Antibodies against the RGM a protein and uses thereof

• US 9,605,069 B2
• Filed: 01/07/2015
• Issued: 03/28/2017
• Est. Priority Date: 02/29/2008
• Status: Active Grant

• Current Assignee: Abbvie Deutschland GmbH & Company KG (Abbvie Incorporated)
• Original Assignee: Abbvie Deutschland GmbH & Company KG (Abbvie Incorporated), Abbvie Incorporated
• Inventors: Mueller, Bernhard K., Schmidt, Martin, Barlow, Eve, Leddy, Mary, Hsieh, Chung-Ming, Bardwell, Philip
• Primary Examiner(s): Goddard, Laura B
• Assistant Examiner(s): Natarajan, Meera
• Application Number:
  US14/591,445
• Publication Number:
  US 20150183871A1
• Time in Patent Office: 811 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 : Framework region [FR]
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The subject invention relates to isolated proteins, particularly monoclonal antibodies, which bind and neutralize RGM A protein. Specifically, these antibodies have the ability to inhibit the binding of RGM A to its receptor and/or coreceptors. These antibodies or portions thereof of the invention are useful for detecting RGM A and for inhibiting RGM A activity, for example in a human suffering from a disorder including but nor limited to multiple sclerosis, mammalian brain trauma, spinal cord injury, stroke, neurodegenerative diseases, and schizophrenia.

Claims

1. A method for reducing human RGM A activity comprising:

contacting human RGM A with an isolated antibody comprising an antigen binding domain, said antibody capable of binding an epitope of a RGM molecule such that human RGA activity is reduced, said antigen binding domain comprising;

a) a heavy chain variable domain and a light chain variable domain each having at least three complementary determining regions, wherein the at least three complementary determining regions of the heavy chain variable domain have the amino acid sequence of SEQ ID NO;

57, SEQ ID NO;

58 and SEQ ID NO;

59 and the at least three complementary determining regions of the light chain variable domain have the amino acid sequence of SEQ ID NO;

60, SEQ ID NO;

61 and SEQ ID NO;

62;

or

b) a heavy chain variable domain and a light chain variable domain wherein the heavy chain variable domain has the amino acid sequence selected from the group consisting of;

SEQ ID NOS;

35, 36, 37, 38, 39, 40, 41, 42, 43, 47, 48, 49 and 50 and the light chain variable domain has the amino acid sequence selected from the group consisting of SEQ ID NO;

44, 45, 46, 51, 52, 53 and 54.

7. The method of claim 1, 2, 3, 4 or 5, wherein the antibody further comprises a human acceptor framework, wherein said human acceptor framework comprises at least one amino acid sequence selected from the group consisting of:

SEQ ID NO;

15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 and 33.

9. The method of claim 1, 2, 3, 4 or 5, wherein:

a) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

35 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

b) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

36 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

c) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

37 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

d) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

38 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

e) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

39 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

f) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

40 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

g) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

41 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

h) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

42 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

i) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

43 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

j) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

35 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

k) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

36 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

l) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

37 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

m) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

38 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

n) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

39 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

o) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

40 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

p) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

41 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

q) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

42 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

r) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

43 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

s) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

35 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

t) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

36 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

u) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

37 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

v) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

38 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

w) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

39 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

x) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

40 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

y) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

41 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

z) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

42 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

aa) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

43 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

bb) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

47 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

cc) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

47 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

dd) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

47 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

ee) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

47 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

51;

ff) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

47 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

52;

gg) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

47 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

53;

hh) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

47 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

54;

ii) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

48 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

jj) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

48 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

kk) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

48 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

ll) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

48 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

51;

mm) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

48 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

52;

nn) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

48 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

53;

oo) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

48 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

54;

pp) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

49 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

qq) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

50 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

rr) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

49 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

ss) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

50 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

tt) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

49 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

uu) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

50 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

vv) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

50 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

51;

ww) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

50 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

52;

xx) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

50 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

53;

or

yy) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

50 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

54.

