Near-Infrared Photoimmunotherapy: Photoactivatable Antibody-Drug Conjugates (ADCs).

Cancer treatment has been founded traditionally on the three approaches of surgery, radiation, and chemotherapy with the latter recognized as the obvious systemic treatment approach applicable to disease that has spread. Although significant progress has been made over nearly 100 years of developing systemic treatments, it remains clear that use of the toxic agents involved is a two-edged sword with normal organ toxicities always needing to be balanced with and against administration of relevant therapeutic doses. With the advent of monoclonal antibodies targeted against tumor-associated antigens that could be used as carriers of potently toxic chemotherapy drugs, it was thought that such antibody-drug conjugates (ADCs) could engender the answer to the toxicity/therapeutic equation by shifting the equation more toward beneficial therapeutic efficacy. However, over 40 or so years, antibody-drug conjugates have not significantly affected the toxicity/therapy balance paradigm in most cancer indications, especially in solid tumors. Ideally, a further step may be required in that a non-tumor-targeted antibody-drug conjugate should be essentially nontoxic in its native administered form, with toxic effects unleashed only at the site of targeted tumors. A new approach that employs this principle is the use of an antibody-drug conjugate that is essentially nontoxic to normal tissues by virtue of requiring an extra step of light activation to become potent. We describe the preclinical data and first clinical results gained over the past few years by use of antibody-drug conjugates wherein the drug comprises a near-infrared photoactivatable dye delivered to tumors by a monoclonal antibody and is subsequently activated to a toxic entity solely at sites of tumors.

Development of a MR-visible compound for tracing neuroanatomical connections in vivo.

Traditional studies of neuroanatomical connections require injection of tracer compounds into living brains, then histology of the postmortem tissue. Here, we describe and validate a compound that reveals neuronal connections in vivo, using MRI. The classic anatomical tracer CTB (cholera-toxin subunit-B) was conjugated with a gadolinium-chelate to form GdDOTA-CTB. GdDOTA-CTB was injected into the primary somatosensory cortex (S1) or the olfactory pathway of rats. High-resolution MR images were collected at a range of time points at 11.7T and 7T. The transported GdDOTA-CTB was visible for at least 1 month post-injection, clearing within 2 months. Control injections of non-conjugated GdDOTA into S1 were not transported and cleared within 1-2 days. Control injections of Gd-Albumin were not transported either, clearing within 7 days. These MR results were verified by classic immunohistochemical staining for CTB, in the same animals. The GdDOTA-CTB neuronal transport was target specific, monosynaptic, stable for several weeks, and reproducible.

Radioactivity-synchronized fluorescence enhancement using a radionuclide fluorescence-quenched dye.

We demonstrate the first evidence of radioactivity-synchronized fluorescence quenching of a near-infrared light-emitting dye by a radionuclide, (64)Cu, and subsequent fluorescence enhancement upon (64)Cu decay to the daughter isotopes (64)Ni and (64)Zn. The dynamic switch from high radioactivity and low fluorescence to low radioactivity and high fluorescence is potentially useful for developing complementary multimodal imaging and detection platforms for chemical, environmental, and biomedical applications as well as for unraveling the mechanisms of metal-induced dynamic fluorescence changes.

Preclinical therapy of breast cancer with a radioiodinated humanized anti-EGP-1 monoclonal antibody: advantage of a residualizing iodine radiolabel.

BACKGROUND: A humanized monoclonal antibody (MAb), hRS7, labeled with 131I-IMP-R4, was evaluated for the preclinical radioimmunotherapy (RAIT) of breast cancer. 131I-IMP-R4 is an improved residualizing form of 131I that overcomes the short tumor residence time associated with conventionally radioiodinated MAbs. RS7, an internalizing MAb, recognizes epithelial glycoprotein-1, which is highly expressed in the carcinomas of breast, lung, ovary, and prostate. METHODS: A humanized version of RS7 was generated by CDR-grafting and transfection. In vivo experiments were carried out in nude mice bearing subcutaneous MDA-MB-468 human breast cancer xenografts. Therapy experiments were performed using established tumors with mean tumor volume (MTV) of 0.3 cm3, and single administrations, at approximately 70% of the estimated maximum tolerated doses (MTD), of the residualizing 131I-IMP-R4-hRS7 and 131I-hRS7 prepared by the conventional chloramine-T method [131I-hRS7 (CT)]. Therapeutic specificity was determined by comparison with untreated and non-specific MAb controls. RESULTS: hRS7 was functionally very similar to murine and chimeric RS7. A biodistribution study using 125I-IMP-R4-hRS7 and 131I-hRS7 (CT) indicated a dosimetric advantage for the former. The MTVs 8 weeks post-treatment were 20, 163, and 280% of the starting MTVs of 131I-IMP-R4-hRS7-treated, 131I-hRS7 (CT)-treated, and untreated groups, respectively. Complete remissions were seen in 5 of 11 [and 6 of 8] mice treated with 131I-IMP-R4-hRS7, and in 1 of 11 mice treated with 131I-hRS7(CT). 131I-IMP-R4-hRS7 was significantly more efficacious than 131I-hRS7 (CT) [ P = 0.01 for AUC] and the control 131I-IMP-R4-MAb. CONCLUSION: 131I-IMP-R4-hRS7 is a promising new agent for RAIT, providing significant therapeutic advantage in comparison to the conventionally 131I-labeled antibody.