# US 2014/0154255 A1 · Anti-vegf antibodies and their uses

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- Number: US 2014/0154255 A1
- Document ID: US20140154255A1
- Status: Published application
- Kind: A1
- Application number: 14/090,361
- Filed: 2013-11-26
- Published: 2014-06-05
- Earliest claimed: 2012-11-30
- Assignees: AbbVie Biotherapeutics Inc.
- Applicants: AbbVie Biotherapeutics Inc.
- Inventors: Yoshiko AKAMATSU
- Web page: https://patentgrep.com/patent/US20140154255A1

## CPC

- C07K 16/22: against growth factors {; against growth regulators}
- A61K 47/6845: {the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon}
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 27/02: Ophthalmic agents
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/02: Immunomodulators
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/41: Glycosylation, sialylation, or fucosylation
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/524: CH2 domain
- C07K 2317/526: CH3 domain
- C07K 2317/565: Complementarity determining region [CDR]
- 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
- Y02P 20/582: Recycling of unreacted starting or intermediate materials
- 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
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

The present disclosure relates to antibodies directed to vascular endothelial growth factor (“VEGF”) and uses of such antibodies, for example to treat diseases associated with the activity and/or overproduction of VEGF.

## Claims

### Claim 1

An anti-VEGF antibody or an anti-VEGF binding fragment of an antibody which comprises a VEGF heavy chain variable region comprising CDRs having amino acid sequences corresponding to SEQ ID NO:3 (CDR-H1), SEQ ID NO:4 (CDR-H2), and SEQ ID NO:5 (CDR-H3), and a VEGF light chain variable region comprising CDRs having amino acid sequences corresponding SEQ ID NO:6 (CDR-L1), SEQ ID NO:7 (CDR-L2) and SEQ ID NO:8, wherein CDR-H1 and/or CDR-H3 comprises one or more of the substitutions in Table 21, and optionally one or more mutations or combinations of mutations selected from one or more of Tables 6, 7, 8, 9, 19, 12-1 to 12-9, 13-16, 21, or 22, wherein the six CDRs altogether have up to 17 amino acid substitutions as compared to CDR sequences of the antibody bevacizumab or the antibody ranibizumab.

### Claim 2 (depends on 1)

The anti-VEGF antibody or anti VEGF binding fragment of claim 1 which comprises one or more substitutions selected from T30K; T30N, N31H; N31L; N31W; N31Y; H97F; H97Y; S100aQ; and S100aT.

### Claim 3 (depends on 1)

The anti-VEGF antibody or anti VEGF binding fragment of claim 1 which comprises one or more substitutions selected from T28G; T28R; T28Y; T30R; and S100aA.

### Claim 4 (depends on 1)

The anti-VEGF antibody or anti VEGF binding fragment of claim 1 which comprises one or more substitutions selected from N31F; N31H; and N31Y.

### Claim 5 (depends on 1)

The anti-VEGF antibody or anti VEGF binding fragment of claim 1 which comprises one or more substitutions selected T30N; N31F; N31H, N31W and N31Y; and S100aT.

### Claim 6 (depends on 1)

The anti-VEGF antibody or an anti-VEGF binding fragment of claim 1 which comprises the substitution T30K.

### Claim 7 (depends on 1)

The anti-VEGF antibody or an anti-VEGF binding fragment of claim 1 which comprises the substitution T30N.

### Claim 8 (depends on 1)

The anti-VEGF antibody or an anti-VEGF binding fragment of claim 1 which comprises the substitution N31H.

### Claim 9 (depends on 1)

The anti-VEGF antibody or an anti-VEGF binding fragment of claim 1 which comprises the substitution N31L.

### Claim 10 (depends on 1)

The anti-VEGF antibody or an anti-VEGF binding fragment of claim 1 which comprises the substitution N31W.

### Claim 11 (depends on 1)

The anti-VEGF antibody or an anti-VEGF binding fragment of claim 1 which comprises the substitution N31Y.

