Relationship of the CD22 immunotoxin dose and the tumour establishment in a SCID mice model

Immunotoxins (ITs) may be very potent to erradicate tumour growth in vivo. We investigated the influence of the IT-dose. in relation to the establishm ent of the tumour, on the anti-tumour activity of CD22-recombinant (rec) ri cin A fur a disseminated tumour (Ramos) in SCID mice. Furthermore, the enha ncement of the IT cytotoxicity in vivo by chloroquine was assessed. CD22-re c ricin A appeared to be highly effective. Paralysis of the hind legs was s ignificantly delayed by a very low IT-dose of 2 mug administered intravenou sly (i.v.) 7 days after i.v. inoculation of the tumour cells. Even a dose o f 30 mug administered 21 days after inoculation of the target cells signifi cantly delayed the onset of paralysis up to 8 days compared with the median paralysis time (MPT) of the control group. The efficacy of treatment was o bviously influenced by the establishment of the tumour, the tumour load and localisation. The anti-tumour activity of 10 and 30 mug IT diminished when the IT was administered after increasing the time lag following inoculatio n of tumour cells. Delaying IT administration resulted in growth of solid t umours. This implies that cells migrate to sanctuaries protected from the I T indicating that the anti-tumour activity was influenced by the accessibil ity of the IT to the target cells. The in vivo anti-tumour activity of CD22-rec ricin A could not be enhanced by simultaneously administered chloroquine, despite the continuous infusion with an intraperitoneally (i.p.) implanted mini-osmotic pump. Ex vivo expe riments revealed that the maximally tolerated serum concentration (3.9 muM) was too low to be effective. In conclusion, CD22-rec ricin A is highly eff ective for in vivo treatment of B-cell malignancies, in particular if treat ment is started when the tumour load is low and before migration takes plac e to poorly accessible sanctuaries.