Anti-CD33 antibodies and uses thereof
Anti-CD33 antibodies are described. The anti-CD33 antibodies can bind within the V-set Ig-like domain or the C2-set Ig-like domain of CD33. Epitopes FIG. 1 A on the C2-set Ig-like domain can provide a “pan-binding” site, to which the cognate antibody will bind regardless of whether the CD33 molecule also contains the V-set domain (as in, for example, CD33 FL ) or not (as in, for example, CD33 ΔE2 ). Alternative epitopes on the C2-set Ig-like domain are accessible for binding if the V-set domain is absent (e.g., as in CD33 ΔE2 ). Antibodies that bind an epitope on the C2-set Ig-like domain (whether they exhibit pan or V-set absent binding) are directed at novel therapeutic targets can increase therapeutic efficacy against CD-33-related disorders. Also described are molecules comprising a binding-competent domain from at least one described anti-CD33 antibody, including scFvs, bi-specific antibody molecules, chimeric antigen receptors, and immunoconjugates. Methods of use are also provided.
1. A CD33-binding isolated monoclonal antibody or CD33-binding fragment thereof comprising
a variable light chain comprising
a complementarity determining region light (CDRL)1 having the sequence as set forth in SEQ ID NO: 133,
a CDRL2 having the sequence as set forth in SEQ ID NO: 134, and
a CDRL3 having the sequence as set forth in SEQ ID NO: 135, and
a variable heavy chain comprising
a CDR heavy (H)1 having the sequence as set forth in SEQ ID NO: 130,
a CDRH2 having the sequence as set forth in SEQ ID NO: 131, and
a CDRH3 having the sequence as set forth in SEQ ID NO: 132.
2. The CD33-binding isolated monoclonal antibody or CD33-binding fragment thereof of claim 1 , wherein
the variable light chain has the sequence as set forth in SEQ ID NO: 20 or a sequence having at least 90% sequence identity thereto and
the variable heavy chain has the sequence as set forth in SEQ ID NO: 21 or a sequence having at least 90% sequence identity thereto.
3. The CD33-binding isolated monoclonal antibody or CD33-binding fragment thereof of claim 1 , in the form of a whole antibody, a single chain variable fragment (scFv), or an immunoconjugate.
4. A bispecific antibody molecule or bispecific antigen binding fragment thereof comprising the variable light chain and the variable heavy chain of the CD33-binding monoclonal antibody or antigen binding fragment thereof of claim 1 .
5. The bispecific antibody molecule or bispecific antigen binding fragment thereof of claim 4 , wherein the bispecific antibody molecule or bispecific antigen binding fragment thereof further comprises a CD3 binding domain or a CD8 binding domain.
6. The bispecific antibody molecule or bispecific antigen binding fragment thereof of claim 5 , wherein the CD3 binding domain comprises
a variable light chain comprising
a CDRL1 having the sequence as set forth in SEQ ID NO: 38,
a CDRL2 having the sequence as set forth in SEQ ID NO: 39, and
B a CDRL3 having the sequence as set forth in SEQ ID NO: 40, and
a variable heavy chain comprising
a CDRH1 having the sequence as set forth in SEQ ID NO: 41,
a CDRH2 having the sequence as set forth in SEQ ID NO: 42, and
a CDRH3 having the sequence as set forth in SEQ ID NO: 43.
7. The bispecific antibody molecule or bispecific antigen binding fragment thereof of claim 5 , wherein the CD8 binding domain comprises
a variable light chain comprising
a CDRL1 having the sequence as set forth in SEQ ID NO: 69,
a CDRL2 having the sequence as set forth in SEQ ID NO: 70, and
B a CDRL3 having the sequence as set forth in SEQ ID NO: 71, and
a variable heavy chain comprising
a CDRH1 having the sequence as set forth in SEQ ID NO: 72,
a CDRH2 having the sequence as set forth in SEQ ID NO: 73, and
a CDRH3 having the sequence as set forth in SEQ ID NO: 74.
8. A chimeric antigen receptor (CAR) comprising
an extracellular component comprising a CD33-binding isolated monoclonal antibody or 1 CD33-binding fragment thereof of claim 1 ,
a transmembrane domain, and
an effector domain,
wherein the transmembrane domain links the extracellular component to the effector domain.
9. The CD33-binding isolated monoclonal antibody or CD33-binding fragment thereof of claim 1 , wherein the CD33-binding isolated monoclonal antibody or CD33-fragment thereof is covalently conjugated to polyethylene glycol (PEG).
10. The CD33-binding isolated monoclonal antibody or CD33-binding 1 fragment thereof of claim 1 , wherein the CD33-binding isolated monoclonal antibody or CD33-binding fragment thereof is part of an antibody-drug conjugate comprising maytansinoid, dolastatin, auristatin, calicheamicin, pyrrolobenzodiazepine (PBD), nemorubicin, anthracycline, duocarmycin, vinca alkaloid, taxane, trichothecene, camptothecin, or elinafide.
11. A composition comprising the CD33-binding isolated monoclonal 1 antibody or CD33-binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier.