# US 12,110,335 B2 · Bispecific anti-VEGF and anti-TrkB binding molecules for the treatment of eye diseases

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- Number: US 12,110,335 B2
- Document ID: US12110335B2
- Status: Granted
- Kind: B2
- Application number: 17/505,672
- Filed: 2021-10-20
- Published: 2022-04-21
- Granted: 2024-10-08
- Earliest claimed: 2020-10-21
- Assignees: Boehringer Ingelheim International GmbH
- Applicants: Boehringer Ingelheim International GmbH
- Inventors: Peter Michael Benz; Remko Alexander Bakker; Holger Fuchs; Fei Han; Sandeep Kumar; Sarah Low; Justin M. Scheer; Leo Thomas
- Web page: https://patentgrep.com/patent/US12110335B2

## CPC

- C07K 16/2863: {against receptors for growth factors, growth regulators}
- A61P 27/02: Ophthalmic agents
- C07K 16/22: against growth factors {; against growth regulators}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/14: Specific host cells or culture conditions, e.g. components, pH or temperature
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/30: characterized by aspects of specificity or valency
- C07K 2317/31: multispecific
- C07K 2317/35: Valency
- C07K 2317/53: Hinge
- C07K 2317/54: F(ab')2
- C07K 2317/55: Fab or Fab'
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/64: comprising a combination of variable region and constant region components
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/75: Agonist effect on antigen
- 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: 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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

This invention relates to binding molecules that bind specifically Vascular Endothelial Growth Factor (VEGF) and Tropomyosin receptor kinase B (TrkB) and their use in medicine, pharmaceutical compositions comprising the same, and methods of using the same as agents for treatment and/or prevention of diseases of the eye.

