Human anti-CD33 antibodies and uses thereof
A suite of novel human anti-CD33 antibodies is described. The provided antibodies are pan-binders, binding the C2-set Ig-like domain in the presence or absence of the V-set Ig-like domain of CD33 or are V-set binders, binding the V-set Ig-like domain of CD33. The antibodies provide novel therapeutic and diagnostic tools against CD33-related disorders, such as acute myeloid leukemia (AML).
1 . A CD33-binding antibody or antigen binding fragment thereof comprising a six-member complementarity determining region (CDR) set, wherein the six-member CDR set comprises:
(i) a CDRL1 having the sequence as set forth in SEQ ID NO: 24,
a CDRL2 having the sequence as set forth in SEQ ID NO: 25,
a CDRL3 having the sequence as set forth in SEQ ID NO: 26,
a CDRH1 having the sequence as set forth in SEQ ID NO: 27,
a CDRH2 having the sequence as set forth in SEQ ID NO: 28, and
a CDRH3 having the sequence as set forth in SEQ ID NO: 29; according to North;
(ii) a CDR having the sequence as set forth in SEQ ID NO: 183,
a CDRL2 having the sequence AAS,
a CDRL3 having the sequence as set forth in SEQ ID NO: 26,
a CDRH1 having the sequence as set forth in SEQ ID NO: 184,
a CDRH2 having the sequence as set forth in SEQ ID NO: 185, and
a CDRH3 having the sequence as set forth in SEQ ID NO: 29; according toe IMGT;
(iii) a CDRL1 having the sequence as set forth in SEQ ID NO: 24,
a CDRL2 having the sequence as set forth in SEQ ID NO: 204,
a CDRL3 having the sequence as set forth in SEQ ID NO: 26,
a CDRH1 having the sequence as set forth in SEQ ID NO: 205,
a CDRH2 having the sequence as set forth in SEQ ID NO: 206, and
a CDRH3 having the sequence as set forth in SEQ ID NO: 207; according to Kabat; or
(iv) a CDRL1 having the sequence as set forth in SEQ ID NO: 24,
a CDRL2 having the sequence as set forth in SEQ ID NO: 204,
a CDRL3 having the sequence as set forth in SEQ ID NO: 26,
a CDRH1 having the sequence as set forth in SEQ ID NO: 222,
a CDRH2 having the sequence as set forth in SEQ ID NO: 223, and
a CDRH3 having the sequence as set forth in SEQ ID NO: 207, according to Chothia.
2 . The CD33-binding antibody or antigen binding fragment thereof of claim 1 , comprising a variable light chain comprising at least 90% sequence identity to SEQ ID NO: 55 and a variable heavy chain comprising at least 90% sequence identity to SEQ ID NO: 56.
3 . The CD33-binding antibody or antigen binding fragment thereof of claim 1 , comprising a variable light chain comprising SEQ ID NO: 55 and a variable heavy chain comprising SEQ ID NO: 56.
4 . The CD33-binding antibody or antigen binding fragment thereof of claim 1 , further comprising an Fc region, wherein the Fc region comprises M428L/N434S, or G236A/S239D/A330L/I332E and wherein the numbering is according to the EU index.
5 . The CD33-binding antibody or antigen binding fragment thereof of claim 1 , wherein the antigen binding fragment is a single chain variable fragment (scFv).
6 . The CD33-binding antibody or antigen binding fragment thereof of claim 5 , wherein the scFv comprises a Gly-Ser linker comprising SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131, SEQ ID NO: 132, SEQ ID NO: 133, or SEQ ID NO: 134.
7 . The CD33-binding antibody or antigen binding fragment thereof of claim 5 , wherein the scFv has the sequence of SEQ ID NO: 234 or SEQ ID NO:235.
8 . A conjugate antibody comprising the CD33-binding antibody or antigen binding fragment thereof of claim 1 , wherein the CD33-binding antibody or antigen binding fragment thereof is conjugated to an immunotoxin, a drug, or a radioisotope.
9 . The conjugate antibody of claim 8 , wherein, the immunotoxin is selected from the group consisting of holotoxin, hemitoxin, abrin, bouganin, Bryodin 1, diphtheria toxin (DT), gelonin, mistletoe lectin, modeccin, pokeweed antiviral protein (PAP), Pseudomonas exotoxin (PE), ricin, and saporin.
10 . The conjugate antibody of claim 8 , wherein the drug is selected from the group consisting of monomethyl auristatin E (MMAE), vedotin, dolastatin, auristatin, calicheamicin, pyrrolobenzodiazepine (PBD), nemorubicin, PNU-159682, anthracycline, duocarmycin, vinca alkaloid, taxane, trichothecene, CC1065, camptothecin, elinafide, taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracinedione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, and propranolol.
11 . The conjugate antibody of claim 8 wherein the radioisotope is selected from the group consisting of 72 As, 74 As, 131 I, 49 In, 90 Y, 177 Lu, 211 At, 225 Ac, 212 Bi, 213 Bi, 225 Ac, 228 Ac, 111 Ag, 124 Am, 74 As, 211 At, 209 At, 194 Au, 128 Ba, 7 Be, 206 Bi, 245 Bk, 246 Bk, 76 Br, 11 C, 47 Ca, 254 Cf, 242 Cm, 51 Cr, 67 Cu, 153 Dy, 157 Dy, 159 Dy, 165 Dy, 166 Dy, 171 Er, 250 Es, 254 Es, 147 Eu, 157 Eu, 52 Fe, 59 Fe, 251 Fm, 252 Fm, 253 Fm, 66 Ga, 72 Ga, 146 Gd, 153 Gd, 68 Ge, 170 Hf, 171 Hf, 193 mHg, 193 mHg, 160 mHo, 130 I, 131 I, 135 I, 114 mIn, 185 Ir, 42 K, 43 K, 76 Kr, 79 Kr, 81 mKr, 132 La, 262 Lr, 169 Lu, 174 mLu, 176 mLu, 257 Md, 260 Md, 28 Mg, 52 Mn, 90 Mo, 24 Na, 95 Nb, 138 Nd, 57 Ni, 66 Ni, 234 Np, 15 O, 182 Os, 189 mOs, 191 Os, 32 P, 201 Pb, 101 Pd, 143 Pr, 191 Pt, 243 Pu, 225 Ra, 81 Rb, 188 Re, 105 Rh, 211 Rn, 103 Ru, 35 S, 44 Sc, 72 Se, 153 Sm, 125 Sn, 91 Sr, 173 Ta, 154 Tb, 127 Te, 234 Th, 45 Ti, 166 Tm, 230 U, 237 U, 240 U, 48 V, 178 W, 181 W, 188 W, 125 Xe, 127 Xe, 133 Xe, 133 mXe, 135 Xe, 85 mY, 86 Y, 90 Y, 93 Y, 169 Yb, 175 Yb, 65 Zn, 71 mZn, 86 Zr, 95 Zr, and 97 Zr.
12 . A multispecific antibody comprising the CD33-binding antibody or antigen binding fragment thereof of claim 1 , and a second antibody or antigen binding fragment thereof that binds CD3.
13 . A composition comprising one of the CD33-binding antibody or antigen binding fragments thereof of claim 1 and a pharmaceutically acceptable carrier.