### Claim 12 (depends on 1)

The anti-VEGF antibody or an anti-VEGF binding fragment of claim 1 which comprises the substitution H97F.

### Claim 13 (depends on 1)

The anti-VEGF antibody or an anti-VEGF binding fragment of claim 1 which comprises the substitution H97Y.

### Claim 14 (depends on 1)

The anti-VEGF antibody or an anti-VEGF binding fragment of claim 1 which comprises the substitution S100aQ.

### Claim 15 (depends on 1)

The anti-VEGF antibody or an anti-VEGF binding fragment of claim 1 which comprises the substitution S100aT.

### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)

The antibody of any of claims 1 to 15, which is a DVD-Ig in which said VEGF heavy and light chain variable regions together form a VEGF binding portion and which further comprises a second binding portion, said second binding portion comprising second heavy chain and light chain variable regions which together bind to a second target.

### Claim 17

A DVD-Ig comprising:
(a) a VEGF binding portion comprising a VEGF heavy chain variable region comprising CDRs having amino acid sequences corresponding to SEQ ID NO:3 (CDR-H1), SEQ ID NO:4 (CDR-H2), and SEQ ID NO:5 (CDR-H3) and a VEGF light chain variable region comprising CDRs having amino acid sequences corresponding SEQ ID NO:6 (CDR-L1), SEQ ID NO:7 (CDR-L2) and SEQ ID NO:8, wherein CDRs of the VEGF binding portion include one or more substitutions as compared to bevacizumab or ranibizumab selected from N31F in CDR-H1; K64S in CDR-H2; K64Q in CDR-H2; Y53F in CDR-H2; H97E in CDR-H3; H97D in CDR-H3; H97P in CDR-H3; Y98F in CDR-H3; Y99E in CDR-H3; Y99D in CDR-H3; S100aG in CDR-H3; and T51A in CDR-L2, wherein the anti-VEGF binding portion optionally has one or more additional mutations or combinations of mutations selected from one or more of Tables 6, 7, 8, 9, 10, 11, 12-1 to 12-9, 13-16, or 21-22, wherein the six CDRs of the VEGF binding portion altogether have up to 17 amino acid substitutions as compared to CDR sequences of the antibody bevacizumab or the antibody ranibizumab; and
(b) a second binding portion comprising second heavy and light chain variable regions which together bind to a second target.

### Claim 18 (depends on 16, 17)

The antibody of claim 16 or claim 17, wherein the second binding portion is on the outside of the VEGF binding portion.

### Claim 19 (depends on 16, 17)

The antibody of claim 16 or claim 17, wherein the VEGF binding portion is on the outside of the second binding portion.

### Claim 20 (depends on 16, 17, 18, 19)

The antibody of any one of claims 16 to 19, wherein the VEGF and second heavy chain variable regions are connected via a short linker, optionally ASTKGP (SEQ ID NO:427) or GGGGSG (SEQ ID NO:430).

### Claim 21 (depends on 16, 17, 18, 19)

The antibody of any one of claims 16 to 19, wherein the VEGF and second heavy chain variable regions are connected via a medium linker, optionally GGGGSGGGGS (SEQ ID NO:431).

### Claim 22 (depends on 16, 17, 18, 19)

The antibody of any one of claims 16 to 19, wherein the VEGF and second heavy chain variable regions are connected via a long linker, optionally ASTKGPSVFPLAP (SEQ ID NO:429) or GGGGSGGGGSGGGG (SEQ ID NO:432).

### Claim 23 (depends on 16, 17, 18, 19, 20, 21, 22)

The antibody of any one of claims 16 to 22, wherein the VEGF and second light chain variable regions are connected via a short linker, optionally TVAAP (SEQ ID NO: 418), QPKAAP (SEQ ID NO: 421), or GGSGG (SEQ ID NO: 423).

