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NZ766556B2 - Bispecific t cell activating antigen binding molecules - Google Patents
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NZ766556B2 - Bispecific t cell activating antigen binding molecules - Google Patents

Bispecific t cell activating antigen binding molecules Download PDF

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Publication number
NZ766556B2
NZ766556B2 NZ766556A NZ76655615A NZ766556B2 NZ 766556 B2 NZ766556 B2 NZ 766556B2 NZ 766556 A NZ766556 A NZ 766556A NZ 76655615 A NZ76655615 A NZ 76655615A NZ 766556 B2 NZ766556 B2 NZ 766556B2
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amino acid
seq
fab
acid sequence
molecule
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NZ766556A
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NZ766556A (en
Inventor
Oliver Ast
Marina Bacac
Jung Sabine Imhof
Christiane Jaeger
Christian Klein
Stefan Klostermann
Michael Molhoj
Joerg Thomas Regula
Wolfgang Schaefer
Pablo Umana
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F Hoffmann La Roche Ag
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Publication of NZ766556A publication Critical patent/NZ766556A/en
Publication of NZ766556B2 publication Critical patent/NZ766556B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3053—Skin, nerves, brain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
    • C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/515—Complete light chain, i.e. VL + CL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/526—CH3 domain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/54—F(ab')2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/64—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a combination of variable region and constant region components
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/66—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a swap of domains, e.g. CH3-CH2, VH-CL or VL-CH1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/71—Decreased effector function due to an Fc-modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention generally relates to novel bispecific antigen binding molecules for T cell activation and re-direction to specific target cells. The T cell activating bispecific antigen-binding molecule comprises Fab binding arms which bind CD3 and CD20, a VH and VL replacement in the anti-CD3 Fab and a charge modification in the CL and CH1 constant domains of the anti-CD20 Fab.

Claims (37)

Claims
1. A T cell activating bispecific antigen-binding molecule comprising a first ptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18, a second polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19, 5 a third polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 20, and a fourth polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 21, wherein the T cell ting bispecific antigen-binding molecule (a) a first Fab molecule which specifically binds to CD20, wherein the first Fab molecule 10 comprises a heavy chain complementarity determining region (CDR) 1 comprising the amino acid sequence of SEQ ID NO: 46, a heavy chain CDR 2 comprising the amino acid sequence of SEQ ID NO: 47, a heavy chain CDR 3 comprising the amino acid sequence of SEQ ID NO: 48, a light chain CDR 1 comprising the amino acid ce of SEQ ID NO: 49, a light chain CDR 2 comprising the amino acid sequence of SEQ ID NO: 50, and a light chain CDR 3 comprising the 15 amino acid ce of SEQ ID NO: 51; (b) a second Fab molecule which specifically binds to CD3, wherein the second Fab molecule comprises a heavy chain CDR 1 comprising the amino acid sequence of SEQ ID NO: 4, a heavy chain CDR 2 comprising the amino acid sequence of SEQ ID NO: 5, a heavy chain CDR 3 sing the amino acid sequence of SEQ ID NO: 6, a light chain CDR 1 comprising the 20 amino acid sequence of SEQ ID NO: 8, a light chain CDR 2 comprising the amino acid sequence of SEQ ID NO: 9, and a light chain CDR 3 comprising the amino acid sequence of SEQ ID NO: 10, wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain of the second Fab molecule, respectively, are replaced by each other, and (c) a third Fab molecule which ically binds to CD20, wherein the third Fab 25 molecule comprises a heavy chain CDR 1 comprising the amino acid sequence of SEQ ID NO: 46, a heavy chain CDR 2 comprising the amino acid sequence of SEQ ID NO: 47, a heavy chain CDR 3 comprising the amino acid sequence of SEQ ID NO: 48, a light chain CDR 1 comprising the amino acid sequence of SEQ ID NO: 49, a light chain CDR 2 comprising the amino acid sequence of SEQ ID NO: 50, and a light chain CDR 3 comprising the amino acid ce of 30 SEQ ID NO: 51, and wherein: (i) in the constant domain CL of the first Fab molecule and the third Fab molecule, the amino acid at position 123 and 124, according to Kabat, is tuted by lysine (K), arginine (R), or histidine (H), and, in the constant domain CH1 of the first Fab molecule and the third Fab molecule, one or both of the amino acids at positions 147 and 213, according to the Kabat EU index, are substituted by glutamic acid (E) or aspartic acid (D); or (ii) in the nt domain CL of the second Fab molecule, the amino acid at position 124, according to Kabat, is substituted by lysine (K), arginine (R), or ine (H), and, in the 5 constant domain CH1 of the second Fab le, one or both of the amino acids at positions 147 and 213, according to the Kabat EU index, are substituted by glutamic acid (E) or aspartic acid (D).
