Improved pretargeted delivery of radiolabelled hapten to human tumour xenograft in mice by avidin chase of circulating bispecific antibody.
OBJECTIVE
Pretargeted therapy with radiolabelled bivalent haptens and bispecific antibodies has shown promising results, but blood clearance of the activity-carrying haptens under conditions designed for radioimmunotherapy is relatively slow. Thus, the chase of excess circulating bispecific antibody by biotinylation of the bispecific antibody and injection of avidin before hapten administration was tested with a view to increasing tumour-to-blood activity ratios.


METHODS
The anti-carcinoembryonic antigen (CEA) x anti-diethylene triamine penta-acetic acid-indium (di-DTPA-indium) bispecific antibody (hMN-14x734) was derivatised with NHS-LC-biotin and injected into LS-174T tumour-bearing nude mice at a dose of 3.5 nmol, followed by avidin and finally by the 125I-labelled di-DTPA-indium hapten (1 nmol). Blood samples were collected, animals sacrificed and tumours and normal tissues counted.


RESULTS
Avidin chased up to 72% of the circulating antibody in the liver and the spleen within 30 min. When the labelled hapten was injected 3 h after avidin, tumour to blood ratios measured 3 and 24 h after hapten injection were significantly improved by the chase (3.5-fold), whereas tumour uptake was not significantly reduced. Uptake in normal tissues was unchanged (liver, kidney) or decreased (muscle), with the exception of spleen, in which uptake of both antibody and hapten was increased by the avidin chase.


CONCLUSIONS
The chase strategy reduces hapten concentration in blood and thus should reduce bone marrow exposure. The use of two different recognition systems limits possible interference between the chase and targeting steps.
Mirallié
Eric
E
Cancer Research Department, Inserm U601, Institut de Biologie, Université de Nantes, 9 quai Moncousu, 44093, Nantes Cedex 1, France.
Saï-Maurel
Catherine
C
Faivre-Chauvet
Alain
A
Regenet
Nicolas
N
Chang
Chien-Hsing
CH
Goldenberg
David M
DM
Chatal
Jean-François
JF
Barbet
Jacques
J
Thedrez
Philippe
P
D000818:Animals; D000906:Antibodies / Q000097:blood* / Q000276:immunology / Q000627:therapeutic use; D001360:Avidin / Q000008:administration & dosage*; D002272:Carcinoembryonic Antigen / Q000097:blood* / Q000627:therapeutic use; D002277:Carcinoma / Q000378:metabolism* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000532:radiotherapy; D004338:Drug Combinations; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D009928:Organ Specificity / Q000187:drug effects; D016499:Radioimmunotherapy / Q000379:methods; D014018:Tissue Distribution / Q000187:drug effects
D000906:Antibodies; D002272:Carcinoembryonic Antigen; D004338:Drug Combinations; D007457:Iodine Radioisotopes; D001360:Avidin