### Claim 24 (depends on 16, 17, 18, 19, 20, 21, 22)

The antibody of any one of claims 16 to 22, wherein the VEGF and second light chain variable regions are connected via a medium linker, optionally GGSGGGGSG (SEQ ID NO:424).

### Claim 25 (depends on 16, 17, 18, 19, 20, 21, 22)

The antibody of any one of claims 16 to 22, wherein the VEGF and second light chain variable regions are connected via a long linker, optionally TVAAPSVFIFPP (SEQ ID NO:420), QPKAAPSVTLFPP (SEQ ID NO:422), or GGSGGGGSGGGGS (SEQ ID NO:425).

### Claim 26 (depends on 16, 17, 18, 19, 20, 21, 22, 23, 24, 25)

The antibody of any one of claims 16 to 25, wherein the second target is DLL4.

### Claim 27 (depends on 26)

The antibody of claim 26, wherein the CDRs second heavy and light chain variable regions have the CDR sequences of the CDRs of DLL4 binding portions SEQ ID NO:413 and SEQ ID NO:414.

### Claim 28 (depends on 27)

The antibody of claim 27, wherein the second heavy and light chain variable regions have the sequences of the DLL4 binding portions of SEQ ID NO:413 and SEQ ID NO:414.

### Claim 29 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)

The antibody or binding fragment of any one of claims 1-28, wherein CDR-H2 includes the substitution K64S.

### Claim 30 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)

The antibody or binding fragment of any one of claims 1-28, wherein CDR-H2 includes the substitution K64Q.

### Claim 31 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)

The antibody or binding fragment of any one of claims 1-28, wherein CDR-H2 includes the substitutions Y53F and K64Q.

### Claim 32 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31)

The antibody or binding fragment of any one of claims 1-12 and 14-31, wherein CDR-H3 includes the substitutions H97E and Y98F.

### Claim 33 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32)

The antibody or binding fragment of any one of claims 1-32, wherein CDR-L2 includes the substitution T51A, and wherein CDR-L2 in said VEGF antibody does not consist of a CDR-L2 sequence set forth in Table 13.

### Claim 34 (depends on 1, 2, 3, 4, 5, 6, 7, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33)

The antibody or binding fragment of any one of claims 1-7 and 12-33, wherein said CDR-H1 includes the substitution N31F, and wherein CDR-H1 in said VEGF antibody does not consist of a CDR-H1 sequence set forth in Tables 12-1 to 12-9.

### Claim 35 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34)

The antibody or binding fragment of any one of claims 1-11 and 14-34, wherein said CDR-H3 includes the substitution H97E, and wherein CDR-H3 in said VEGF antibody does not consist of a CDR-H3 sequence set forth in Tables 12-1 to 12-9.

### Claim 36 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31)

The antibody or binding fragment of any one of claims 1-11, 14-31, and 33-34, wherein said CDR-H3 includes the substitution H97D, and wherein CDR-H3 in said VEGF antibody does not consist of a CDR-H3 sequence set forth in Tables 12-1 to 12-9.

### Claim 37 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31)

The antibody or binding fragment of any one of claims 1-11, 14-31, and 33-34, wherein said CDR-H3 includes the substitution H97P, and wherein CDR-H3 in said VEGF antibody does not consist of a CDR-H3 sequence set forth in Tables 12-1 to 12-9.

### Claim 38 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37)

The antibody or binding fragment of any one of claims 1-37, wherein said CDR-H3 includes the substitution Y99E, and wherein CDR-H3 in said VEGF antibody does not consist of a CDR-H3 sequence set forth in Tables 12-1 to 12-9.

### Claim 39 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37)

The antibody or binding fragment of any one of claims 1-37, wherein said CDR-H3 includes the substitution Y99D, and wherein CDR-H3 in said VEGF antibody does not consist of a CDR-H3 sequence set forth in Tables 12-1 to 12-9.