2. A T cell activating bispecific antigen-binding molecule comprising a first polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18, a second 10 polypeptide sequence that is at least 95% identical to the amino acid ce of SEQ ID NO: 19, a third polypeptide ce that is at least 95% identical to the amino acid sequence of SEQ ID NO: 20, and a fourth ptide sequence that is at least 95% cal to the amino acid sequence of SEQ ID NO: 21, wherein the T cell activating bispecific antigen-binding molecule comprises: 15 (a) a first Fab molecule which specifically binds to CD20, wherein the first Fab molecule ses a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 30 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 31; (b) a second Fab le which specifically binds to CD3, wherein the second Fab molecule comprises a heavy chain variable region comprising the amino acid sequence of SEQ 20 ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7, wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain of the second Fab molecule, respectively, are replaced by each other, and (c) a third Fab molecule which specifically binds to CD20, wherein the third Fab molecule a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 30 25 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 31, and wherein: (i) in the constant domain CL of the first Fab molecule and the third Fab molecule, the amino acid at position 124, according to Kabat, is substituted by lysine (K), arginine (R), or histidine (H), and, in the constant domain CH1 of the first Fab molecule and the third Fab 30 molecule, one or both of the amino acids at positions 147 and 213, according to the Kabat EU index, are substituted by glutamic acid (E) or aspartic acid (D); or (ii) in the constant domain CL of the second Fab molecule, the amino acid at position 124, according to Kabat, is substituted by lysine (K), arginine (R), or histidine (H), and, in the constant domain CH1 of the second Fab molecule, one or both of the amino acids at positions 147 and 213, according to the Kabat EU index, are substituted by glutamic acid (E) or aspartic acid (D).
3. The T cell activating bispecific antigen-binding molecule of claim 1, wherein the first 5 polypeptide sequence is at least 96% identical to the amino acid sequence of SEQ ID NO: 18, the second polypeptide sequence is at least 96% identical to the amino acid sequence of SEQ ID NO: 19, the third polypeptide sequence is at least 96% identical to the amino acid ce of SEQ ID NO: 20, and/or the fourth polypeptide sequence is at least 96% identical to the amino acid sequence of SEQ ID NO: 21. 10
4. The T cell activating bispecific antigen-binding molecule of claim 1, n the first polypeptide sequence is at least 97% identical to the amino acid sequence of SEQ ID NO: 18, the second polypeptide sequence is at least 97% identical to the amino acid sequence of SEQ ID NO: 19, the third polypeptide ce is at least 97% identical to the amino acid sequence of SEQ ID NO: 20, and/or the fourth ptide sequence is at least 97% identical to the amino acid 15 sequence of SEQ ID NO: 21.
5. The T cell activating bispecific antigen-binding molecule of claim 1, n the first polypeptide sequence is at least 98% cal to the amino acid sequence of SEQ ID NO: 18, the second polypeptide sequence is at least 98% identical to the amino acid ce of SEQ ID NO: 19, the third polypeptide ce is at least 98% identical to the amino acid sequence of SEQ 20 ID NO: 20, and/or the fourth polypeptide sequence is at least 98% identical to the amino acid sequence of SEQ ID NO: 21.
6. The T cell activating bispecific n-binding molecule of claim 1, wherein the first polypeptide sequence is at least 99% identical to the amino acid sequence of SEQ ID NO: 18, the second polypeptide sequence is at least 99% identical to the amino acid ce of SEQ ID NO: 25 19, the third polypeptide sequence is at least 99% identical to the amino acid sequence of SEQ ID NO: 20, and/or the fourth polypeptide sequence is at least 99% identical to the amino acid sequence of SEQ ID NO: 21.
7. The T cell activating bispecific antigen-binding molecule of claim 1, wherein the first polypeptide comprises the amino acid sequence of SEQ ID NO: 18, the second polypeptide 30 comprises the amino acid sequence of SEQ ID NO: 19, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 20, or the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 21.
8. A T cell activating bispecific antigen-binding molecule, wherein the T cell activating bispecific antigen-binding molecule comprises a first polypeptide comprising the amino acid 5 sequence of SEQ ID NO: 18, a second ptide sing the amino acid sequence of SEQ ID NO: 19, a third polypeptide comprising the amino acid sequence of SEQ ID NO: 20, and a fourth polypeptide comprising the amino acid ce of SEQ ID NO: 21.
9. The T cell activating bispecific antigen-binding molecule of claim 1, wherein, in the constant domain CL of the first Fab molecule, the amino acid at position 124, according to Kabat, 10 is substituted by lysine (K), arginine (R), or histidine (H); and, in the constant domain CH1 of the first Fab molecule, one or both of the amino acids at positions 147 and 213, ing to the Kabat EU index, are substituted by glutamic acid (E) or aspartic acid (D).
