Proposal for translational analysis and development of clinical radiolabeled immunoglobulin therapy.
OBJECTIVE
Radiolabeled immunoglobulin therapy (RIT) can be a selective, effective, low-toxicity outpatient cancer therapy. A consensus on the best approach for the preclinical and clinical development of RIT reagents needs to be developed. We report the M.D. Anderson Cancer Center prior experience in translating RIT from laboratory to clinic for the treatment of Hodgkin's disease and propose a flow diagram for the development of RIT for other malignancies.


METHODS
Three different animal models are described: nude mice bearing human tumor xenografts, normal beagle dogs, and normal rhesus monkeys. We produced and purified antibodies and prepared chelate-immunoconjugates reactive with six different human tumor-associated antigens. The Igs used were derived from rabbits, mice, and humans (human-derived RIT reagents being less immunogenic in human patients). Eighty patients with refractory Hodgkin's disease were treated with radiolabeled antiferritin.


RESULTS
We recommend a two-injection scheme using, (1) an indium-111-labeled radioimmunoconjugate for diagnosis, pharmacokinetic studies, and dosimetry, and (2) a yttrium-90-labeled radioimmunoconjugate for therapy. The animal models provide useful data on tumor targeting, radiotoxicology, and undesirable biodistributions. A 70% response rate is obtained in patients with advanced recurrent Hodgkin's disease. More extensive preclinical testing allows for safer and more effective clinical RIT studies.


CONCLUSIONS
We recommend, (1) preclinical optimization of chelation chemistry, Ig size, Ig origin, route of administration, and fractionation, (2) new clinical Phase I-III studies more appropriate for RIT development than the classical Phase I-III studies used for the development of chemotherapeutic agents, and (3) more extensive preclinical testing of RIT reagents.
Vriesendorp
H M
HM
Department of Radiotherapy, University of Texas, M.D. Anderson Cancer Center, Houston 77030, USA.
Quadri
S M
SM
Jaeckle
K A
KA
Freedman
R S
RS
Cromeens
D M
DM
D000818:Animals; D002985:Clinical Protocols; D004285:Dogs; D006689:Hodgkin Disease / Q000532:radiotherapy*; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use; D008253:Macaca mulatta; D051379:Mice; D008819:Mice, Nude; D011817:Rabbits; D016499:Radioimmunotherapy / Q000379:methods; D015021:Yttrium Radioisotopes / Q000627:therapeutic use
D018796:Immunoconjugates; D015021:Yttrium Radioisotopes