## Claims

### Claim 1

One or more isolated nucleic acid molecules encoding a binding molecule comprising: (i) a light chain comprising the amino acid sequence of SEQ ID NO:41 and a heavy chain comprising the amino acid sequence of SEQ ID NO:42, or (ii) a light chain comprising the amino acid sequence of SEQ ID NO:43 and a heavy chain comprising the amino acid sequence of SEQ ID NO:44, or (iii) a light chain comprising the amino acid sequence of SEQ ID NO:45 and a heavy chain comprising the amino acid sequence of SEQ ID NO:46, or (iv) a light chain comprising the amino acid sequence of SEQ ID NO:47 and a heavy chain comprising the amino acid sequence of SEQ ID NO:48, or (v) a light chain comprising the amino acid sequence of SEQ ID NO:49 and a heavy chain comprising the amino acid sequence of SEQ ID NO:50, or (vi) a light chain comprising the amino acid sequence of SEQ ID NO:51 and a heavy chain comprising the amino acid sequence of SEQ ID NO:52, or (vii) a light chain comprising the amino acid sequence of SEQ ID NO:53 and a heavy chain comprising the amino acid sequence of SEQ ID NO:54, or (viii) a light chain comprising the amino acid sequence of SEQ ID NO:55 and a heavy chain comprising the amino acid sequence of SEQ ID NO:56, or (ix) a light chain comprising the amino acid sequence of SEQ ID NO:57 and a heavy chain comprising the amino acid sequence of SEQ ID NO:58, or (x) a light chain comprising the amino acid sequence of SEQ ID NO:59 and a heavy chain comprising the amino acid sequence of SEQ ID NO:60, or (xi) a light chain comprising the amino acid sequence of SEQ ID NO:61 and a heavy chain comprising the amino acid sequence of SEQ ID NO:62, or (xii) a light chain comprising the amino acid sequence of SEQ ID NO:63 and a heavy chain comprising the amino acid sequence of SEQ ID NO:64, or (xiii) a light chain comprising the amino acid sequence of SEQ ID NO:65 and a heavy chain comprising the amino acid sequence of SEQ ID NO:66, or (xiv) a light chain comprising the amino acid sequence of SEQ ID NO:67 and a heavy chain comprising the amino acid sequence of SEQ ID NO:68, or (xv) a light chain comprising the amino acid sequence of SEQ ID NO:69 and a heavy chain comprising the amino acid sequence of SEQ ID NO:70, or (xvi) a light chain comprising the amino acid sequence of SEQ ID NO:71 and a heavy chain comprising the amino acid sequence of SEQ ID NO:72, or (xvii) a light chain comprising the amino acid sequence of SEQ ID NO:73 and a heavy chain comprising the amino acid sequence of SEQ ID NO:74, or (xviii) a light chain comprising the amino acid sequence of SEQ ID NO:75 and a heavy chain comprising the amino acid sequence of SEQ ID NO:76, or (xix) a light chain comprising the amino acid sequence of SEQ ID NO:77 and a heavy chain comprising the amino acid sequence of SEQ ID NO:78, or (xx) a light chain comprising the amino acid sequence of SEQ ID NO:79 and a heavy chain comprising the amino acid sequence of SEQ ID NO:80, or (xxi) a light chain comprising the amino acid sequence of SEQ ID NO:81 and a heavy chain comprising the amino acid sequence of SEQ ID NO:82, or (xxii) a light chain comprising the amino acid sequence of SEQ ID NO:83 and a heavy chain comprising the amino acid sequence of SEQ ID NO:84, or (xxiii) a light chain comprising the amino acid sequence of SEQ ID NO:85 and a heavy chain comprising the amino acid sequence of SEQ ID NO:86, or (xxiv) a light chain comprising the amino acid sequence of SEQ ID NO:87 and a heavy chain comprising the amino acid sequence of SEQ ID NO:88, or (xxv) a light chain comprising the amino acid sequence of SEQ ID NO:89 and a heavy chain comprising the amino acid sequence of SEQ ID NO:90, or (xxvi) a light chain comprising the amino acid sequence of SEQ ID NO:91 and a heavy chain comprising the amino acid sequence of SEQ ID NO:92, or (xxvii) a light chain comprising the amino acid sequence of SEQ ID NO:93 and a heavy chain comprising the amino acid sequence of SEQ ID NO:94, or (xxviii) a light chain comprising the amino acid sequence of SEQ ID NO:95 and a heavy chain comprising the amino acid sequence of SEQ ID NO:96, or (xxix) a light chain comprising the amino acid sequence of SEQ ID NO:97 and a heavy chain comprising the amino acid sequence of SEQ ID NO:98, or (xxx) a light chain comprising the amino acid sequence of SEQ ID NO:99 and a heavy chain comprising the amino acid sequence of SEQ ID NO:100, or (xxxi) a light chain comprising the amino acid sequence of SEQ ID NO:101 and a heavy chain comprising the amino acid sequence of SEQ ID NO:102, or (xxxii) a light chain comprising the amino acid sequence of SEQ ID NO:103 and a heavy chain comprising the amino acid sequence of SEQ ID NO:104, or (xxxiii) a light chain comprising the amino acid sequence of SEQ ID NO:105 and a heavy chain comprising the amino acid sequence of SEQ ID NO:106, or (xxxiv) a light chain comprising the amino acid sequence of SEQ ID NO:107 and a heavy chain comprising the amino acid sequence of SEQ ID NO:108, or (xxxv) a light chain comprising the amino acid sequence of SEQ ID NO:109 and a heavy chain comprising the amino acid sequence of SEQ ID NO:110, or (xxxvi) a light chain comprising the amino acid sequence of SEQ ID NO:111 and a heavy chain comprising the amino acid sequence of SEQ ID NO:112, or (xxxvii) a light chain comprising the amino acid sequence of SEQ ID NO:113 and a heavy chain comprising the amino acid sequence of SEQ ID NO:114, or (xxxviii) a light chain comprising the amino acid sequence of SEQ ID NO:115 and a heavy chain comprising the amino acid sequence of SEQ ID NO:116, or (xxxix) a light chain comprising the amino acid sequence of SEQ ID NO:117 and a heavy chain comprising the amino acid sequence of SEQ ID NO:118, or (xl) a light chain comprising the amino acid sequence of SEQ ID NO:119 and a heavy chain comprising the amino acid sequence of SEQ ID NO:120, or (xli) a light chain comprising the amino acid sequence of SEQ ID NO:121 and a heavy chain comprising the amino acid sequence of SEQ ID NO:122, or (xlii) a light chain comprising the amino acid sequence of SEQ ID NO:123 and a heavy chain comprising the amino acid sequence of SEQ ID NO:124, or (xliii) a light chain comprising the amino acid sequence of SEQ ID NO:125 and a heavy chain comprising the amino acid sequence of SEQ ID NO:126, or (xliv) a light chain comprising the amino acid sequence of SEQ ID NO:127 and a heavy chain comprising the amino acid sequence of SEQ ID NO:128, or (xlv) a light chain comprising the amino acid sequence of SEQ ID NO:129 and a heavy chain comprising the amino acid sequence of SEQ ID NO:130, or (xlvi) a light chain comprising the amino acid sequence of SEQ ID NO:131 and a heavy chain comprising the amino acid sequence of SEQ ID NO:132, or (xlvii) a light chain comprising the amino acid sequence of SEQ ID NO:133 and a heavy chain comprising the amino acid sequence of SEQ ID NO:134, or (xlviii) a light chain comprising the amino acid sequence of SEQ ID NO:135 and a heavy chain comprising the amino acid sequence of SEQ ID NO:136, or (xlix) a light chain comprising the amino acid sequence of SEQ ID NO:137 and a heavy chain comprising the amino acid sequence of SEQ ID NO:138, or (l) a light chain comprising the amino acid sequence of SEQ ID NO:139 and a heavy chain comprising the amino acid sequence of SEQ ID NO:140, or (ii) a light chain comprising the amino acid sequence of SEQ ID NO:141 and a heavy chain comprising the amino acid sequence of SEQ ID NO:142, or (lii) a light chain comprising the amino acid sequence of SEQ ID NO:143 and a heavy chain comprising the amino acid sequence of SEQ ID NO:144.