2. A method for decreasing hRGM A binding to Neogenin receptor in a subject in need thereof, comprising the step of administering to the subject an isolated antibody comprising an antigen binding domain, said antibody capable of binding an epitope of a RGM molecule, said antigen binding domain comprising:

a) a heavy chain variable domain and a light chain variable domain each having at least three complementary determining regions, wherein the at least three complementary determining regions of the heavy chain variable domain have the amino acid sequence of SEQ ID NO;

57, SEQ ID NO;

58 and SEQ ID NO;

59 and the at least three complementary determining regions of the light chain variable domain have the amino acid sequence of SEQ ID NO;

60, SEQ ID NO;

61 and SEQ ID NO;

62;

or

b) a heavy chain variable domain and a light chain variable domain wherein the heavy chain variable domain has the amino acid sequence selected from the group consisting of;

SEQ ID NOS;

35, 36, 37, 38, 39, 40, 41, 42, 43, 47, 48, 49 and 50 and the light chain variable domain has the amino acid sequence selected from the group consisting of SEQ ID NO;

44, 45, 46, 51, 52, 53 and 54.

3. A method for decreasing hRGM A binding to bone morphogenetic protein-2 and bone morphogenetic protein-4 (BMP-2 and BMP-4) in a subject in need thereof, comprising the step of administering to the subject an isolated antibody comprising an antigen binding domain, said antibody capable of binding an epitope of a RGM molecule, said antigen binding domain comprising:

a) a heavy chain variable domain and a light chain variable domain each having at least three complementary determining regions, wherein the at least three complementary determining regions of the heavy chain variable domain have the amino acid sequence of SEQ ID NO;

57, SEQ ID NO;

58 and SEQ ID NO;

59 and the at least three complementary determining regions of the light chain variable domain have the amino acid sequence of SEQ ID NO;

60, SEQ ID NO;

61 and SEQ ID NO;

62;

or

b) a heavy chain variable domain and a light chain variable domain wherein the heavy chain variable domain has the amino acid sequence selected from the group consisting of;

SEQ ID NOS;

35, 36, 37, 38, 39, 40, 41, 42, 43, 47, 48, 49 and 50 and the light chain variable domain has the amino acid sequence selected from the group consisting of SEQ ID NO;

44, 45, 46, 51, 52, 53 and 54.

4. A method of treating a subject for a disorder associated with RGM A activity comprising the step of administering alone or in combination with other therapeutic agents an isolated antibody comprising an antigen binding domain, said antibody capable of binding an epitope of a RGM molecule, said antigen binding domain comprising:

a) a heavy chain variable domain and a light chain variable domain each having at least three complementary determining regions, wherein the at least three complementary determining regions of the heavy chain variable domain have the amino acid sequence of SEQ ID NO;

57, SEQ ID NO;

58 and SEQ ID NO;

59 and the at least three complementary determining regions of the light chain variable domain have the amino acid sequence of SEQ ID NO;

60, SEQ ID NO;

61 and SEQ ID NO;

62;

or

b) a heavy chain variable domain and a light chain variable domain wherein the heavy chain variable domain has the amino acid sequence selected from the group consisting of;

SEQ ID NOS;

35, 36, 37, 38, 39, 40, 41, 42, 43, 47, 48, 49 and 50 and the light chain variable domain has the amino acid sequence selected from the group consisting of SEQ ID NO;

44, 45, 46, 51, 52, 53 and 54.

6. The method of claim 4 or 5, wherein the disorder comprises neurological diseases selected from the group consisting of Amyotrophic Lateral Sclerosis, Brachial Plexus Injury, Brain Injury, including traumatic brain injury, Cerebral Palsy, Guillain Barre, Leukodystrophies, Multiple Sclerosis, Post Polio, Spina Bifida, Spinal Cord Injury, Spinal Muscle Atrophy, Spinal Tumors, Stroke, Transverse Myelitits;

dementia, senile dementia, mild cognitive impairment, Alzheimer-related dementia, Huntington'"'"'s chorea, tardive dyskinesia, hyperkinesias, manias, Morbus Parkinson, steel-Richard syndrome, Down'"'"'s syndrome, myasthenia gravis, nerve trauma, vascular amyloidosis, cerebral hemorrhage I with amyloidosis, brain inflammation, acute confusion disorder, amyotrophic lateral sclerosis, glaucoma and Alzheimer'"'"'s disease.

