# US 10,865,236 B2 · Bispecific antigen-binding molecules that bind a staphylococcus target antigen and a complement component and uses thereof

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- Number: US 10,865,236 B2
- Document ID: US10865236B2
- Status: Granted
- Kind: B2
- Application number: 16/143,901
- Filed: 2018-09-27
- Published: 2019-04-04
- Granted: 2020-12-15
- Earliest claimed: 2017-09-29
- Assignees: Regeneron Pharmaceuticals, Inc.
- Applicants: Regeneron Pharmaceuticals, Inc.
- Inventors: Brinda Prasad; Andrew J. Murphy; Karolina Meagher; Peter Mason
- Web page: https://patentgrep.com/patent/US10865236B2

## CPC

- C07K 16/1271: Micrococcaceae (F); Staphylococcaceae (F), e.g. Staphylococcus (G)
- A61K 39/40: bacterial
- A61P 31/04: Antibacterial agents
- C07K 16/18: against material from animals or humans
- C12N 15/62: DNA sequences coding for fusion proteins
- A61K 2039/505: {comprising antibodies}
- A61K 2039/572: {cytotoxic response}
- C07K 2317/31: multispecific
- C07K 2317/734: Complement-dependent cytotoxicity [CDC]
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

According to certain embodiments, the present disclosure provides bispecific antigen-binding molecules comprising a first antigen-binding domain that specifically binds a Staphylococcus species target antigen and a second antigen binding domain that binds a complement component. In certain embodiments, the bispecific antigen-binding molecules of the present disclosure are capable of binding to the Staphylococcus species target antigen with an EC50 of about 10 nM or less, and/or are capable of promoting complement deposition on the Staphylococcus species with an EC50 of about 10 nM. The antibodies of the disclosure are useful for treating diseases in which inhibition or reduction of the growth of a Staphylococcus species is desired and/or therapeutically beneficial, for example, for treating staphylococcal infections including a skin infection, cellulitis, pneumonia, meningitis, urinary tract infection, toxic shock syndrome, endocarditis, osteomyelitis, bacteremia, or sepsis, or for preventing or treating a staphylococcus infection that occurs as a result of a surgical procedure.

## Claims

### Claim 1

An isolated bispecific antigen binding molecule comprising:
a) a first antigen-binding domain that binds Staphylococcus aureus IsdB antigen, wherein the first antigen-binding domain comprises three heavy chain complementarity determining regions (HCDRs) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 138 and three light chain complementarity determining regions (LCDRs) contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 146; and
b) a second antigen-binding domain that binds a complement component C1q, wherein the second antigen-binding domain comprises three HCDRs contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and three LCDRs contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 146.

### Claim 2 (depends on 1)

The isolated bispecific antigen binding molecule of claim 1, wherein the bispecific antigen binding molecule binds to the Staphylococcus aureus IsdB antigen with an EC50 of about 10 nM or less.

### Claim 3 (depends on 1)

The isolated bispecific antigen binding molecule of claim 1, wherein the bispecific antigen binding molecule promotes human C1q deposition on Staphylococcus aureus with an EC50 of about 10 nM or less.

### Claim 4 (depends on 1)

The isolated bispecific antigen binding molecule of claim 1, wherein the first antigen-binding domain binds to a Staphylococcus aureus IsdB protein comprising an amino acid sequence of amino acids 3 to 574 if SEQ ID NO: 169.

### Claim 5 (depends on 1)

The isolated bispecific antigen binding molecule of claim 1, wherein the complement component C1q is a human C1q.

### Claim 6 (depends on 1)

The isolated bispecific antigen binding molecule of claim 1, wherein the first antigen binding domain binds to Staphylococcus aureus IsdB with a KD of less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 5 nM, less than about 1 nM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, less than about 20 pM, less than about 10 pM, less than about 5 pM, less than about 4 pM, less than about 2 pM, less than about 1 pM, less than about 0.5 pM, less than about 0.2 pM, less than about 0.1 pM, or less than about 0.05 pM, as measured in a surface plasmon resonance assay.

### Claim 7 (depends on 1)

The isolated bispecific antigen binding molecule of claim 1, wherein the second antigen binding domain binds to complement component C1q with a KD of less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 5 nM, less than about 1 nM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, less than about 20 pM, less than about 10 pM, less than about 5 pM, less than about 4 pM, less than about 2 pM, less than about 1 pM, less than about 0.5 pM, less than about 0.2 pM, less than about 0.1 pM, or less than about 0.05 pM, as measured in a surface plasmon resonance assay.

### Claim 8 (depends on 1)

The isolated bispecific antigen binding molecule of claim 1, wherein the first antigen-binding domain comprises:
a) a heavy chain CDR1 (HCDR1) comprising the amino acid sequence of SEQ ID NO:140, a heavy chain CDR2 (HCDR2) comprising the amino acid sequence of SEQ ID NO:142, and a heavy chain CDR3 (HCDR3) comprising the amino acid sequence of SEQ ID NO:144; and a light chain CDR1 (LCDR1) comprising the amino acid sequence of SEQ ID NO:148, a light chain CDR2 (LCDR2) comprising the amino acid sequence of SEQ ID NO:150, and a light chain CDR3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:152.

### Claim 9 (depends on 1)

The isolated bispecific antigen binding molecule of claim 1, wherein the first antigen binding domain comprises an HCVR/LCVR pair comprising the amino acid sequences of SEQ ID NOs: 138/146.

### Claim 10 (depends on 1)

The isolated bispecific antigen binding molecule of claim 1, wherein the bispecific antigen binding molecule blocks the binding of the human C1q to human IgG1-k with an IC50 of about 10 nM or less.

### Claim 11 (depends on 10)

The isolated bispecific antigen binding molecule of claim 10, wherein the bispecific antigen binding molecule blocks the binding of the human C1q to human IgM with an IC50 of about 50 nM or less.

### Claim 12 (depends on 1)

The isolated bispecific antigen binding molecule of claim 1, wherein the second antigen-binding domain comprises:
b) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and an LCDR1 comprising the amino acid sequence of SEQ ID NO: 148, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 152.

### Claim 13 (depends on 1)

The isolated bispecific antigen binding molecule of claim 1, wherein the second antigen binding domain comprises an HCVR/LCVR pair comprising the amino acid sequences of SEQ ID NOs: 2/146.

### Claim 14 (depends on 1)

The isolated bispecific antigen binding molecule of claim 1, comprising:
a) a first antigen-binding domain that comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO:140, an HCDR2 comprising the amino acid sequence of SEQ ID NO:142, an HCDR3 comprising the amino acid sequence of SEQ ID NO:144, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152; and
b) a second antigen binding domain that comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO:4, an HCDR2 comprising the amino acid sequence of SEQ ID NO:6, an HCDR3 comprising the amino acid sequence of SEQ ID NO:8, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152.

### Claim 15 (depends on 1)

The isolated bispecific antigen binding molecule of claim 1, wherein
a) the first antigen binding domain comprises an HCVR comprising the amino acid sequence of SEQ ID NO:138 and an LCVR comprising the amino acid sequence of SEQ ID NO:146; and
b) the second antigen binding domain comprises an HCVR comprising the amino acid sequence of SEQ ID NO:2 and an LCVR comprising the amino acid sequence of SEQ ID NO:146.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising the bispecific antigen-binding molecule of claim 1, and a pharmaceutically acceptable carrier or diluent.