of Natural Killer cells expressing the higher affinity variant (158V) of CD16a (FcγRIIIa), the antibody is capable of killing MOLP-8 cells by ADCC with an EC 50 of about 0.14 ng/mL and/or
f) in the presence of Natural Killer cells expressing the lower affinity variant (158F) of CD16a (FcγRIIIa), the antibody is capable of killing MOLP-8 cells by ADCC with an EC 50 of about 0.28 ng/mL.

### Claim 12 (depends on 10)

The pharmaceutical composition of claim 10, wherein in the presence of human PMBCs expressing the higher affinity variant (158V) of CD16a (FcγRIIIa), the antibody is capable of killing MOLP-8 cells by ADCP with an EC 50 of about 31.87 ng/mL.

### Claim 13 (depends on 2)

The pharmaceutical composition of claim 2, wherein the antibody is capable of improving survival of mice in a murine tumor model, wherein mice in the model express human CD16a (158F), and wherein the mice have been injected with 500,000 EL4 cells expressing human CD38.

### Claim 14

A method for preparing a pharmaceutical composition comprising an antibody that specifically binds human CD38, wherein the antibody comprises
a) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 2 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
b) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 3 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
c) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 4 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
d) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 5 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 8, or
e) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 5 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 9, or
f) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 6 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 8, or
g) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 6 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 9,
the method comprising the steps of:
i) expressing the antibody in a cell culture;
ii) subjecting the antibody to at least one purification step selected from the group consisting of chromatography and ultrafiltration to produce a purified antibody solution; and
iii) adjusting the purified antibody solution to produce a formulated antibody comprising
the purified antibody at a concentration of 50 mg/mL,
sucrose at a concentration of 8% w/v,
L-histidine at a concentration of 10 mM, and
polysorbate 80 at a concentration of 0.05% v/v,
wherein the formulated antibody has a pH of 6.2; and
iv) lyophilizing the formulated antibody,
thereby preparing the pharmaceutical composition.

### Claim 15

A method for preparing a reconstituted formulated antibody, comprising
a) providing a lyophilized antibody formulation comprising sucrose, L-histidine, polysorbate 80, and an antibody that specifically binds human CD38; and
b) reconstituting the lyophilized antibody formulation in a diluent, wherein the reconstituted antibody formulation comprises
the antibody at a concentration of 50 mg/mL,
sucrose at a concentration of 8% w/v,
L-Histidine at a concentration of 10 mM, and
polysorbate 80 at a concentration of 0.05% v/v,
wherein the reconstituted antibody formulation has a pH of 6.2;
wherein the antibody comprises
i) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 2 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
ii) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 3 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
iii) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 4 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
iv) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 5 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 8, or
v) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 5 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 9, or
vi) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 6 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 8, or
vii) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 6 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 9.

### Claim 16

A method of treating a patient in need thereof, comprising administering to the patient one or more doses of an antibody that specifically binds human CD38, wherein the patient has a disease that comprises CD38-expressing cells, wherein the antibody comprises
a) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 2 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
b) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 3 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
c) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 4 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 7, or
d) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 5 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 8, or
e) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 5 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 9, or
f) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 6 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 8, or
g) a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 6 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 9.

### Claim 17

(canceled)

### Claim 18 (depends on 16)

The method of claim 16, wherein the disease is of hematological origin.

### Claim 19 (depends on 18)

The method of claim 18, wherein the disease of hematological origin is selected from the group consisting of: amyloidosis, non-Hodgkin's lymphoma (NHL), Waldenstrom's disease, multiple myeloma (MM), acute lymphocytic leukemia (ALL), and acute myelogenous leukemia (AML).

### Claim 20 (depends on 16)

The method of claim 16, wherein the one or more doses of antibody is provided as a lyophilized antibody formulation and wherein prior to administration, the lyophilized antibody formulation is reconstituted forming a reconstituted antibody formulation such that the reconstituted antibody formulation has a pH of 6.2 and comprises the antibody at a concentration of 50 mg/mL in a liquid comprising 10 mM L-histidine, 8% (w/v) sucrose, and 0.05% (v/v) polysorbate 80.

### Claim 21 (depends on 16)

The method of claim 16, wherein the antibody is administered at a dose of 20 mg/kg, 10 mg/kg, 5 mg/kg, 3 mg/kg, or 1.5 mg/kg.

### Claim 22 (depends on 16)

The method of claim 16, wherein the pharmaceutical composition comprises a formulated antibody, wherein the formulated antibody comprises the antibody present at a concentration of 50 mg/mL, sucrose at a concentration of 8% (w/v), L-histidine at a concentration of 10 mM, and polysorbate 80 (PS80) at a concentration of 0.05% (v/v), wherein the formulated antibody has a pH of 6.2.

### Claim 23 (depends on 16)

The method of claim 16, wherein the antibody has an isoelectric point (pI) of 5.8 to 9.0 when measured by capillary isoelectric focusing (cIEF).

### Claim 24 (depends on 16)

The method of claim 16, wherein amino acid at position 1 of the HC amino acid sequence is pyroglutamine.

### Claim 25 (depends on 16)

The method of claim 16, wherein the antibody comprises a main charge variant and at least one acidic charge variant and wherein the antibody has at least one of
a) the HC of the at least one charge variant comprises at least one deamidated asparagine selected from the group consisting of N289, N318, N387, and N392 as numbered according to SEQ ID NO: 1, or
b) the antibody comprises a main charge variant and least one acidic charge variant, wherein the main charge variant comprises at least 71% of the antibody and the acidic charge variant comprises no more than 30% of the antibody, or
c) the main charge variant has an isoelectric point (pI) of 7.5 and wherein the one or more acidic charge variant has pI of 5.8 when measured by capillary isoelectric focusing (cIEF).

### Claim 26 (depends on 16)

The method of claim 16, wherein the antibody comprises at least one basic charge variant, and wherein the antibody has at least one of
a) the basic charge variant comprises no more than 4% of the antibody, or
b) the one or more basic charge variants has a pI of 9.0 when measured by capillary isoelectric focusing (cIEF).