Anti-CD38 antibodies and formulations

Patent metadata

Field	Value
Publication number	US-11655302-B2
Application number	US-202016896784-A
Country	US
Kind code	B2
Filing date	Jun 9, 2020
Priority date	Jun 10, 2019
Publication date	May 23, 2023
Grant date	May 23, 2023

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.

First claim

We 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.

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.

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.

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

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

6. 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).

7. 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).

8. 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).

9. 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 (FcyRIIIa) having phenylalanine at amino acid position 158 (158F) with a KD of 96 nM as measured by binding to FcγRllla 158F-expressing HEK cells and wherein the antibody binds FcγRllla 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.

10. 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.

11. The pharmaceutical composition of claim 10 , wherein
a) in the presence of Natural Killer cells expressi

Assignees

• Sanofi Sa

Inventors

• Chiron Blondel Marielle
• Lemoine Cendrine
• Virone-Oddos Angela
• Cameron Béatrice
• Dumas Jacques
• Fournier Alain
• Kingsbury Jonathan
• Murray Brian
• Ostberg Nathan
• Patke Sanket
• Zhang Zichuan

Classifications

• C07K16/2896 Primary

  against molecules with a "CD"-designation, not provided for elsewhere · CPC title

• C07K2317/72

  Increased effector function due to an Fc-modification · CPC title

• A61K47/26

  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 · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/94

  Stability, e.g. half-life, pH, temperature or enzyme-resistance · CPC title