BACKGROUND:  Conventional chemotherapy, currently used in the treatment of cancer is not capable of differentiating between cancer cells and any other cell types with elevated metabolism. Therefore, normal tissue toxicity is the limiting factor of non-specific chemotherapeutics. To avoid destruction of normal cells, targeted cancer therapeutics are delivered specifically at the tumor site, where they exert their cytotoxic effect. Targeting is achieved via recognition of a specific tumor antigen that is abundantly expressed by the tumor cells and either completely absent or present in miniscule amounts in normal tissues. Successful targeting of a tumor antigen is a function of both specificity and affinity; however the serum pharmacokinetics (PK) of the agent defines its bioavailability and ability to achieve maximum anti-tumor effect. Furthermore, PK is crucial in molecular imaging applications, where the tumor targeting molecule may be a carrier of a positron or gamma emitting radionuclide (PET, SPECT), or a paramagnetic agent (MRI). The PK profile of the carrier molecule controls how early suitable contrast is achieved, in order to differentiate the disease from the general background. It is important to note that the optimal PK for therapy is not suitable for imaging and vice versa. Therefore, it is absolutely advantageous to be able to control the PK of targeted anti-tumor drugs and diagnostics for achieving maximum tumor killing and acquiring unambiguous images, respectively.

INNOVATION:  Researchers at UCLA have identified a specific domain of a prevalent human protein, and novel conserved mutations within that domain, that has the ability to modify and/or extend the serum half life of an attached molecule such as a tumor targeting molecule (peptide, aptamer, or small chemicals), imaging agent, or a therapeutic functional group.

POTENTIAL APPLICATIONS 

• Attach tumor targeting peptides, aptamers (RNA or DNA molecules) or small chemical molecules to the protein scaffold to specifically target the entire molecule to the tumor
• Label the targeted scaffolds possessing suitable pharmacokinetics with imaging agents for diagnostic purposes in imaging applications
• Conjugate anti-tumor drugs to the targeted scaffolds for cancer therapy with tunable pharmacokinetics

ADVANTAGES

• Ability to extend and fine tune the serum half life of the molecule attached to the protein scaffold
• Non-immunogenic human protein
• Low molecular mass of 23kDa
• Small size allows it to clear through the kidney rather than the liver, allowing for visualization of tumors located in the abdominal area in imaging applications, which would otherwise be obscured by high liver signal
• Low molecular mass agents exit the circulation more rapidly, reach their targets and penetrate deeper in tumor masses, which ultimately improves the range of therapeutic effect

DEVELOPMENT-TO-DATE:  The protein scaffold fused to an antibody fragment has been tested in mice. In addition, the scaffold and its variants alone (without a targeting entity attached) have been injected in mice to confirm the spectrum of serum half lives it can provide.

Reference: UCLA Case No. 2009-535