CD3 binding antibodies
The present invention relates to novel human CD3 antigen-binding polypeptides and their preparation and use in the treatment and/or diagnosis of various diseases, and also relates to bispecific antibody molecules capable of activating immune effector cells and their use in diagnosis and/or treatment of various diseases.
1. A multispecific antibody comprising:
(i) a first binding moiety that has binding specificity for human CD3δε, comprising a heavy chain variable domain comprising:
(a) a CDR1 sequence comprising GGSIRSGGHY (SEQ ID NO: 72), a CDR2 sequence comprising ISYSGST (SEQ ID NO: 73), and a CDR3 sequence comprising ARWRHDILTAYPYYYYGMDV (SEQ ID NO: 74); or
(b) a CDR1 sequence comprising GGSIRSGGHY (SEQ ID NO: 72), a CDR2 sequence comprising IHHSGST (SEQ ID NO: 75), and a CDR3 sequence comprising ARWRHDIFTTYPYYYYGMDV (SEQ ID NO: 76); or
(c) a CDR1 sequence comprising GGSISSGGHY (SEQ ID NO: 77), a CDR2 sequence comprising IHYSGST (SEQ ID NO: 78), and a CDR3 sequence comprising ARWRHDIFAAYPYYYYGMDV (SEQ ID NO: 79); or
(d) a CDR1 sequence comprising GGSIRSGGHY (SEQ ID NO: 72), a CDR2 sequence comprising IHRSGNP (SEQ ID NO: 80), and a CDR3 sequence comprising ARWRHDIFAAYPYYYYGMDV (SEQ ID NO: 79); or
(e) a CDR1 sequence comprising GGSISSGGHY (SEQ ID NO: 77), a CDR2 sequence comprising IHHSGST (SEQ ID NO: 75), and a CDR3 sequence comprising ARWRHDIFAAYPYYYYGMDV (SEQ ID NO: 79);
a light chain variable domain comprising a CDR1 sequence comprising QSVSSN (SEQ ID NO: 81), a CDR2 sequence comprising GAS, and a CDR3 sequence comprising QQYNNWPWT (SEQ ID NO: 82); and
(ii) a second binding moiety that has binding specificity for a pathogen antigen.
2. The multispecific antibody of claim 1 , wherein:
the CDR1, CDR2 and CDR3 sequences in the heavy chain variable domain of the first binding moiety are present in a human VH framework; and
the CDR1, CDR2 and CDR3 sequences in the light chain variable domain of the first binding moiety are present in a human Vkappa framework.
3. The multispecific antibody of claim 2 , wherein:
the heavy chain variable domain of the first binding moiety comprises a sequence having at least 95% identity to the framework region of SEQ ID NO: 18, SEQ ID NO: 1, SEQ ID NO: 6, SEQ ID NO: 13, or SEQ ID NO: 39; and
the light chain variable domain of the first binding moiety comprises a sequence having at least 95% identity to the framework region of SEQ ID NO: 69.
4. The multispecific antibody of claim 3 , wherein:
the heavy chain variable domain of the first binding moiety comprises the sequence of SEQ ID NO: 18, SEQ ID NO: 1, SEQ ID NO: 6, SEQ ID NO: 13, or SEQ ID NO: 39; and
the light chain variable domain of the first binding moiety comprises the sequence of SEQ ID NO: 69.
5. The multispecific antibody of claim 1 , wherein the second binding moiety comprises a single heavy chain variable region, in a single or tandem configuration.
6. The multispecific antibody of claim 1 , wherein the first binding moiety comprises a light chain polypeptide subunit and a heavy chain polypeptide subunit, and wherein the second binding moiety comprises a heavy chain polypeptide subunit.
7. The multispecific antibody of claim 6 , wherein:
the light chain polypeptide subunit of the first binding moiety comprises a light chain constant domain (CL);
the heavy chain polypeptide subunit of the first binding moiety comprises a heavy chain constant domain comprising a CH1 domain, a CH2 domain, and a CH3 domain; and
the heavy chain polypeptide subunit of the second binding moiety comprises a CH2 domain and a CH3 domain, but no CH1 domain.
8. The multispecific antibody of claim 7 , wherein the CH2 and CH3 domains of the heavy chain constant domain of the heavy chain polypeptide subunit of the first binding moiety and the CH2 and CH3 domains of the heavy chain polypeptide subunit of the second binding moiety together form an Fc region.
9. The multispecific antibody of claim 8 , wherein the Fc region has been engineered to reduce effector functions.
10. The multispecific antibody of claim 8 , wherein the Fc region has been engineered to reduce homodimer formation.
11. The multispecific antibody of claim 8 , wherein the Fc region comprises a native-sequence human IgG1 Fc region or a native sequence human IgG4 Fc region.
12. A bispecific antibody comprising:
a first polypeptide subunit comprising:
a light chain variable domain (VL) comprising the sequence of SEQ ID NO: 69; and
a light chain constant domain (CL);
a second polypeptide subunit comprising:
a heavy chain variable domain (VH) comprising:
(i) the sequence of SEQ ID NO: 18; or
(ii) the sequence of SEQ ID NO: 1; or
(iii) the sequence of SEQ ID NO: 6; or
(iv) the sequence of SEQ ID NO: 13; or
(v) the sequence of SEQ ID NO: 39; and
a heavy chain constant domain (CH) comprising a CH1 domain, a hinge region, a CH2 domain, and a CH3 domain;
wherein the light chain variable domain and the heavy chain variable domain together form a first binding moiety that has binding specificity for human CD3δε; and
a third polypeptide subunit comprising:
a single heavy chain variable region, in a single or tandem configuration, that has binding specificity to a pathogen antigen; and
a heavy chain constant domain (CH) comprising a hinge region, a CH2 domain, and a CH3 domain, in the absence of a CH1 domain.
13. A kit for treating a disease or condition in an individual in need, comprising:
a bispecific antibody comprising:
a first polypeptide subunit comprising:
a light chain variable domain (VL) comprising the sequence of SEQ ID NO: 69; and
a light chain constant domain (CL);
a second polypeptide subunit comprising:
a heavy chain variable domain (VH) comprising:
(i) the sequence of SEQ ID NO: 18; or
(ii) the sequence of SEQ ID NO: 1; or
(iii) the sequence of SEQ ID NO: 6; or
(iv) the sequence of SEQ ID NO: 13; or
(v) the sequence of SEQ ID NO: 39; and
a heavy chain constant domain (CH) comprising a CH1 domain, a hinge region, a CH2 domain, and a CH3 domain;
wherein the light chain variable domain and the heavy chain variable domain together form a first binding moiety that has binding specificity for human CD3δε; and
a third polypeptide subunit comprising:
a single heavy chain variable region, in a single or tandem configuration, that has binding specificity to a pathogen antigen; and
a heavy chain constant domain (CH) comprising a hinge region, a CH2 domain, and a CH3 domain, in the absence of a CH1 domain; and
and instructions for use.