Antibodies for Cancer Therapeutics and Diagnostics

Several antibody-based therapies are currently available to cancer patients, but these agents often cause dose-limiting side effects as they target both healthy and cancer cells. To reduce the toxicity associated with these therapies, LICR is exploring the potential of monoclonal antibodies (mAbs) that target cell surface molecules expressed selectively on cancer cells. These mAbs are being engineered to deliver chemotherapeutics, radioisotopes (radioimmunotherapy; RIT), nanoparticles, and small interfering RNA (siRNA) molecules directly to cancer cells. The mAbs are also being engineered so that they can be used to detect and visualize tumors for both diagnostic and prognostic purposes.

Development of the Hu3S193 Targeted Antibody for Radioimmunotherapy

The mAb, hu3S193, which was developed by the LICR New York and Melbourne Branches, binds selectively to the Ley antigen. As the Ley antigen is over-expressed on almost 90% of epithelial cell tumors and associated metastases, it is an attractive target for antibody therapy. The mAb hu3S193 has been shown to induce a potent anti-tumor response in vitro and in vivo, and is currently being tested by LICR spin-off company, Recepta Biopharma, in phase I/II clinical trials.

A team from the LICR Melbourne Center is applying their expertise in antibody development, and the hu3S193 antibody in particular, to address two major challenges to the development of effective RITs: inconsistent penetration of the reagent into tumors, and toxicity caused by the accumulation of radiolabeled mAbs in the bone marrow. To overcome these limitations, the LICR team is engineering and testing fragments of the hu3S193 antibody in an attempt to create smaller molecules with new, different biophysical properties. The immunoreactivity and binding affinity of one of these fragments, the scFv multimer fragment, were significantly improved compared to another hu3S193 antibody fragment tested, but the scFv multimer fragment appeared to be quickly metabolized and excreted via the kidneys1. This property limits the clinical potential of the hu3S193 scFv multimer, as retention of the radiochemicals might cause renal toxicity. The team is now engaging in work to improve the stability of the scFv multimer and prevent renal accumulation.

Identification of the MX35 Ovarian Cancer-Specific Antibody Target

The mAb MX35, which was generated by investigators at the LICR New York Branch and their collaborators, reacts with approximately 90% of human ovarian epithelial cell cancers. However, the identity of the cell surface molecule to which the antibody binds has proved elusive. A team of investigators from the LICR New York and Uppsala Branches and LICR Affiliates in Kyiv (Ukraine) recently succeeded in identifying this molecule as the sodium-dependent phosphate transport protein 2b (NaPi2b)2. The identification of this one molecule suggests an entirely new family of cell surface molecules as potential targets for antibody therapies. An early-phase clinical trial with MX35 demonstrated good tumor localization with no evidence for accumulation in normal tissues in ovarian cancer patients. To further explore the potential of NaPi2b as an antibody target for ovarian and other types of cancer, the team is investigating the expression of NaPi2b in normal human tissues and a variety of tumor types. In addition, the team has generated several new antibodies against surface epitopes of NaPi2b and is exploring the effect of antibody binding on phosphate uptake in cancer cells3. In preparation for clinical trials the antibody has been humanized at the New York Branch and the humanized antibody is now being prepared for clinical evaluation by Recepta Biopharma.

References

  1. 1. Kelly MP, Lee FT, Tahtis K, Power BE, Smyth FE, Brechbiel MW, Hudson PJ, Scott AM. Tumor Targeting by a Multivalent Single-Chain Fv (scFc) Anti-Lewis Y Antibody Construct. Cancer Biother Radiopharm (2008) 23(4): 411-423
  2. 2. Yin BW, Kiyamova R, Chua R, Caballero OL, Gout I, Gryshkova V, Bhaskaran N, Souchelnytskyi S, Hellman U, Filonenko V, Jungbluth AA, Odunsi K, Lloyd KO, Old LJ, Ritter G. Monoclonal antibody MX35 detects the membrane transporter NaPi2b (SLC34A2) in human carcinomas. Cancer Immun (2008) 8:3
  3. 3. Kiyamova R, Gryshkova V, Ovcharenko G, Lituyev D, Malyuchik S, Usenko V, Khozhayenko Y, Gurtovyy V, Yin B, Ritter G, Old L, Filonenko V, Gout I. Development of monoclonal antibodies specific for the human sodium-dependent phosphate co-transporter NaPi2b. Hybridoma (Larchmt) (2008) 27(4):277-84
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