### Claim 40 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)

The antibody or binding fragment of any one of claims 1-13 and 18-39, wherein said CDR-H3 includes the substitution S100aG, and wherein CDR-H3 in said VEGF antibody does not consist of a CDR-H3 sequence set forth in Tables 12-1 to 12-9.

### Claim 41 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)

The antibody or binding fragment of any one of claims 1-13, and 18-40, wherein said CDR-H3 includes the substitution S100aG, and wherein position 3 in CDR-H3 of said VEGF antibody is not tyrosine.

### Claim 42 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41)

The antibody or binding fragment of any one of claims 1-41, wherein CDR-H1 includes at least one substitution selected from T28P, N31F, N31G and N31M, and wherein CDR-H1 in said VEGF antibody does not consist of a CDR-H1 sequence set forth in Tables 12-1 to 12-9.

### Claim 43 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42)

The antibody or binding fragment of any one of claims 1-42, wherein CDR-H3 includes at least one substitution selected from H97A, H97Q, H97S, H97T, S100aD, S100aE, and S100aV, and wherein CDR-H3 in said VEGF antibody does not consist of a CDR-H3 sequence set forth in Tables 12-1 to 12-9.

### Claim 44 (depends on 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43)

The antibody or binding fragment of any one of claims 8-43, wherein CDR-H1 includes the substitution T30W, T30R or T30Q, and wherein CDR-H1 in said VEGF antibody does not consist of a CDR-H1 sequence set forth in Tables 12-1 to 12-9.

### Claim 45 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44)

The antibody or binding fragment of any one of claims 1-44, wherein CDR-H2 includes at least one substitution selected from Y53F, T58F, A61G, A61K, A61R, A61H, A61Y, K64G, K64E, R65L, R65T, R65A, R65E, and R65D, and wherein CDR-H2 in said VEGF antibody does not consist of a CDR-H2 sequence set forth in Tables 12-1 to 12-9.

### Claim 46 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45)

The antibody or binding fragment of any one of claims 1-45, wherein CDR-H3 includes at least one substitution selected from Y98F and Y100eF, and wherein CDR-H3 in said VEGF antibody does not consist of a CDR-H3 sequence set forth in Tables 12-1 to 12-9.

### Claim 47 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)

The antibody or binding fragment of any one of claims 1-18, wherein the heavy chain CDRs include a combination of substitutions selected from:
(a) N31F in CDR-H1, H97D in CDR-H3, Y99D in CDR-H3, and S100aG in CDR-H3;
(b) N31F in CDR-H1, H97P in CDR-H3, Y99D in CDR-H3, and S100aG in CDR-H3;
(c) N31F in CDR-H1, H97P in CDR-H3, and Y99E in CDR-H3;
(d) N31F in CDR-H1, H97E in CDR-H3, and Y99E in CDR-H3;
(e) N31F in CDR-H1, H97D in CDR-H3, and Y99E in CDR-H3;
(f) N31F in CDR-H1, H97E in CDR-H3, Y99D in CDR-H3, and S100aG in CDR-H3;
(g) N31F in CDR-H1, Y99D in CDR-H3, and S100aG in CDR-H3;
(h) N31F in CDR-H1, H97P in CDR-H3, and Y99D in CDR-H3;
(i) N31F in CDR-H1, H97D in CDR-H3, and S100aG in CDR-H3;
(j) N31F in CDR-H1 and S100aG in CDR-H3;
(k) N31F in CDR-H1, H97P in CDR-H3, and S100aG in CDR-H3.

### Claim 48 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47)

The anti-VEGF antibody or anti-VEGF binding fragment of any one of claims 1 to 47, wherein the six CDRs altogether have up to 16, up to 15, up to 14, up to 13, up to 12, up to 11, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, or up to 4 amino acid substitutions as compared to CDR sequences of the antibody bevacizumab or the antibody ranibizumab.

### Claim 49 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46)

The anti-VEGF antibody or anti-VEGF binding fragment of any one of claims 1 to 46, wherein any individual CDR has no more than three amino acid substitutions as compared to the corresponding CDR sequence of the antibody bevacizumab or the antibody ranibizumab.

