Bispecific Antigen-Binding Constructs Targeting HER2
US-2018282429-A1 · Oct 4, 2018 · US
Antigen-binding constructs targeting HER2
US11028182B2 · US · B2
| Field | Value |
|---|---|
| Publication number | US-11028182-B2 |
| Application number | US-201615572364-A |
| Country | US |
| Kind code | B2 |
| Filing date | May 13, 2016 |
| Priority date | May 13, 2015 |
| Publication date | Jun 8, 2021 |
| Grant date | Jun 8, 2021 |
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- Title
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Abstract
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Described herein are high affinity antigen binding constructs, e.g., antibodies, directed to the ECD2 domain of HER2. The antigen-binding constructs comprise at least one antigen-binding polypeptide construct that binds to ECD2 of HER2 (HER2 ECD2) with increased affinity compared to a wild-type 2C4 antibody. Such antigen-binding polypeptide constructs comprise one or more amino acid modifications in the framework region and/or CDRs compared to the amino acid sequence of a wild-type 2C4 antibody that increase affinity of the antigen-binding polypeptide construct for ECD2 by 2-fold or greater. The antigen-binding constructs can inhibit the growth of HER2-expressing breast cancer cells and gastric cancer cells. Antigen-binding constructs in biparatopic format are internalized in HER2-expressing cells.
First claim
Opening claim text (preview).
The invention claimed is: 1. An antigen-binding construct comprising a variant first antigen-binding polypeptide construct which monovalently binds a first HER2 ECD2 (human epidermal growth factor receptor 2 extracellular domain 2) antigen, the variant first antigen-binding polypeptide construct comprising a heavy chain variable (VH) domain as set forth in SEQ ID NO:2 and a light chain variable (VL) domain as set forth in SEQ ID NO:11 and comprising an amino acid modification at position 75 in the VH domain (Kabat numbering) wherein the lysine at position 75 has been substituted with a tryptophan (H_K75W), glutamic acid (H_K75E), or tyrosine (H_K75Y), optionally wherein the variant first antigen-binding polypeptide construct comprises H_K75W and further comprises the following substitutions or set of substitutions, numbering according to Kabat numbering system: H_T30Q; or H_T30Y; or H_G56Y; or H_S99W; or L_Y49W; or L_Y96G; or H_S99W and L_Y49W; or L_Y49W and L_Y96G; or H_T30Q and L_Y49W; or H_T30Q and H_S99W; or H_T30Q and L_Y96G; or H_T30Y and L_Y49W; or H_S99W and L_Y49W and L_Y96G; or H_T3000 and H_S99W and L_Y96G or H_T3000 and H_S99W and L_Y49W; or H_T3000 and L_Y49W and L_Y96G; or H_T30Y and L_Y49W and L_Y96G, and optionally wherein the variant first antigen-binding polypeptide construct comprises H_K75E and further comprises the following substitutions or set of substitutions, numbering according to Kabat numbering system L_Y49W; or H_T30Q; or H_S74W; or H_S99W. 2. The antigen-binding construct of claim 1 , wherein the variant first antigen-binding polypeptide construct comprises H_K75W. 3. The antigen-binding construct of claim 1 , wherein the variant first antigen-binding polypeptide construct comprises H_K75W and further comprises the following substitutions or set of substitutions, numbering according to Kabat numbering system: H_T30Q; or H_T30Y; or H_G56Y; or H_S99W; or L_Y49W; or L_Y96G; or H_S99W and L_Y49W; or L_Y49W and L_Y96G; or H_T30Q and L_Y49W; or H_T30Q and H_S99W; or H_T30Q and L_Y96G; or H_T30Y and L_Y49W; or H_S99W and L_Y49W and L_Y96G; or H_T30Q and H_S99W and L_Y96G or H_T30Q and H_S99W and L_Y49W; or H_T30Q and L_Y49W and L_Y96G; or H_T30Y and L_Y49W and L_Y96G. 4. The antigen-binding construct of claim 1 , wherein the variant first antigen-binding polypeptide construct comprises H_K75E. 5. The antigen-binding construct of claim 1 , wherein the variant first antigen-binding polypeptide construct comprises H_K75E and further comprises the following substitutions or set of substitutions, numbering according to Kabat numbering system L_Y49W; or H_T30Q; or H_S74W; or H_S99W. 6. The antigen-binding construct of claim 1 , wherein the variant first antigen-binding polypeptide construct comprises H_K75Y. 7. The antigen-binding construct of claim 1 , wherein the variant first antigen-binding polypeptide construct is a Fab. 8. The antigen-binding construct of claim 1 , wherein the antigen-binding construct is one-armed. 9. The antigen binding construct of claim 7 , further comprising a first linker polypeptide operably linked to the variant first antigen-binding polypeptide construct. 10. The antigen-binding construct of claim 1 , wherein the antigen-binding construct comprises a second antigen-binding polypeptide construct that binds to a second antigen. 11. The antigen-binding construct of claim 10 , further comprising a first linker polypeptide operably linked to the variant first antigen-binding polypeptide construct, and a second linker polypeptide operably linked to the second antigen-binding polypeptide construct. 