Targeted Radiotherapy in the Conditioning Prior to Haematopoietic Stem Cell Transplantation: Results of a Phase I Radiation Dose Escalation Study Using Yttrium-90-Labelled Anti-CD66 Monoclonal Antibody Demonstrating High BM Uptake of Radiation.

We report the results of a phase I clinical study using a radiolabelled murine anti-CD66 IgG₁ monoclonal antibody (TheraPharm GmbH) as part of the transplant conditioning schedule for patients receiving either autologous or allogeneic stem cell transplants (SCT) for myeloma or acute myeloid leukaemia. This was a radiation dose escalation study using increasing doses of yttrium-90 (Y-90) as the therapeutic radionuclide. A total of eighteen patients have been treated over four Y-90 radiation dose levels. All patients received an initial infusion of indium-111 (In-111)-labelled anti-CD66 for biodistribution and dosimetry determination. If favourable dosimetry was demonstrated, patients went on to receive the therapy dose of radiation, the dose of Y-90 infused calculated from the patient’s body weight. The Y-90 dose levels were as follows: 5, 10, 25 and 37.5MBq /kilogram (lean) body weight.

Patient characteristics: Age 21-67 yrs (median 54 yrs); 14 male, 4 female; myeloma 14, AML 4; autologous SCT 14, reduced intensity allogeneic SCT 4. Patients undergoing autologous SCT for myeloma received Y-90 labelled anti-CD66 on day -14 and melphalan 200mg/m² on day -2. Patients undergoing reduced intensity allogeneic SCT received Y-90-labelled anti-CD66 on day -14 in addition to a reduced intensity schedule of fludarabine, melphalan and CAMPATH 1H.

Results: Excellent bone marrow targeting was seen in all patients and in the majority low uptake by non-haematopoietic organs, in particular liver uptake was consistently low. There was a close correlation between the administered dose of Y-90 and the dose delivered to the bone marrow but not for the radiation dose received by the liver. Mean absorbed radiation doses (cGy per MBq infused Y-90): bone marrow 10.23 +/- 1.8 cGy/MBq; liver 2.67 +/- 2.0 cGy/MBq; spleen 7.10 +/- 3.75 cGy/MBq. Total absorbed radiation doses at each dose level are in table 1.

No additional toxicity due to the addition of targeted radiation was seen. Engraftment: neutrophils >0.5 by day + 13.8 (11-22) platelets >50 day +12.7 (10-22), no graft failures were seen. In two patients with myeloma, focal uptake of In-111-labelled antibody was seen suggesting in vivo targeting of myeloma, consistent with the expression of the antigen on plasma cells demonstrated by Flow cytometry.

Conclusions: The anti-CD66 monoclonal antibody showed consistently excellent BM targeting and very low uptake by non-haematopoietic organs. Up to 25 Gy of additional radiation was delivered to the bone marrow with no additional toxicity. This particular monoclonal antibody may have a role in stem cell transplantation for a wide range of haematological malignancies, providing significant dose escalation without toxicity in autologous and allogeneic protocols. AntiCD66 may be particularly appropriate in transplantation for myeloma.