### Claim 50 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46)

The anti-VEGF antibody or anti-VEGF binding fragment of any one of claims 1 to 46, wherein any individual CDR has no more than two amino acid substitutions as compared to the corresponding CDR sequence of the antibody bevacizumab or the antibody ranibizumab.

### Claim 51 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50)

The anti-VEGF antibody or anti-VEGF binding fragment of any one of claims 1 to 50 which is a monoclonal antibody or anti-VEGF binding fragment of a monoclonal antibody, respectively.

### Claim 52 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51)

The antibody or binding fragment of any one of claims 1 to 51 which is a human or humanized antibody, or anti-VEGF binding fragment of a humanized or humanized antibody, respectively.

### Claim 53 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52)

The antibody or binding fragment of any one of claims 1 to 52 which is an IgG.

### Claim 54 (depends on 53)

The antibody or binding fragment of claim 53 which is an IgG1.

### Claim 55 (depends on 53)

The antibody or binding fragment of claim 53 which is an IgG2.

### Claim 56 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55)

The antibody or binding fragment of any one of claims 1 to 55 which is a dual-variable domain (DVD) immunoglobulin.

### Claim 57 (depends on 56)

The antibody or binding fragment of claim 56 which has an anti-DLL4 variable binding domain.

### Claim 58 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57)

The antibody or binding fragment of any one of claims 1 to 57 which includes one or more mutations in the Fc region that increase ADCC activity.

### Claim 59 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58)

The antibody or binding fragment of any one of claims 1 to 58 which is non-fucosylated.

### Claim 60 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59)

The antibody or binding fragment of any one of claims 1 to 59 which includes one or more mutations in the Fc region that increase binding to FcγR.

### Claim 61 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59)

The antibody or binding fragment of any one of claims 1 to 59 which includes one or more mutations in the Fc region that increase binding to FcRn.

### Claim 62 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54)

The antibody or binding fragment of any one of claims 1 to 54 which includes one or more mutations in the Fc region that decrease ADCC activity.

### Claim 63 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62)

The antibody or binding fragment of any one of claims 1 to 62 which has, other than said one or more mutations, a VH sequence corresponding to SEQ ID NO:1 and a VL sequence corresponding to SEQ ID NO:2.

### Claim 64 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55)

The antibody or binding fragment of any one of claims 1-15, 29-55, and 58-63 which has, other than said one or more mutations, a heavy chain sequence corresponding to SEQ ID NO:9 and a light chain sequence corresponding to SEQ ID NO:10.

### Claim 65 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63)

The antibody or binding fragment of any one of claims 1 to 63 which has an affinity that is 1.5- to 50-fold greater than the affinity of an antibody having a VH sequence corresponding to SEQ ID NO:1 and a VL sequence corresponding to SEQ ID NO:2.

### Claim 66 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63)

The antibody or binding fragment of any one of claims 1 to 63 which has an affinity that is 1.5- to 50-fold greater than the affinity of an antibody having a heavy chain sequence corresponding to SEQ ID NO:9 and a light chain sequence corresponding to SEQ ID NO:10.

### Claim 67 (depends on 65)

The antibody or binding fragment of claim 65 which has a 2- to 30-fold greater than the affinity of an antibody having a VH sequence corresponding to SEQ ID NO:1 and a VL sequence corresponding to SEQ ID NO:2.

### Claim 68 (depends on 66)

The antibody or binding fragment of claim 66 which has a 2- to 30-fold greater than the affinity of an antibody having a heavy chain sequence corresponding to SEQ ID NO:9 and a light chain sequence corresponding to SEQ ID NO:10

### Claim 69 (depends on 65, 66, 67, 68)

The antibody or binding fragment of any one of claims 65 to 68, wherein the affinity is a measure of KD as analyzed by a biosensor.

