Abstract
637
Objectives Anti-CD45 RIT conditioning may substitute total body irradiation in hematopoietic cell transplantation (HCT) preparative regimens for NHL. We optimized the anti-CD45 MAb (B10-CA12.10C12) dose for RIT in a canine model using the alpha (α) emitter 211At, to achieve efficient targeting and pharmacokinetics with minimal normal tissue toxicity.
Methods Eight normal dogs were injected with either 0.75 (n=5) or 1.0 mg/kg (n=3) of 211At-B10-CA12.10C12 (11.5-36.7 MBq/kg); 2 were euthanized and necropsied 19-22 h post injection (p.i.), and 6 received autologous HCT 3 days after 211At-RIT following lymph node (LN) and bone marrow (BM) biopsy at 2-4 and/or 19 h p.i. Blood was sampled to study toxicity and clearance of 211At and MAb. CD45 targeting and sub-organ MAb localization was evaluated by flow cytometry and immunohistochemistry. 211At distribution (activity and absorbed dose) was assessed at the micro scale using 2 novel α-imaging systems: α-camera and iQID.
Results Biological half-lives for circulating 211At and MAb were 2.4 ± 0.6 and 2.5 ± 1.9 h, respectively, for 0.75 mg MAb/kg and 3.1 ± 0.4 and 2.4 ± 0.9 h for 1.0 mg/kg. Flow analysis showed a slight increase in binding to target cells in blood using the higher dose. Blood and BM were efficiently targeted by 0.75 mg/kg but LN cells remained sub-saturated even at 1.0 mg/kg. Successful BM targeting was verified by α-imaging. LNs displayed a heterogeneous 211At distribution, with efficient targeting of lymphocyte rich regions. All dogs experienced transient hepatic toxicity; 1 treated with 1.0 mg/kg developed ascites and was euthanized 136 days p.i.
Conclusions 211At-anti-CD45 RIT with 0.75 mg MAb/kg efficiently targeted blood and BM without severe toxicity. Ongoing studies will reveal if the LN uptake suffices for curative therapy of relapsed NHL in dogs.
Research Support NIH grant CA172528.