### Claim 2 (depends on 1)

A viral vector comprising the isolated nucleic acid molecule of claim 1.

### Claim 3 (depends on 1)

An expression vector comprising a nucleic acid molecule according to claim 1.

### Claim 4 (depends on 3)

A host cell transfected with an expression vector of claim 3.

### Claim 5 (depends on 4)

A method of manufacturing a binding molecule, comprising
(a) cultivating a host cell according to claim 4 under conditions allowing expression of the binding molecule;
(b) recovering the binding molecule; and
c) further purifying and/or modifying and/or formulating the binding molecule.

### Claim 6 (depends on 1)

The one or more isolated nucleic acid molecules of claim 1, wherein the binding molecule comprises: (i) a light chain comprising the amino acid sequence of SEQ ID NO:41 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 42, or (ii) a light chain comprising the amino acid sequence of SEQ ID NO:43 and a heavy chain comprising the amino acid sequence of SEQ ID NO:44, or (iii) a light chain comprising the amino acid sequence of SEQ ID NO:45 and a heavy chain comprising the amino acid sequence of SEQ ID NO:46, or (iv) a light chain comprising the amino acid sequence of SEQ ID NO:47 and a heavy chain comprising the amino acid sequence of SEQ ID NO:48, or (v) a light chain comprising the amino acid sequence of SEQ ID NO:49 and a heavy chain comprising the amino acid sequence of SEQ ID NO:50.

### Claim 7 (depends on 1)

The one or more isolated nucleic acid molecules of claim 1, wherein the binding molecule comprises: (vi) a light chain comprising the amino acid sequence of SEQ ID NO:51 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 52, or (vii) a light chain comprising the amino acid sequence of SEQ ID NO:53 and a heavy chain comprising the amino acid sequence of SEQ ID NO:54, or (viii) a light chain comprising the amino acid sequence of SEQ ID NO:55 and a heavy chain comprising the amino acid sequence of SEQ ID NO:56, or (ix) a light chain comprising the amino acid sequence of SEQ ID NO:57 and a heavy chain comprising the amino acid sequence of SEQ ID NO:58, or (x) a light chain comprising the amino acid sequence of SEQ ID NO:59 and a heavy chain comprising the amino acid sequence of SEQ ID NO:60.

### Claim 8 (depends on 1)

The one or more isolated nucleic acid molecules of claim 1, wherein the binding molecule comprises: (xi) a light chain comprising the amino acid sequence of SEQ ID NO:61 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 62, or (xii) a light chain comprising the amino acid sequence of SEQ ID NO:63 and a heavy chain comprising the amino acid sequence of SEQ ID NO:64, or (xiii) a light chain comprising the amino acid sequence of SEQ ID NO:65 and a heavy chain comprising the amino acid sequence of SEQ ID NO:66, or (xiv) a light chain comprising the amino acid sequence of SEQ ID NO:67 and a heavy chain comprising the amino acid sequence of SEQ ID NO:68, or (xv) a light chain comprising the amino acid sequence of SEQ ID NO:69 and a heavy chain comprising the amino acid sequence of SEQ ID NO:70.

### Claim 9 (depends on 1)

The one or more isolated nucleic acid molecules of claim 1, wherein the binding molecule comprises: (xxi) a light chain comprising the amino acid sequence of SEQ ID NO:81 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 82, or (xxii) a light chain comprising the amino acid sequence of SEQ ID NO:83 and a heavy chain comprising the amino acid sequence of SEQ ID NO:84, or (xxiii) a light chain comprising the amino acid sequence of SEQ ID NO:85 and a heavy chain comprising the amino acid sequence of SEQ ID NO:86, or (xxiv) a light chain comprising the amino acid sequence of SEQ ID NO:87 and a heavy chain comprising the amino acid sequence of SEQ ID NO:88, or (xxv) a light chain comprising the amino acid sequence of SEQ ID NO:89 and a heavy chain comprising the amino acid sequence of SEQ ID NO:90.

