Small pretargeting constructs with infinite affinity for radiochelates

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DESCRIPTION (provided by applicant): Pretargeting is a notable advance in radioimaging and radiotherapy. It allows tumor-avid antibodies and other targeting molecules that have excellent specificity and affinity but poor pharmacokinetic properties to be used in conjunction with small radioactive effectors (e.g., radiochelates) that have superior pharmacokinetic behavior. The key is a bifunctional pretargeting probe, in which the targeting module (e.g., tumor-avid antibody) is linked to another module that specifically captures the radioactive effector. A pretargeting regimen then plays out in two stages. In the first, the bifunctional probe is administered and allowed to home in vivo to the tumor or other target cells or tissue by virtue of its targeting module. Although it may take a day or more for non-targeted probe to clear the body because of its poor pharmacokinetics, it is not radioactive, so the subject experiences no radiation burden and there is no loss of short-lived isotope. Once the probe has cleared, the second stage is implemented: administration of the radioactive effector. It clears from the body rapidly, but during its brief residence some of it is captured by target-bound bifunctional probe molecules via their effector-capture modules. Thus can an effective radioimaging or radiotherapy payload be delivered to the target while imposing a very low background or non- Couples covalently in vivo therapeutic radiation burden on the subject. hel To date, effector-capture modules have been macromolecular. We hope to demonstrate that small Targeting peptides can serve just as well. Using novel phage display module Peptide covalent technology, we will select peptides that couple rapidly, effector-capture selectively, and covalently to small radiochelate effectors with module excellent pharmacokinetic characteristics. Such peptides l retargeti would have important advantages over macromolecular effector-capture modules: (1) They are easy to fuse genetically or couple chemically (in multiple copies if appropriate) to any targeting module; a single generic radiochelate could be used with an unlimited repertoire of stable, non-radioactive bifunctional probes. (2) They can be synthesized chemically, making fully synthetic pretargeting probes possible; mirror-image peptides would capture the opposite radiochelate isomer and be resistant to proteolytic degradation. (3) They will not be immunogenic, and therefore can be used more than once in the same subject. PUBLIC HEALTH RELEVANCE Cancer doctors increasingly rely on radioactive probes that home specifically to a patient's cancer cells. The radioactive probes can be used both to image the cancers for effective diagnosis and to deliver lethal radiation specifically to the cells to help cure the disease, both without invasive surgery. The purpose of this research is to improve and simplify "pretargeting," a new procedure for using probes that can dramatically sharpen diagnostic images and reduce the harmful radiation side-effects patients suffer.