### Claim 70 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69)

The antibody or binding fragment of any one of claims 1 to 69 which is purified.

### Claim 71 (depends on 70)

The antibody or binding fragment of claim 70 which is purified to at least 85%, at least 90%, at least 95% or at least 98% homogeneity.

### Claim 72 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71)

The antibody or binding fragment of any one of claims 1-71, wherein the heavy chain includes at least one substitution selected from A61F in CDR-H2, A61E in CDR-H2, A61D in CDR-H2, D62L in CDR-H2, D62G in CDR-H2, D62Q in CDR-H2, D62T in CDR-H2, D62K in CDR-H2, D62R in CDR-H2, D62E in CDR-H2, D62H in CDR-H2, K64S in CDR-H2, K64V in CDR-H2, K64Q in CDR-H2, R65V in CDR-H2, R65F in CDR-H2, R65H in CDR-H2, R65N in CDR-H2, R65S in CDR-H2, R65Q in CDR-H2, R65K in CDR-H2, R65I in CDR-H2, and Y98H in CDR-H3.

### Claim 73 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72)

An antibody-drug conjugate comprising an anti-VEGF antibody or anti-VEGF binding fragment according to any one of claims 1 to 72.

### Claim 74 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73)

A pharmaceutical composition comprising an anti-VEGF antibody or anti-VEGF binding fragment according to any one of claims 1 to 72 or an antibody-drug conjugate according to claim 73, and a pharmaceutically acceptable carrier.

### Claim 75 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72)

A nucleic acid comprising a nucleotide sequence encoding anti-VEGF antibody or anti-VEGF binding fragment of any one of claims 1 to 72.

### Claim 76 (depends on 75)

A vector comprising the nucleic acid of claim 75.

### Claim 77 (depends on 76)

A prokaryotic host cell transformed with a vector according to claim 76.

### Claim 78 (depends on 76)

A eukaryotic host cell transformed with a vector according to claim 76.

### Claim 79 (depends on 75)

A eukaryotic host cell engineered to express the nucleotide sequence of claim 75.

### Claim 80 (depends on 79)

The eukaryotic host cell of claim 79 which is a mammalian host cell.

### Claim 81 (depends on 79, 80)

A method of producing anti-VEGF antibody or anti-VEGF binding fragment, comprising: (a) culturing the eukaryotic host cell of claim 79 or claim 80 and (b) recovering the anti-VEGF antibody or anti-VEGF binding fragment antibody.

### Claim 82 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74)

A method of treating cancer, comprising administering to a human patient in need thereof a therapeutically effective amount of anti-VEGF antibody or anti-VEGF binding fragment according to any one of claims 1 to 72, an antibody-drug conjugate according to claim 73, or a pharmaceutical composition according to claim 74.

### Claim 83 (depends on 82)

The method of claim 82, wherein the cancer is metastatic carcinoma of the colon, metastatic carcinoma of the rectum, non-squamous non-small cell lung cancer, or metastatic HER2-negative breast cancer.

### Claim 84 (depends on 83)

The method of claim 83, wherein the cancer is non-squamous non-small cell lung cancer which is unresectable, locally advanced, recurrent or metastatic.

### Claim 85 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74)

A method of treating age-related macular degeneration, comprising administering to a human patient in need thereof a therapeutically effective amount of anti-VEGF antibody or anti-VEGF binding fragment according to any one of claims 1 to 72, an antibody-drug conjugate according to claim 73, or a pharmaceutical composition according to claim 74.

### Claim 86 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74)

A method of treating an immune disorder, comprising administering to a human patient in need thereof a therapeutically effective amount of anti-VEGF antibody or anti-VEGF binding fragment according to any one of claims 1 to 72, an antibody-drug conjugate according to claim 73, or a pharmaceutical composition according to claim 74.

### Claim 87 (depends on 86)

The method of claim 86, wherein the immune disorder is rheumatoid arthritis or Grave's disease.