### Claim 10 (depends on 1)

The one or more isolated nucleic acid molecules of claim 1, wherein the binding molecule comprises: (xxvi) a light chain comprising the amino acid sequence of SEQ ID NO:91 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 92, or (xxvii) a light chain comprising the amino acid sequence of SEQ ID NO: 93 and a heavy chain comprising the amino acid sequence of SEQ ID NO:94, or (xxviii) a light chain comprising the amino acid sequence of SEQ ID NO:95 and a heavy chain comprising the amino acid sequence of SEQ ID NO:96, or (xxix) a light chain comprising the amino acid sequence of SEQ ID NO:97 and a heavy chain comprising the amino acid sequence of SEQ ID NO:98, or (xxx) a light chain comprising the amino acid sequence of SEQ ID NO:99 and a heavy chain comprising the amino acid sequence of SEQ ID NO:100.

### Claim 11 (depends on 1)

The one or more isolated nucleic acid molecules of claim 1, wherein the binding molecule comprises: (xxxi) a light chain comprising the amino acid sequence of SEQ ID NO:101 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 102, or (xxxii) a light chain comprising the amino acid sequence of SEQ ID NO: 103 and a heavy chain comprising the amino acid sequence of SEQ ID NO:104, or (xxxiii) a light chain comprising the amino acid sequence of SEQ ID NO:105 and a heavy chain comprising the amino acid sequence of SEQ ID NO:106, or (xxxiv) a light chain comprising the amino acid sequence of SEQ ID NO:107 and a heavy chain comprising the amino acid sequence of SEQ ID NO:108, or (xxxv) a light chain comprising the amino acid sequence of SEQ ID NO:109 and a heavy chain comprising the amino acid sequence of SEQ ID NO:110.

### Claim 12 (depends on 1)

The one or more isolated nucleic acid molecules of claim 1, wherein the binding molecule comprises: (xxxvi) a light chain comprising the amino acid sequence of SEQ ID NO:111 and a heavy chain comprising the amino acid sequence of SEQ ID NO:112, or (xxxvii) a light chain comprising the amino acid sequence of SEQ ID NO:113 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 114, or (xxxviii) a light chain comprising the amino acid sequence of SEQ ID NO: 115 and a heavy chain comprising the amino acid sequence of SEQ ID NO:116, or (xxxix) a light chain comprising the amino acid sequence of SEQ ID NO:117 and a heavy chain comprising the amino acid sequence of SEQ ID NO:118, or (x1) a light chain comprising the amino acid sequence of SEQ ID NO:119 and a heavy chain comprising the amino acid sequence of SEQ ID NO:120.

### Claim 13 (depends on 1)

The one or more isolated nucleic acid molecules of claim 1, wherein the binding molecule comprises: (xli) a light chain comprising the amino acid sequence of SEQ ID NO:121 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 122, or (xlii) a light chain comprising the amino acid sequence of SEQ ID NO: 123 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 124, or (xliii) a light chain comprising the amino acid sequence of SEQ ID NO:125 and a heavy chain comprising the amino acid sequence of SEQ ID NO:126, or (xliv) a light chain comprising the amino acid sequence of SEQ ID NO:127 and a heavy chain comprising the amino acid sequence of SEQ ID NO:128, or (xlv) a light chain comprising the amino acid sequence of SEQ ID NO:129 and a heavy chain comprising the amino acid sequence of SEQ ID NO:130.

### Claim 14 (depends on 1)

The one or more isolated nucleic acid molecules of claim 1, wherein the binding molecule comprises: (xlvi) a light chain comprising the amino acid sequence of SEQ ID NO:131 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 132, or (xlvii) a light chain comprising the amino acid sequence of SEQ ID NO: 133 and a heavy chain comprising the amino acid sequence of SEQ ID NO:134, or (xlviii) a light chain comprising the amino acid sequence of SEQ ID NO:135 and a heavy chain comprising the amino acid sequence of SEQ ID NO:136, or (xlix) a light chain comprising the amino acid sequence of SEQ ID NO:137 and a heavy chain comprising the amino acid sequence of SEQ ID NO:138, or (1) a light chain comprising the amino acid sequence of SEQ ID NO:139 and a heavy chain comprising the amino acid sequence of SEQ ID NO:140.

### Claim 15 (depends on 1)

The one or more isolated nucleic acid molecules of claim 1, wherein the binding molecule comprises: (li) a light chain comprising the amino acid sequence of SEQ ID NO: 141 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 142, or (lii) a light chain comprising the amino acid sequence of SEQ ID NO: 143 and a heavy chain comprising the amino acid sequence of SEQ ID NO:144.