Immunoconjugates--monoclonal antibodies (mAbs) coupled to highly toxic agents, including radioisotopes and toxic drugs (ineffective when administered systemically alone)--are becoming a significant component of anticancer treatments. By combining the exquisite targeting specificity of mAbs with the enhanced tumor-killing power of toxic effector molecules, immunoconjugates permit sensitive discrimination between target and normal tissue, resulting in fewer toxic side effects than most conventional chemotherapeutic drugs. Two radioimmunoconjugates, ibritumomab tiuxetan (Zevalin) and tositumomab-131I (Bexxar), and one drug conjugate, gemtuzumab ozogamicin (Mylotarg), are now on the market. For the next generation of immunoconjugates, advances in protein engineering will permit greater control of mAb targeting, clearance and pharmacokinetics, resulting in significantly improved delivery to tumors of radioisotopes and potent anticancer drugs. Pre-targeting strategies, which separate the two functions of antibody-based localization and delivery or generation of the toxic agent into two steps, also promise to afford superior tumor targeting and therapeutic efficacy. Several challenges in optimizing immunoconjugates remain, however, including poor intratumoral mAb uptake, normal tissue conjugate exposure and issues surrounding drug potency and conditional release from mAb carriers. Nonetheless, highly promising results from preclinical models will continue to drive the clinical development of this therapeutic class.

Arming antibodies: prospects and challenges for immunoconjugates

1. Health care is a human right. 2. The care of the individual is at the center of health care, but the whole system needs to work to improve the health of populations. 3. The health care system must treat illness, alleviate suffering and disability, and promote health. 4. Cooperation with each other, those served, and those in other sectors is essential for all who work in health care. 5. All who provide health care must work to improve it. 6. Do no harm.

https://www.journalacs.org/article/S1072-7515(00)00768-7/pdf

Is this a practical approach

Potential technetium small molecule radiopharmaceuticals.

99mTc-Labeled Small Peptides as Diagnostic Radiopharmaceuticals.

Designed ankyrin repeat proteins (DARPins) can recognize targets with specificities and affinities that equal or surpass those of antibodies, but because of their robustness and extreme stability, they allow a multitude of more advanced formats and applications. This review highlights recent advances in DARPin design, illustrates their properties, and gives some examples of their use. In research, they have been established as intracellular, real-time sensors of protein conformations and as crystallization chaperones. For future therapies, DARPins have been developed by advanced, structure-based protein engineering to selectively induce apoptosis in tumors by uncoupling surface receptors from their signaling cascades. They have also been used successfully for retargeting viruses. In ongoing clinical trials, DARPins have shown good safety and efficacy in macular degeneration diseases. These developments all ultimately exploit the high stability, solubility, and aggregation resistance of these molecules, permitting a wide range of conjugates and fusions to be produced and purified.

Designed Ankyrin Repeat Proteins (DARPins): Binding Proteins for Research, Diagnostics, and Therapy

Stable one-step technetium-99m labeling of His-tagged recombinant proteins
with a novel Tc(I)–carbonyl complex

Stable one-step technetium-99m labeling of His-tagged recombinant proteins with a novel Tc(I)-carbonyl complex.

A new peptide labeling method that uses the organometallic aquaion [99mTc(H2O)3(CO)3]+ has been developed. METHODS: A selection of amino acids was labeled at different concentrations with the organometallic aquaion, and the labeling yield was determined by high-performance liquid chromatography. This investigation has shown histidine to be a very potent ligand, with specific activities of up to 6 TBq/micromol (160 Ci/micromol) ligand. Histidine derivatives have been coupled to neurotensin(8-13) (NT[8-13]) and have been labeled with the aquaion, resulting in high specific activities with (N(alpha)-histidinyl)acetic acid-NT(8-13) similar to those with histidine. RESULTS: Histidine derivatives of NT(8-13) labeled using this approach fully retained their receptor affinity, showing KD values of all investigated NT analogs below 1 nmol/L on colon carcinoma HT29 cells. Biodistrbution experiments in BALB/c mice showed complete clearance of (N(alpha)-histidinyl)acetic acid-NT(8-13) from the blood after 24 h and no unwanted accumulation in any tissue. CONCLUSION: The novel labeling method using the organometallic 99mTc-aquaion combines the advantage of highest specific activities with minimal functionalization of proteins and peptides under retention of biologic affinity.

Organometallic 99mTc-aquaion labels peptide to an unprecedented high specific activity.

Metal carbonyl syntheses XXII. Low pressure carbonylation of [MOCl4]− and [MO4]−: the technetium(I) and rhenium(I) complexes [NEt4]2[MCl3(CO)3]☆

By R. Alberto·**, R. Schibli, U. Abram, A. Egli, F. F. (Russ) Knapp and P. A. Schubiger 1 Paul Scherrer Institute, Division of Radiopharmacy, CH-5232 Villigen/Switzerland 2 Oak Ridge National Laboratory, Health Sciences Research Division, Oak Ridge TN 37831 3 University of Tübingen, Institute of Inorganic Chemistry, D-72076 Tübingen/Germany 4 Universität Zürich, Institute of Inorganic Chemistry, CH-8057 Zürich/Switzerland

/pdf/potential-of-the-m-co-3-m-re-tc-moiety-for-the-labeling-of-6o9qbksisn.pdf

A. Egli

Papers

Stable one-step technetium-99m labeling of His-tagged recombinant proteins with a novel Tc(I)-carbonyl complex.

Organometallic 99mTc-aquaion labels peptide to an unprecedented high specific activity.

Metal carbonyl syntheses XXII. Low pressure carbonylation of [MOCl4]− and [MO4]−: the technetium(I) and rhenium(I) complexes [NEt4]2[MCl3(CO)3]☆

Potential of the "[M(CO)3]+" (M = Re, Tc) moiety for the labeling of biomolecules

Steps towards [(C5Me5)TcO3]: Novel synthesis of [(C5Me5)Tc(CO)3] from [{Tc(μ3−OH)(CO)3}4] and oxidation of [(C5Me5)M(CO)3] (M = Tc, Re) with Br2