10. The T cell activating bispecific antigen-binding molecule of claim 9, wherein, in the constant domain CH1 of the first Fab molecule, the amino acid at position 147, according to the 15 Kabat EU index, is substituted by glutamic acid (E) or aspartic acid (D).
11. The T cell activating bispecific antigen-binding molecule of claim 10, wherein, in the constant domain CH1 of the first Fab molecule, the amino acid at position 123, according to Kabat, is tuted by lysine (K), arginine (R), or histidine (H); and, the amino acid at position 213, according to the Kabat EU index, is substituted by ic acid (E) or aspartic acid (D). 20
12. The T cell ting bispecific antigen-binding molecule of claim 11, wherein, in the constant domain CL of the first Fab le, the amino acid at position 124, according to Kabat, is substituted by lysine (K), and the amino acid at position 123, according to Kabat, is tuted by arginine (R); and in the constant domain CH1 of the first Fab molecule, the amino acid at position 147, according to the Kabat EU index, is substituted by glutamic acid 25 (E), and the amino acid at position 213, according to the Kabat EU index, is substituted by glutamic acid (E).
13. The T cell ting bispecific antigen-binding le of claim 11, wherein, in the constant domain CL of the first Fab molecule, the amino acid at position 124, according to Kabat, is substituted by lysine (K), and the amino acid at position 123, according to Kabat, is substituted 30 by lysine (K), and in the constant domain CH1 of the first Fab molecule, the amino acid at position 147, according to the Kabat EU index, is substituted by glutamic acid (E), and the amino acid at position 213, according to the Kabat EU index, is substituted by glutamic acid (E).
14. The T cell activating ific antigen-binding molecule of claim 1, wherein the second Fab le comprises a heavy chain variable region comprising the amino acid sequence of 5 SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7.
15. The T cell activating ific antigen-binding molecule of claim 1, wherein the first Fab molecule and the third Fab molecule each comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 30 and a light chain variable region 10 comprising the amino acid sequence of SEQ ID NO: 31.
16. The T cell activating bispecific antigen-binding molecule of claim 1, wherein the T cell activating bispecific antigen-binding molecule comprises an Fc domain comprising a modification promoting ation of a first subunit of the Fc domain and a second subunit of the Fc domain. 15 17. The T cell activating bispecific n-binding molecule of claim 16, wherein, in the
17. CH3 domain of the first subunit of the Fc domain, an amino acid residue is ed with an amino acid residue having a larger side chain volume, thereby generating a protuberance within the CH3 domain of the first subunit which is positionable in a cavity within the CH3 domain of the second subunit, and in the CH3 domain of the second t of the Fc domain an amino acid 20 residue is replaced with an amino acid residue having a smaller side chain volume, y generating a cavity within the CH3 domain of the second subunit within which the protuberance within the CH3 domain of the first subunit is onable.
18. The T cell activating ific antigen-binding le of claim 16, wherein the amino acid residue having a larger side chain volume is selected from the group consisting of arginine 25 (R), phenylalanine (F), tyrosine (Y), and tryptophan (W), and the amino acid residue having a smaller side chain volume is selected from the group consisting of alanine (A), serine (S), threonine (T), and valine (V).
19. The T cell activating bispecific antigen-binding molecule of claim 16, wherein, in the CH3 domain of the first subunit of the Fc domain, the threonine residue at position 366, 30 according to the Kabat EU index, is replaced with a tryptophan residue (T366W), and in the CH3 domain of the second subunit of the Fc domain, the tyrosine residue at on 407, according to the Kabat EU index, is replaced with a valine residue (Y407V).
20. The T cell activating bispecific antigen-binding molecule of claim 16, wherein, in the first subunit of the Fc domain, the serine residue at position 354, according to the Kabat EU 5 index, is replaced with a cysteine residue ), or the glutamic acid e at position 356, according to the Kabat EU index, is replaced with a cysteine residue (E356C), and, in the second subunit of the Fc domain, the tyrosine e at position 349, according to the Kabat EU index, is replaced by a cysteine residue (Y349C).
21. The T cell activating bispecific antigen-binding molecule of claim 16, wherein the first 10 subunit of the Fc domain comprises amino acid substitutions S354C and T366W, according to the Kabat EU index, and the second subunit of the Fc domain ses amino acid tutions Y349C, T366S, L368A, and Y407V.
22. The T cell activating bispecific antigen-binding molecule of claim 15, wherein the Fc domain exhibits reduced binding affinity to an Fc or and/or reduced effector function, as 15 compared to a native IgG1 Fc domain.
23. The T cell activating bispecific antigen-binding molecule of claim 15, wherein the Fc domain comprises one or more amino acid substitution that reduces binding to an Fc receptor and/or effector function.
24. The T cell activating bispecific antigen-binding le of claim 23, wherein the one or 20 more amino acid substitution is at one or more position selected from the group of L234, L235, and P329, according to the Kabat EU index.
