Anti-GD2 antibody
The invention relates to anti-ganglioside GD2 antibodies that comprise an antibody variable domain and antibody constant domains, wherein the variable domain comprises a heavy and light chain variable region comprising respectively at least the CDR3 of the heavy chain variable region of antibody ch14.18 and at least the CDR3 of the light chain variable region of antibody ch14.18; and an IgA hinge and C H 2 domain and to methods of treatment of subjects with a GD2 positive tumor, preferably neuroblastoma with these antibodies.
1. An engineered antibody that comprises:
(a) an IgG variable region that comprises:
(i) a heavy chain variable domain that comprises:
a complementarity determining region 1 (CDR1) comprising an amino acid sequence GSSFTGYN (SEQ ID NO: 14),
a complementarity determining region 2 (CDR2) comprising an amino acid sequence IDPYYGGT (SEQ ID NO: 15), and
a complementarity determining region 3 (CDR3) comprising an amino acid sequence VSGMEY (SEQ ID NO: 16), and
(ii) a light chain variable domain that comprises:
a complementarity determining region 1 (CDR1) comprising an amino acid sequence QSLVHRNGNTY (SEQ ID NO: 17),
a complementarity determining region 2 (CDR2) comprising an amino acid sequence KVS (SEQ ID NO: 18), and
a complementarity determining region 3 (CDR3) comprising an amino acid sequence of QSTHVPPLT (SEQ ID NO: 19); and
(b) a heavy chain constant region that comprises an IgA CH1 heavy chain constant domain, an IgA CH2 heavy chain constant domain, an IgA hinge domain, and an IgA CH3 heavy chain constant domain, wherein the heavy chain constant region comprises:
(ii) an amino acid substitution at N337 according to Bur scheme corresponding to N207 of SEQ ID NO: 11; 1338 according to Bur scheme corresponding to 1208 of SEQ ID NO: 11; and T339 according to Bur scheme corresponding to T209 of SEQ ID NO: 11,
(ii) an amino acid substitution at N166 according to Bur scheme corresponding to N49 of SEQ ID NO: 11,
(iii) an amino acid substitution at P221 according to Bur scheme corresponding to P104 of SEQ ID NO: 11,
(iv) an amino acid substitution at C311 according to Bur scheme corresponding to C181 of SEQ ID NO: 11,
(v) a deletion of amino acid C471 according to Bur scheme corresponding to C341 of SEQ ID NO: 11,
(vi) a deletion of amino acid Y472 according to Bur scheme corresponding to Y342 of SEQ ID NO: 11, or
(vii) a combination thereof.
2. The engineered antibody of claim 1 , wherein the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 3, and wherein the light chain variable domain comprises an amino acid sequence of SEQ ID NO: 4.
3. The engineered antibody of claim 1 , wherein the IgA CH1 heavy chain constant domain, the IgA CH2 heavy chain constant domain, the IgA hinge domain, and the IgA CH3 heavy chain constant domain are human IgA CH1, CH2, and CH3 heavy chain constant domains.
4. The engineered antibody of claim 1 , wherein the IgA CH1 heavy chain constant domain, the IgA CH2 heavy chain constant domain, the IgA hinge domain, and the IgA CH3 heavy chain constant domain are IgA1 CH1, CH2, and CH3 heavy chain constant domains, or IgA2 CH1, CH2, and CH3 heavy chain constant domains.
5. The engineered antibody of claim 1 , wherein the heavy chain constant region comprises:
(i) a N337T amino acid substitution at N337 according to Bur scheme, wherein said N337 corresponds to N207 of SEQ ID NO: 11, a I338L amino acid substitution at I338 according to Bur scheme, wherein said I338 corresponds to I208 of SEQ ID NO: 11, and a T339S amino acid substitution at T339 according to Bur scheme, wherein said T339 corresponds to T209 of SEQ ID NO: 11,
(ii) a N166G amino acid substitution at N166 according to Bur scheme, wherein said N166 corresponds to N49 of SEQ ID NO: 11,
(iii) a P221R amino acid substitution at P221 according to Bur scheme, wherein said P221 corresponds to P104 of SEQ ID NO: 11,
(iv) a C311S amino acid substitution at C311 according to Bur scheme, wherein said C311 corresponds to C181 of SEQ ID NO: 11,
(v) a deletion of amino acid C471 according to Bur scheme corresponding to C341 of SEQ ID NO: 11,
(vi) a deletion of amino acid Y472 according to Bur scheme corresponding to Y342 of SEQ ID NO: 11, or
(vii) a combination thereof.
6. The engineered antibody of claim 1 , wherein the engineered antibody exhibits increased antibody-dependent cell mediated cytotoxicity (ADCC) relative to a corresponding IgG antibody as measured in a suitable in vitro ADCC assay.
7. The engineered antibody of claim 1 , wherein the engineered antibody exhibits decreased complement-dependent cytotoxicity (CDC) relative to a corresponding IgG antibody as measured in a suitable in vitro CDC assay.