Selection of reagents for human radioimmunotherapy.
Promising response rates are noted in patients with refractory Hodgkin's disease after radioimmunoglobulin therapy (RIT) with Yttrium-90 labeled polyclonal antiferritin. To explore the most efficacious selection of RIT reagents for use in humans, experimental animal data are reviewed for radiolabeled antiferritin and B72.3. Nude mice with subcutaneously implanted human malignancies provide an excellent primary screen for radiolabeled antibodies under consideration for use in humans. They provide information on the potential of a new reagent to target a human malignancy in vivo. The other determinant of the therapeutic ratio of RIT reagents--normal tissue toxicity--is best analyzed in large animals, such as dogs. Hematologic toxicity is dose limiting in all species and best predicted by a prescription of radiolabeled antibodies in mCi per kilogram body weight and the presence or absence of bone marrow targeting. Per cGy, RIT is more effective in causing BM damage in dogs than in rats. In dogs, bone marrow transplantation with autologous cryopreserved bone marrow cells or G-CSF treatment can accelerate hemopoietic recovery and granulopoiesis, respectively, after RIT. When dose escalation beyond bone marrow toxicity is performed, the liver (dog) or the intestinal tract (rat) become the next dose limiting tissue in dose escalation studies. Significant improvement in RIT results will be achieved when the normal liver uptake of chelated monoclonal antibody in dogs and in human patients can be prevented. The described animal models and continued investigations of RIT in patients with endstage Hodgkin's disease will allow for further improvement in the therapeutic ratio of RIT and the applicability of RIT in humans.
Vriesendorp
H M
HM
Johns Hopkins Oncology Center, Section of Radiobiology, Baltimore, MD 21205.
Quadri
S M
SM
Stinson
R L
RL
Onyekwere
O C
OC
Shao
Y
Y
Klein
J L
JL
Leichner
P K
PK
Williams
J R
JR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001853:Bone Marrow / Q000528:radiation effects; D004285:Dogs; D005260:Female; D005293:Ferritins / Q000276:immunology; D006689:Hodgkin Disease / Q000532:radiotherapy*; D006801:Humans; D007205:Indium Radioisotopes / Q000627:therapeutic use; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D011879:Radiotherapy Dosage; D015021:Yttrium Radioisotopes / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D015021:Yttrium Radioisotopes; D005293:Ferritins