12. The antigen-binding construct of claim 11 , wherein the second antigen is a HER2 ECD2 antigen and the second antigen-binding polypeptide construct is identical to the variant first antigen-binding polypeptide construct. 13. The antigen-binding construct of claim 11 , wherein the second antigen is a HER2 ECD4 antigen and the second antigen-binding polypeptide construct is an scFv comprising the VH and VL domain of trastuzumab and a glycine-serine linker. 14. The antigen-binding construct according to claim 9 , wherein the first linker polypeptide is operably linked to a heterodimeric human IgG1 Fc comprising a first Fc polypeptide and a second Fc polypeptide each comprising a different CH3 sequence. 15. The antigen-binding construct according to claim 11 , wherein the first and second linker polypeptides are operably linked to a heterodimeric human IgG1 Fc comprising a first Fc polypeptide and a second Fc polypeptide each comprising a different CH3 sequence. 16. The antigen-binding construct of claim 14 , wherein the CH3 sequence of each Fc polypeptide comprises one or more modifications that promote the formation of a heterodimeric Fc with stability comparable to a wild-type homodimeric Fc, the heterodimeric IgG1 Fc having a) the modifications L351Y_F405A_Y407V in the first Fc polypeptide, and the modifications T366L_K392M_T394W in the second polypeptide; or b) the modifications L351Y_F405A_Y407V in the first Fc polypeptide, and the modifications T366L_K392L_T394W in the second Fc polypeptide; or c) the modifications T350V_L351Y_F405A_Y407V in the first Fc polypeptide, and the modifications T350V_T366L_K392L_T394W in the second Fc polypeptide; or d) the modifications T350V_L351Y_F405A_Y407V in the first Fc polypeptide, and the modifications T350V_T366L_K392M_T394W in the second Fc polypeptide; or e) the modifications T350V_L351Y_S400E_F405A_Y407V in the first Fc polypeptide, and the modifications T350V_T366L_N390R_K392M_T394W in the second Fc polypeptide; or f) the modifications T350V_L351Y_F405A_Y407V in the first Fc polypeptide, and the modifications T366I_N390R_K392M_T394W in the second Fc polypeptide; or g) the modifications L351Y_S400E_F405A_Y407V in the first Fc polypeptide, and the modifications T350V_T366L_K392L_T394W in the second Fc polypeptide, wherein the numbering of amino acid residues in the Fc is according to the EU numbering system. 17. The antigen-binding construct of claim 15 , wherein the CH3 sequence of each Fc polypeptide comprises one or more modifications that promote the formation of a heterodimeric Fc with stability comparable to a wild-type homodimeric Fc, the heterodimeric IgG1 Fc having a) the modifications L351Y_F405A_Y407V in the first Fc polypeptide, and the modifications T366L_K392M_T394W in the second polypeptide; or b) the modifications L351Y_F405A_Y407V in the first Fc polypeptide, and the modifications T366L_K392L_T394W in the second Fc polypeptide; or c) the modifications T350V_L351Y_F405A_Y407V in the first Fc polypeptide, and the modifications T350V_T366L_K392L_T394W in the second Fc polypeptide; or d) the modifications T350V_L351Y_F405A_Y407V in the first Fc polypeptide, and the modifications T350V_T366L_K392M_T394W in the second Fc polypeptide; or e) the modifications T350V_L351Y_S400E_F405A_Y407V in the first Fc polypeptide, and the modifications T350V_T366L_N390R_K392M_T394W in the second Fc polypeptide; or f) the modifications T350V_L351Y_F405A_Y407V in the first Fc polypeptide, and the modifications T366I_N390R_K392M_T394W in the second Fc polypeptide; or g) the modifications L351Y_S400E_F405A_Y407V in the first Fc polypeptide, and the modifications T350V_T366L_K392L_T394W in the second Fc polypeptide, wherein the numbering of amino acid residues in the Fc is according to the EU numbering system. 18. The antigen-binding construct of claim 1 , wherein the VH consists of
Assignees
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of the breast · CPC title
involving compounds localised on the membrane of tumour or cancer cells · CPC title
of the stomach or small intestine · CPC title
Valency · CPC title
CH3 domain · CPC title
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- What does patent US11028182B2 cover?
- Described herein are high affinity antigen binding constructs, e.g., antibodies, directed to the ECD2 domain of HER2. The antigen-binding constructs comprise at least one antigen-binding polypeptide construct that binds to ECD2 of HER2 (HER2 ECD2) with increased affinity compared to a wild-type 2C4 antibody. Such antigen-binding polypeptide constructs comprise one or more amino acid modificatio…
- Who is the assignee on this patent?
- Zymeworks Inc
- What technology area does this patent fall under?
- Primary CPC classification C07K16/32. Mapped technology areas include Chemistry & Metallurgy.
- When was this patent published?
- Publication date Tue Jun 08 2021 00:00:00 GMT+0000 (Coordinated Universal Time) (B2). Legal status and post-grant events are not shown on this page.
- What related patents are in patentsdb?
- We list 4 related publications on this page (citations in our corpus or others sharing the same primary CPC).