# US 12,180,272 B2 · Antigen binding molecule formats

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- Number: US 12,180,272 B2
- Document ID: US12180272B2
- Status: Granted
- Kind: B2
- Application number: 17/666,107
- Filed: 2022-02-07
- Published: 2022-07-28
- Granted: 2024-12-31
- Earliest claimed: 2019-08-08
- Assignees: Regeneron Pharmaceuticals, Inc.
- Applicants: Regeneron Pharmaceuticals, Inc.
- Inventors: Tong Zhang; Erica Pyles; Michael Rosconi; Nina Liu; Supriya Patel; Eric Smith; Andrew Murphy; Chia-Yang Lin; Samuel Davis
- Web page: https://patentgrep.com/patent/US12180272B2

## CPC

- C07K 16/244: {Interleukins [IL]}
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 47/6845: {the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61P 35/00: Antineoplastic agents
- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- C07K 16/30: from tumour cells
- C07K 16/46: Hybrid immunoglobulins (hybrids of an immunoglobulin with a peptide not being an immunoglobulin C07K19/00)
- A61K 2039/505: {comprising antibodies}
- C07K 2317/31: multispecific
- C07K 2317/35: Valency
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/522: CH1 domain
- C07K 2317/53: Hinge
- C07K 2317/55: Fab or Fab'
- C07K 2317/64: comprising a combination of variable region and constant region components
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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

Antigen binding molecules (ABMs) comprising Fab domains in non-native configurations, ABM conjugates comprising the ABMs and cytotoxic or cytostatic agents, pharmaceutical compositions containing the ABMs and ABM conjugates, methods of using the ABMs, ABM conjugates and pharmaceutical compositions for treating cancer, nucleic acids encoding the ABMs, cells engineered to express the ABMs, and methods of producing ABMs.

## Claims

### Claim 1

A bispecific antigen-binding molecule comprising:
(a) a first polypeptide chain comprising in an N-to-C terminal orientation:
(i) a first Fc domain; and
(ii) a first Fab domain that binds to a cytokine and comprises a first heavy chain variable region (VH) domain associated with a first light chain variable region (VL) domain; and
(b) a second polypeptide chain comprising in an N-to-C terminal orientation:
(i) a second Fc domain associated with the first Fc domain to form an Fc heterodimer; and
(ii) a second Fab domain that is non-identical to the first Fab domain, binds to the cytokine, and comprises a second VH domain associated with a second VL domain;
(c) a third polypeptide chain associated with the first polypeptide, the third polypeptide comprising in an N-to-C terminal orientation:
(i) the first VL domain; and
(ii) a first constant domain of the light chain (CL) domain; and
(d) a fourth polypeptide chain associated with the second polypeptide, the fourth polypeptide comprising in an N-to-C terminal orientation:
(i) the second VL domain; and
(ii) a second CL domain,
wherein the first Fab domain and the second Fab domain are the only antigen-binding domains in the antigen-binding molecule.

### Claim 2 (depends on 1)

The antigen-binding molecule of claim 1, which comprises a first linker between the first Fc domain and the first VH domain and a second linker between the second Fc domain and the second VH domain.

### Claim 3 (depends on 2)

The antigen-binding molecule of claim 2, wherein the first linker and the second linker have identical amino acid sequences.

### Claim 4 (depends on 1)

The antigen-binding molecule of claim 1, wherein the first polypeptide chain comprises a first hinge domain N-terminal to the first Fc domain and the second polypeptide chain comprises a second hinge domain N-terminal to the second Fc domain.

### Claim 5 (depends on 1)

The antigen-binding molecule of claim 1, which has one hinge region.

### Claim 6 (depends on 1)

The antigen-binding molecule of claim 1, which has two hinge regions.

### Claim 7 (depends on 1)

The antigen-binding molecule of claim 1, wherein the Fc domains in the Fc heterodimer comprise knob-in-hole mutations as compared to a wild type Fc domain.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising the antigen-binding molecule of claim 1 and an excipient.

### Claim 9 (depends on 1)

The antigen-binding molecule of claim 1, which is complexed at a 1:1 ratio with the cytokine.

### Claim 10 (depends on 1)

The antigen-binding molecule of claim 1, wherein the cytokine is thymic stromal lymphopoietin (TSLP), IL-1α, IL-1β, IL-12, IL-18, TNFα, IL-23, IL-13, macrophage migration inhibitory factor (MIF), IL-6, IL-17, IL-20, IL-15, IL-9, IL-4, IL-5, IL-25, TGF-β, CCL25.

### Claim 11 (depends on 1)

The antigen-binding molecule of claim 1, wherein the cytokine is human thymic stromal lymphopoietin (TSLP).