Blood-brain barrier penetrating dual specific binding proteins
AssigneeAbbVie Inc.
InventorsDenise KARAOGLU HANZATIAN, Tariq GHAYUR, Annette J. SCHWARTZ STERMAN, Andrew GOODEARL, Maria Cristina HARRIS
Life of this patent
Estimating the term…
Abstract
Engineered multivalent and multispecific binding proteins capable of penetrating the blood-brain barrier (BBB) are provided, along with methods of making and uses in the prevention, diagnosis, and/or treatment of disease.
Claims48
A dual variable domain (DVD) binding protein that specifically binds to an antigen expressed on brain vascular epithelium of a subject and facilitates uptake of a composition into the brain of the subject.
2-4. (canceled)
6-12. (canceled)
14-16. (canceled)
25-30. (canceled)
A binding protein comprising first and second polypeptide chains, wherein the first polypeptide chain comprises a first VD1-(X1)n-VD2-C-(X2)n, wherein
- VD1 is a first heavy chain variable domain;
- VD2 is a second heavy chain variable domain;
- C is a heavy chain constant domain;
- X1 is a first linker;
- X2 is an Fc region;
- wherein the second polypeptide chain comprises a second VD1-(X1)n-VD2-C-(X2)n, wherein
- VD1 is a first light chain variable domain;
- VD2 is a second light chain variable domain;
- C is a light chain constant domain;
- X1 is a second linker;
- X2 does not comprise an Fc region;
- (X1)n is independently (X1)0 or (X1)1 and (X2)n is independently (X2)0 or (X2)1,
- wherein the first and second X1 linker are the same or different;
- wherein the first X1 linker is not CH1 and/or the second X1 linker is not CL;
- wherein the binding protein specifically binds to a disease target selected from the group consisting of Abeta, BACE, Her-2, RGMA, TNFα and APP;
- and
- (a) VD1 or VD2 heavy chain variable domain comprises three CDRs each, wherein at least one CDR comprises an amino acid sequence selected from the group consisting of SEQ ID NO:
- 109, 110, 111, 121, 123, 136, 137, 138, 139, 140, 141, 142, 143, 147, 148, 149, 164, 165, 166, 172, 173, and 174;
- (b) VD1 and VD2 heavy chain variable domains independently comprise three CDRs each comprising amino acid sequences selected from the group consisting of SEQ ID NO:
- 109, 110, 111, 121, 123, 136, 137, 138, 139, 140, 141, 142, 143, 147, 148, 149, 164, 165, 166, 172, 173, and 174;
- or
- (c) VD1 heavy chain variable domain comprises three CDRs each comprising amino acid sequences selected from the group consisting of SEQ ID NO:
- 109, 110, 111, 121, 123, 136, 137, 138, 139, 140, 141, 142, 143, 147, 148, 149, 164, 165, 166, 172, 173, and 174;
- and VD2 heavy chain variable domain comprises three CDRs each comprising amino acid sequences selected from the group consisting of SEQ ID NO:
- 109, 110, 111, 121, 123, 136, 137, 138, 139, 140, 141, 142, 143, 147, 148, 149, 164, 165, 166, 172, 173, and 174;
- and
- wherein
- (a) VD1 or VD2 light chain variable domain comprises three CDRs each comprising amino acid sequences selected from the group consisting of SEQ ID NO:
- 112, 113, 114, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 150, 151, and 152;
- (b) VD1 and VD2 light chain variable domains independently comprise three CDRs each comprising amino acid sequences selected from the group consisting of SEQ ID NO:
- 112, 113, 114, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 150, 151, 152, 167, 168, 169, 175, 176, and 177;
- or
- (c) VD1 light chain variable domain comprises three CDRs each comprising amino acid sequences selected from the group consisting of SEQ ID NO:
- 112, 113, 114, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 150, 151, 152, 167, 168, 169, 175, 176, and 177, and VD2 light chain variable domain comprises three each comprising amino acid sequences selected CDRs from the group consisting of SEQ ID NO:
- 112, 113, 114, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 150, 151, 152, 167, 168, 169, 175, 176, and 177.