25. The T cell activating bispecific antigen-binding molecule of claim 15, wherein each subunit of the Fc domain comprises three amino acid substitutions that reduce binding to an activating Fc receptor and/or reduce effector function, wherein the amino acid substitutions are 25 L234A, L235A, and P329G, according to the Kabat EU index.
26. The T cell activating bispecific antigen-binding le of claim 25, wherein the Fc receptor is an Fc? receptor.
27. The T cell ting bispecific antigen-binding molecule of claim 22, wherein the effector function is antibody-dependent ediated cytotoxicity (ADCC).
28. The T cell activating bispecific antigen-binding molecule of claim 1, wherein the CD3 is CD3 epsilon.
29. The T cell activating bispecific n-binding molecule of claim 16, wherein the Fc domain is an IgG1 Fc domain or an IgG4 Fc domain. 5 30. The T cell activating ific n-binding molecule of claim 19, wherein, in the second subunit of the Fc domain, the threonine residue at position 366, according to the Kabat
30. EU index, is replaced with a serine residue (T366S), and the leucine residue at position 368, according to the Kabat EU index, is replaced with an alanine residue (L368A).
31. A pharmaceutical composition comprising the T cell activating bispecific antigen- 10 binding molecule of claim 1 and a pharmaceutically acceptable carrier.
32. A pharmaceutical composition comprising a T cell activating ific antigen-binding molecule, wherein the T cell activating bispecific n-binding le comprises: (a) a first Fab molecule which specifically binds to CD20, wherein the first Fab molecule comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 30 15 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 31; (b) a second Fab molecule which specifically binds to CD3, n the second Fab molecule ses a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7, wherein the variable s VL and VH of the Fab light chain and the Fab heavy chain of 20 the second Fab molecule, respectively, are replaced by each other; and (c) a third Fab molecule which specifically binds to CD20, wherein the third Fab molecule a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 30 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 31, and wherein: 25 (i) in the constant domain CL of the first Fab molecule and the third Fab molecule, the amino acid at position 124, ing to Kabat, is substituted by lysine (K), arginine (R), or histidine (H), and, in the constant domain CH1 of the first Fab molecule and the third Fab molecule, one or both of the amino acids at positions 147 and 213, according to the Kabat EU index, are substituted by glutamic acid (E) or aspartic acid (D); or 30 (ii) in the constant domain CL of the second Fab molecule, the amino acid at position 124, ing to Kabat, is substituted by lysine (K), arginine (R), or histidine (H), and, in the constant domain CH1 of the second Fab molecule, one or both of the amino acids at ons 147 and 213, according to the Kabat EU index, are substituted by glutamic acid (E) or aspartic acid (D).
33. The pharmaceutical composition of claim 32, wherein the T cell activating bispecific 5 antigen-binding molecule further comprises: (d) an Fc domain comprising a first and a second subunit capable of stable association, wherein: (i) the inus of the Fab heavy chain of the first Fab le is fused to the N- terminus of the Fab heavy chain of the second Fab le, and the C-terminus of the Fab 10 heavy chain of the second Fab molecule and the C-terminus of the Fab heavy chain of the third Fab molecule are each fused to the N-terminus of one of the subunits of the Fc domain, or (ii) the C-terminus of the Fab heavy chain of the second Fab molecule is fused to the N-terminus of the Fab heavy chain of the first Fab molecule, and the C-terminus of the Fab heavy chain of the first Fab molecule and the inus of the Fab heavy chain of the third Fab 15 molecule are each fused to the inus of one of the subunits of the Fc domain.
34. The pharmaceutical composition of claim 33, n the C-terminus of the Fab heavy chain of the first Fab molecule is fused to the N-terminus of the Fab heavy chain of the second Fab molecule, and the C-terminus of the Fab heavy chain of the second Fab molecule and the C- 20 terminus of the Fab heavy chain of the third Fab molecule are each fused to the N-terminus of one of the subunits of the Fc domain.
35. A ceutical composition comprising a T cell activating bispecific n-binding molecule, wherein the T cell activating bispecific antigen-binding molecule comprises a first 25 polypeptide comprising the amino acid sequence of SEQ ID NO: 18, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 19, a third polypeptide comprising the amino acid sequence of SEQ ID NO: 20, and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 21. 30
36. A T cell activating bispecific antigen-binding molecule as claimed in any one of claims 1-30 substantially as described herein and with reference to any example thereof.
37. A pharmaceutical composition as claimed in any one of claims 31-35 substantially as described herein and with referne to any e thereof.
NZ766556A 2015-08-03 Bispecific t cell activating antigen binding molecules NZ766556B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP14179764 2014-08-04
EP15170866 2015-06-05
NZ727600A NZ727600B2 (en) 2014-08-04 2015-08-03 Bispecific t cell activating antigen binding molecules

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