8. The method of claim 4 or 5, wherein the other therapeutic agents are selected from the group consisting of:

Therapeutic agent, imaging agent, cytotoxic agent, angiogenesis inhibitors;

kinase inhibitors;

co-stimulation molecule blockers;

adhesion molecule blockers;

anti-cytokine antibody or functional fragment thereof;

methotrexate;

cyclosporin;

rapamycin;

FK506;

detectable label or reporter;

a TNF antagonist;

an antirheumatic;

a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an erythropoietin, an immunization, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, a radiopharmaceutical, an antidepressant, an antipsychotic, a stimulant, an asthma medication, a beta agonist, an inhaled steroid, an epinephrine or analog, a cytokine, and a cytokine antagonist.

5. A method for reducing RGM A activity in a subject suffering from a disorder in which RGM A activity is detrimental, comprising administering to the subject an isolated antibody comprising an antigen binding domain, said antibody capable of binding an epitope of a RGM molecule, said antigen binding domain comprising:

a) a heavy chain variable domain and a light chain variable domain each having at least three complementary determining regions, wherein the at least three complementary determining regions of the heavy chain variable domain have the amino acid sequence of SEQ ID NO;

57, SEQ ID NO;

58 and SEQ ID NO;

59 and the at least three complementary determining regions of the light chain variable domain have the amino acid sequence of SEQ ID NO;

60, SEQ ID NO;

61 and SEQ ID NO;

62;

or

b) a heavy chain variable domain and a light chain variable domain wherein the heavy chain variable domain has the amino acid sequence selected from the group consisting of;

SEQ ID NOS;

35, 36, 37, 38, 39, 40, 41, 42, 43, 47, 48, 49 and 50 and the light chain variable domain has the amino acid sequence selected from the group consisting of SEQ ID NO;

44, 45, 46, 51, 52, 53 and 54,

alone or in combination with other therapeutic agents.

10. A method of treating a subject suffering from multiple sclerosis, the method comprising the step of administering to the subject an isolated antibody comprising an antigen binding domain, said antibody capable of binding an epitope of a RGM molecule, said antigen binding domain comprising:

a) a heavy chain variable domain and a light chain variable domain each having at least three complementary determining regions, wherein the at least three complementary determining regions of the heavy chain variable domain have the amino acid sequence of SEQ ID NO;

57, SEQ ID NO;

58 and SEQ ID NO;

59 and the at least three complementary determining regions of the light chain variable domain have the amino acid sequence of SEQ ID NO;

60, SEQ ID NO;

61 and SEQ ID NO;

62;

or

b) a heavy chain variable domain and a light chain variable domain wherein the heavy chain variable domain has the amino acid sequence selected from the group consisting of;

SEQ ID NOS;

35, 36, 37, 38, 39, 40, 41, 42, 43, 47, 48, 49 and 50 and the light chain variable domain has the amino acid sequence selected from the group consisting of SEQ ID NO;

44, 45, 46, 51, 52, 53 and 54.

11. The method of claim 10, wherein:

a) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

35 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

b) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

36 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

c) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

37 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

d) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

38 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

e) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

39 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

f) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

40 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

g) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

41 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

h) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

42 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

i) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

43 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

j) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

35 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

k) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

36 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

l) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

37 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

m) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

38 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

n) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

39 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

o) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

40 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

p) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

41 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

q) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

42 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

r) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

43 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

s) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

35 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

t) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

36 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

u) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

37 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

v) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

38 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

w) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

39 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

x) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

40 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

y) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

41 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

z) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

42 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

aa) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

43 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

bb) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

47 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

cc) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

47 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

dd) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

47 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

ee) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

47 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

51;

ff) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

47 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

52;

gg) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

47 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

53;

hh) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

47 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

54;

ii) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

48 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

jj) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

48 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

kk) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

48 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

ll) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

48 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

51;

mm) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

48 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

52;

nn) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

48 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

53;

oo) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

48 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

54;

pp) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

49 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

qq) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

50 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

44;

rr) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

49 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

ss) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

50 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

45;

tt) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

49 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

uu) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

50 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

46;

vv) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

50 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

51;

ww) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

50 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

52;

xx) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

50 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

53;

or

yy) the heavy chain variable domain has the amino acid sequence of SEQ ID NO;

50 and the light chain variable domain has the amino acid sequence of SEQ ID NO;

54.