38-45. (canceled)
53-59. (canceled)
A monospecific binding protein comprising
- a heavy polypeptide chain of comprising an amino acid sequence selected from the group consisting SEQ ID NO:
- 76, 77, 78, 82, 83, 115-117 and 156-158, and a light polypeptide chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO:
- 79, 80, 81, 84, 85, 86, 118, 119, 120, 159, 160 and 161;
- or
- a heavy polypeptide chain comprising an amino acid sequences selected from the group consisting of SEQ ID NO:
- 109, 110, 111, 121, 123, 136, 137, 138, 139, 140, 141, 142, 143, 147, 148, 149, 164, 165, 166, 172, 173, and 174, and a light polypeptide chain comprising an amino acid sequences selected from the group consisting of SEQ ID NO:
- 112, 113, 114, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 150, 151, 152, 167, 168, 169, 175, 176, and 177.
A bispecific binding protein comprising
- a heavy polypeptide chain comprising an amino acid sequence selected from the group consisting SEQ ID NO:
- 76, 77, 78, 82, 83, 115-117 and 156-158, and a light polypeptide chain comprising an amino acid sequences selected from the group consisting of SEQ ID NO:
- 112, 113, 114, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 150, 151, 152, 167, 168, 169, 175, 176, and 177;
- a heavy polypeptide chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO:
- 109, 110, 111, 121, 123, 136, 137, 138, 139, 140, 141, 142, 143, 147, 148, 149, 164, 165, 166, 172, 173, and 174, and a light polypeptide chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO:
- 79, 80, 81, 84, 85, 86, 118, 119, 120, 159, 160, and 161;
- a heavy polypeptide chain comprising an amino acid sequence selected from the group 121, 122, 123, 136, 137, 138, 139, 140, 141, 142, 143, 147, 148, 149, 156-158, 164, 165, 166, 172, 173, and 174, and a light polypeptide chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO:
- 79, 80, 81, 84, 85, 86, 112, 113, 114, 118, 119, 120, 161, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 150, 151, 152, 159, 160, 167, 168, 169, 175, 176, and 177;
- or
- a heavy polypeptide chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO:
- 76, 77, 78, 82, 83, 109, 110, 111, 115-117, 121, 122, 123, 136, 137, 138, 139, 140, 141, 142, 143, 147, 148, 149,156-158, 164, 165, 166, 172, 173, and 174, or comprising an amino acid sequence selected from the group consisting of SEQ ID NO:
- 109, 110, 111, 121, 123, 136, 137, 138, 139, 140, 141, 142, 143, 147, 148, 149, 164, 165, 166, 172, 173, and 174, and a light polypeptide chain comprising an amino acid sequence selected from the group consisting SEQ ID NO:
- 79, 80, 81, 84, 85, 86, 112, 113, 114, 118, 119, 120, 161, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 150, 151, 152, 159, 160, 167, 168, 169, 175, 176, and 177.
63-65. (canceled)
The binding protein of claim 64, wherein In1 comprises the amino sequence of SEQ ID NO:56.
67-69. (canceled)
The binding protein of claim 69, wherein Out1 specifically binds transferrin receptor.
The binding protein of claim 64, wherein Out1 comprises the amino sequence of SEQ ID NO:36.
73-82. (canceled)
84-89. (canceled)
A method of producing a binding protein, comprising culturing a host cell described in any one of claim 86 in culture medium under conditions sufficient to produce the binding protein.
(canceled)
93-117. (canceled)
A humanized antibody that specifically binds:
- TfR comprising an amino acid sequence selected from the group consisting of SEQ ID NO:
- 30-37, 56 and 57;
- or,
- HIR comprising an amino acid sequence selected from the group consisting of SEQ ID NO:
- 104-108.
119-120. (canceled)
Dependencies are inferred from the claim text.