Cell penetrating nucleolytic antibody based cancer therapy
Cancer cells with defects in DNA repair are highly susceptible to DNA-damaging agents, but delivery of therapeutic agents into cell nuclei can be challenging. A sub-set of autoantibodies having nucleolytic activity are capable of nuclear penetration. These antibodies can be used as therapeutic agents targeted towards DNA repair-deficient malignancies.
1. A pharmaceutical composition comprising
a) a cell-penetrating, nucleolytic antibody, or antigen binding fragment thereof, comprising:
a heavy chain variable region comprising respectively the first, second, and third complementarity determining regions (CDRs) of SEQ ID NO:5 or humanized variants thereof, and
a light chain variable region comprising respectively the first, second, and third CDRs of SEQ ID NO:1 or humanized variants thereof,
in a unit dosage between about 0.01 and about 100 mg/kg body weight of a human; and
b) a pharmaceutically acceptable excipient for injection.
2. The pharmaceutical composition of claim 1 , further comprising one or more antineoplastic or radio-sensitizing agents selected from the group consisting of cisplatin, cytoxan, doxorubicin, methotrexate, mitomycin c, nitrogen mustard, hydroxyurea, bevacizumab, cetuximab, rituximab, trastuzumab, tirapazamine, temozolomide, camptothecin, cisplatin, gemcitabine, 5-fluorouracil, hydroxyurea, pentoxifylline, vinorelbine, and combinations thereof.
3. The pharmaceutical composition of claim 1 , in the unit dosage form for intravenous injection or intratumoral injection.
4. The pharmaceutical composition of claim 1 , wherein the antibody or antigen binding fragment thereof, is a monovalent or multivalent single chain variable fragment (scFv).
5. The pharmaceutical composition of claim 1 , wherein
the first light chain CDR comprises the amino acid sequence of SEQ ID NO:2;
the second light chain CDR comprises the amino acid sequence of SEQ ID NO:3;
the third light chain CDR comprises the amino acid sequence of SEQ ID NO:4;
the first heavy chain CDR comprises the amino acid sequence of SEQ ID NO:6;
the second heavy chain CDR comprises the amino acid sequence of SEQ ID NO:7; and
the third heavy chain CDR comprises the amino acid sequence of SEQ ID NO:8.
6. The pharmaceutical composition of claim 1 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:1 and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:5.
7. The pharmaceutical composition of claim 1 , wherein the antibody or antigen binding fragment thereof, is a humanized antibody or an antigen binding fragment thereof.
8. The pharmaceutical composition of claim 7 , wherein
the first light chain CDR comprises the amino acid sequence of SEQ ID NO:2;
the second light chain CDR comprises the amino acid sequence of SEQ ID NO:3;
the third light chain CDR comprises the amino acid sequence of SEQ ID NO:4;
the first heavy chain CDR comprises the amino acid sequence of SEQ ID NO:6;
the second heavy chain CDR comprises the amino acid sequence of SEQ ID NO:7; and
the third heavy chain CDR comprises the amino acid sequence of SEQ ID NO:8.
9. The pharmaceutical composition of claim 1 , wherein the antibody or antigen binding fragment thereof, is a chimeric antibody.
10. The pharmaceutical composition of claim 9 , wherein
the first light chain CDR comprises the amino acid sequence of SEQ ID NO:2;
the second light chain CDR comprises the amino acid sequence of SEQ ID NO:3;
the third light chain CDR comprises the amino acid sequence of SEQ ID NO:4;
the first heavy chain CDR comprises the amino acid sequence of SEQ ID NO:6;
the second heavy chain CDR comprises the amino acid sequence of SEQ ID NO:7; and
the third heavy chain CDR comprises the amino acid sequence of SEQ ID NO:8.
11. The pharmaceutical composition of claim 10 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:1 and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:5.
12. The pharmaceutical composition of claim 1 , wherein the antibody or antigen binding fragment thereof, is not an IgG2a-k mouse monoclonal antibody.