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.
Authors: Orchard Kim , Cooper Margaret , Lewington Valerie , Tristram Maria , Zivanovic Maureen , Thom James , Quadri Syed , Richardson Deborah , Causer Louise , Johnson Peter 
Published: October 2019

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.

Table 1 Organ dose in Gy Dose level MBq per kg BM Liver Spleen 5 4.1 1.4 1.1 10 9.1 1.3 2.4 25 15.6 3.7 12.6 37.5 22.0 7.8 5.3

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.