Figure 2
Figure 2. Anti-Ly49C/I F(ab′)2 enhances the antilymphoma activity of anti-CD20 mAb in vivo and is NK-cell–dependent. (A) C57BL/6 mice were inoculated retro-orbitally with 0.5 × 106 EL4-huCD20 lymphoma tumor cells. (B) After tumor inoculation, mice received (●) rat IgG control, (▪) 250 µg of anti-CD20 mAb (CAT-13) on day 3 and once per week for 3 weeks, (▲) 200 µg of anti-Ly49C/I F(ab′)2 (5E6) on day 3 and twice a week for 3 weeks, or (♦) the combination of both antibodies. Mice were then monitored for overall survival. *P = .042. (C) C57BL/6 mice were inoculated retro-orbitally with 0.5 × 106 EL4-huCD20 lymphoma tumor cells. (D) After tumor inoculation, mice received (●) rat IgG control on day 3; (▪) 50 µL of anti-Asialo-GM1 on days −1, 0, 5, 10, 15, 20, and 25 with 250 µg of anti-CD20 mAb and 200 µg anti-Ly49C/I F(ab′)2 on day 3; (▼) 200 µL liposomal clodronate on day −2 followed by 100 µL of liposomal clodronate on days 0, 4, 8, 12, 16, 20, and 24 with 250 µg of anti-CD20 mAb and 200 µg of anti-Ly49C/I F(ab′)2 on day 3; (♦) 500 µg anti-CD8 mAb on days −1, 0, 5, 10, 15, 20, and 25 with 250 µg of anti-CD20 mAb and 200 µg anti-Ly49C/I F(ab′)2 on day 3; or (▲) 250 µg of anti-CD20 mAb on day 3 and 200 µg of anti-Ly49C/I F(ab′)2 on day 3 with 250 µg of anti-CD20 mAb repeated once per week for 3 weeks and 200 µg of anti-Ly49C/I F(ab′)2 repeated biweekly for 3 weeks. Mice were then monitored for overall survival. *P < .001. All in vivo models were piloted with 5 mice per group and repeated with 10 mice per group. Isotype controls included 5% normal mouse serum and 250 µg of 4D11 (Ly49G2) on day 3 and biweekly for 3 weeks in addition to rat IgG with no effect on tumor growth or survival (representative control, rat IgG, shown). (E) Survival with identical treatment groups but with treatment delayed until day 10 after tumor inoculation. Mice received (●) rat IgG control, (▪) 250 µg of anti-CD20 mAb (CAT-13) on day 10 and once per week for 3 weeks, and (▲) 200 µg of anti-Ly49C/I F(ab′)2 (5E6) on day 10 and biweekly for 3 weeks, or (♦) the combination of both antibodies. *P = .005.

Anti-Ly49C/I F(ab′)2enhances the antilymphoma activity of anti-CD20 mAb in vivo and is NK-cell–dependent. (A) C57BL/6 mice were inoculated retro-orbitally with 0.5 × 106 EL4-huCD20 lymphoma tumor cells. (B) After tumor inoculation, mice received (●) rat IgG control, (▪) 250 µg of anti-CD20 mAb (CAT-13) on day 3 and once per week for 3 weeks, (▲) 200 µg of anti-Ly49C/I F(ab′)2 (5E6) on day 3 and twice a week for 3 weeks, or (♦) the combination of both antibodies. Mice were then monitored for overall survival. *P = .042. (C) C57BL/6 mice were inoculated retro-orbitally with 0.5 × 106 EL4-huCD20 lymphoma tumor cells. (D) After tumor inoculation, mice received (●) rat IgG control on day 3; (▪) 50 µL of anti-Asialo-GM1 on days −1, 0, 5, 10, 15, 20, and 25 with 250 µg of anti-CD20 mAb and 200 µg anti-Ly49C/I F(ab′)2 on day 3; (▼) 200 µL liposomal clodronate on day −2 followed by 100 µL of liposomal clodronate on days 0, 4, 8, 12, 16, 20, and 24 with 250 µg of anti-CD20 mAb and 200 µg of anti-Ly49C/I F(ab′)2 on day 3; (♦) 500 µg anti-CD8 mAb on days −1, 0, 5, 10, 15, 20, and 25 with 250 µg of anti-CD20 mAb and 200 µg anti-Ly49C/I F(ab′)2 on day 3; or (▲) 250 µg of anti-CD20 mAb on day 3 and 200 µg of anti-Ly49C/I F(ab′)2 on day 3 with 250 µg of anti-CD20 mAb repeated once per week for 3 weeks and 200 µg of anti-Ly49C/I F(ab′)2 repeated biweekly for 3 weeks. Mice were then monitored for overall survival. *P < .001. All in vivo models were piloted with 5 mice per group and repeated with 10 mice per group. Isotype controls included 5% normal mouse serum and 250 µg of 4D11 (Ly49G2) on day 3 and biweekly for 3 weeks in addition to rat IgG with no effect on tumor growth or survival (representative control, rat IgG, shown). (E) Survival with identical treatment groups but with treatment delayed until day 10 after tumor inoculation. Mice received (●) rat IgG control, (▪) 250 µg of anti-CD20 mAb (CAT-13) on day 10 and once per week for 3 weeks, and (▲) 200 µg of anti-Ly49C/I F(ab′)2 (5E6) on day 10 and biweekly for 3 weeks, or (♦) the combination of both antibodies. *P = .005.

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