Combination vascular targeted and tumor targeted radioimmunotherapy

Rat MAb 201B, which binds to murine thrombomodulin, can deliver up to 50% o f the injected dose of attached radioisotopes to the lung vascular endothel ium. We have shown previously that intravenous injection of about 30 mu Ci of Bi-213-MAb 201B, which delivers about 15 Gy of alpha irradiation to the lung, is capable of eradicating small lung colonies (500-1000 cells) of the mammary tumor line, EMT-6. Larger tumors (>5000 cells) were not completely cured by this vascular targeted radioimmunotherapy (VT-RAIT) approach. We reasoned that VT-RAIT might make the lung vessels sewing the tumor cells mo re permeable, allowing MAb targeted to the tumor cells to extravasate more readily and mediate more efficient standard radioimmunotherapy (RAIT). Dist ribution experiments with the tumor targeted MAb 13A (RAIT MAb), following VT-RAIT, did not demonstrate a large increase in tumor uptake; however, mic roautoradiography did indicate that MAb 13A was distributed more evenly thr oughout the tumor when administered after VT-RAIT. Therapy experiments on l ung tumors of similar to 5000 cells each, combining Bi-213-MAb 201B (VT-RAI T) with Bi-213-MAb 13A (RAIT) 24 hours later, resulted in a better outcome (3 cured/10 at risk) than for control groups: RAIT only (0/10), VT-RAIT onl y (1/10), or no therapy (0/10). RAIT therapy delivered 48 hours after VT-RA IT had Mo apparent benefit. Bi-213-MAb 201B VT-RAIT followed by Y-90-MAb 13 A Fab' RAIT showed only a slight improvement in tumor cures (2/10) over tha t in control groups: (0/9), (0/10), (0/10), respectively. These results sug gest that optimal timing, dosage, and choice of MAb for RAIT should enhance the double MAb therapy approach significantly.