Pretargeted Radioimmunotherapy Using an Anti-CD45 Antibody-Streptavidin Conjugate and Radiolabeled DOTA-Biotin in Patients with High-Risk Acute Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation

Radioimmunotherapy (RIT) has been employed to decrease relapse after hematopoietic cell transplantation (HCT).  The major limitation of this approach is the slow antibody (Ab) accretion at tumor sites and gradual elimination from circulation.  We have used a pretargeted (P)RIT approach employing the high-affinity streptavidin (SA)-biotin system, in which an anti-CD45 Ab-SA conjugate and the radioactive DOTA-biotin compound are administered separately.  After maximal accumulation of Ab-SA conjugate in CD45⁺ tissues, therapeutic radiobiotin is administered and attaches to the pretargeted Ab-SA conjugate bound specifically to tumor cells, with unbound radiobiotin rapidly excreted by the kidneys.  We have evaluated the safety of PRIT using an anti-CD45 Ab-SA conjugate followed by ⁹⁰Y-DOTA-biotin combined with fludarabine (FLU), 2 Gy total body irradiation (TBI) and matched allogeneic HCT for patients with advanced acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or high-risk myelodysplastic syndrome (MDS).  Seven patients received trace labeled, dosimetric infusions of 0.7 mg/kg anti-CD45 Ab-SA followed 48 hours later by 1.3 mg/m² of ¹¹¹In-DOTA-biotin (5-10 mCi).  The biodistribution of ¹¹¹In-DOTA-biotin was assessed by serial planar gamma camera imaging at multiple time points that revealed optimal targeting of leukemic target tissues.  Five patients then received 0.7 mg/kg anti-CD45 Ab-SA followed 48 hours later by 1.3 mg/m² DOTA-biotin labeled with a therapeutic amount of ⁹⁰Y (62-112 mCi, median 75 mCi) based on OLINDA organ based dosimetry from the ¹¹¹In-DOTA-biotin images.  Of the two patients who did not receive therapeutic infusions, one developed cellulitis and the other was diagnosed with bladder carcinoma.  Approximately one week after ⁹⁰Y-DOTA-biotin PRIT, FLU was administered at 30 mg/m²/day for 3 consecutive days followed by TBI at a dose of 2 Gy (6-7 cGy/min) and then infusion of >2 x 10⁶ CD34-expressing peripheral blood stem cells/kg body weight.  Two grade 3 gastrointestinal adverse events (enterocolitis, typlitis) were identified as unexpected and considered possibly related to PRIT, with the only grade 4 event being cytopenias that are expected during HCT.  No participants were withdrawn from the study due to toxicities.  One of the 5 high-risk AML/MDS patients enrolled remains alive in complete remission a year after protocol treatment.  The other 4 patients died of progressive disease with a median time to relapse of 28 days (range 12-155).  Whether this approach will reduce post-transplant relapse remains to be determined, but further dose escalation is clearly necessary.