Tumour Therapy with Radiolabelled Antibodies

Abstract

The promise of radiolabelled immunoglobulin therapy (RIT) for selective, patient friendly, cancer treatment has not yet been fulfilled. Only patients with haematological malignancies show sizable response rates after RIT. With solid tumours, intravenous administration of radiolabelled antibodies does not provide sufficient tumour targeting. However, intracompartmental administration may solve this problem, particularly if tumour reactive IgM is used. Clinical progress in RIT depends on understanding the important RIT variables: antigen, antibody, radioisotope, conjugation chemistry, activity escalation, fractionation and protein dose. These are reviewed and a new translational decision tree/flow diagram is presented that can limit analysis to the most important RIT variables for a particular disease. These variables may differ depending on the type and stage of cancer, but the guiding principles in RIT development remain the same: selectivity and accountability. The proper application of these principles leads to the definition of a new series of phase I, II, III studies. These studies are more appropriate for the clinical exploration of RIT and place an emphasis on therapeutic ratio rather than toxicity.

Radiolabeled Immunoglobulin Therapy for Patients with Solid Tumors

“…Results reported in this communication, prior translational animal studies, and RIT studies in patients with end-stage Hodgkin's disease [4][5][6]9,26], suggest that a high 'targeted' dose with sharp dose fall-off in adjacent normal tissues may be delivered to patient with solid tumors via intra-tumoral RIT using Y-90 labeled murine IgM against TNC. TNC appears to be a good target as it is abundant in most solid tumors tested and has limited expression in healthy normal tissues.…”

“…Tumor shrinkage was observed 144 h after administration of Y-90 labeled IgM [5,9,13,14]. In contrast 50% of tumor-reactive IgG administered directly into the tumor was washed out in 2 days [4,9,10,4,14]. Aggregated albumen labeled with Y-90 did not diffuse through the whole tumor mass.…”

“…TNC occurs in different isoforms which are generated by alternative splicing and these TNC variants are abundantly expressed at the invasive tumor front [3]. TNC reactive IgM and an intra-tumoral route of administration are introduced to avoid off target effects [4][5][6].…”

“…The I-131 IgG radiation dose to the recurrence could not be determined accurately at the time and might have been too low for cures. Moreover, the gamma emissions of I-131 are too weak to deliver a homogeneous tumor dose and radioactive iodine is enzymatically removed from carrier molecules and taken up in the thyroid gland of the patient or secreted into the stomach of the patient [4,5].…”

“…A low intravenous dose of 2 mg of anti-ferritin rabbit IgG labeled with Y-90 can have significant therapeutic effects [4,[9][10][11]. In the absence of accurate dosimetric methods at the time, a positive dose effect curve could only be demonstrated in patients with HD by increasing the amount of Y-90 administered per kg bodyweight of the patient (not body surface area) from 111MBq to 148MBq and subsequently to 185MBq [9,11].…”