Phase I Study of a Bispecific Ligand-Directed Toxin Targeting CD22 and CD19 (DT2219) for Refractory B-cell Malignancies

Abstract

Background The novel bispecific ligand-directed toxin (BLT) DT2219 consists of a recombinant fusion between the catalytic and translocation enhancing domain of diphtheria toxin (DT) and bispecific single chain variable fragments (scFV) of antibodies targeting human CD19 and CD22. We conducted a phase 1 dose escalation study to assess the safety, maximum tolerated dose (MTD), and preliminary efficacy of DT2219 in patients with relapsed/refractory B cell lymphoma or leukemia. Methods DT2219 was administered intravenously over 2 hours every other day for 4 total doses. Dose was escalated from 0.5 μg/kg/day to 80 μg/kg/day in nine dose cohorts until a dose limiting toxicity (DLT) was observed. Results Twenty-five patients with mature or precursor B-cell lymphoid malignancies expressing CD19 and/or CD22 enrolled to the study. Patients received median 3 prior lines of chemotherapy and 8 failed hematopoietic transplantation. All patients received a single course of DT2219; one patient was retreated. The most common adverse events (AE) including, weight gain, low albumin, transaminitis and fevers were transient grade 1-2 and occurred in patients in higher dose cohorts (≥40 μg/kg/day). Two subjects experienced DLT at dose levels 40 and 60 μg/kg. Durable objective responses occurred in 2 patients; one was complete remission after 2 cycles. Correlative studies showed a surprisingly low incidence of neutralizating antibody (30%). Conclusions We have determined the safety of a novel immunotoxin DT2219 and established it's biologically active dose between 40-80 μg/kg/day ×4. A phase II study exploring repetitive courses of DT2219 is planned.

Safe and Effective Sarcoma Therapy through Bispecific Targeting of EGFR and uPAR

“…Similar to our findings, these events were transient and did not require fluids or pressor agents [39]. None of the treated dogs experienced signs of capillary leak syndrome, the toxicity of greatest concern for immunotoxins [40, 41]. Furthermore, the lack of adverse events similar to those caused by EGFR-targeted therapies [6, 7] suggests that the addition of the uPAR-directed ligand enhances targeting specificity to tumors, leading to diminished toxicity, consistent with our mouse data.…”

“…The use of a Comparison group enabled us to implement a novel adaptive clinical trial design and identify an efficacy signal of eBAT, but it is important to acknowledge the potential bias associated with the lack of a contemporary control group with blinding and randomization, which would more accurately predict efficacy. Our dosing and dose schedule was chosen partly on the basis of a previous study by our group in humans with an anti-B cell cancer targeted toxin [40], and partly on laboratory animal safety data. Still, metastatic disease occurred in about half of the dogs in this eBAT study.…”

“…We intend to use this information to optimize dose schedule in the future. Repeat cycles could prolong remissions as has been shown in studies with targeted Pseudomonas exotoxin in humans [40, 49], re-treatment at relapse could prolong survival, and even the delivery methods could be improved.…”

Efficient Payload Delivery by a Bispecific Antibody–Drug Conjugate Targeting HER2 and CD63

“…Similarly, a fusion protein targeting the EGF receptor and the urokinase receptor (uPAR) was used to target tumor cells through EGFR and tumor stroma through uPAR (29). DT2219, a bispecific recombinant immunotoxin targeting CD19 and CD22 positive B-cell tumors, demonstrated broader reactivity against B-cell malignancies as compared to individual immunotoxins targeting CD19 or CD22 alone (30,31).…”

Therapeutic Targeting of Siglecs using Antibody- and Glycan-Based Approaches

“…Many innovative approaches have enabled the production of bispecific antibodies [24], and recently the first bispecific antibody (blinatumomab) was approved in the U.S. for the treatment of B-ALL. Bispecific antibodies that recognize CD22 and CD19 [25] or CD22 and CD20 [26] on B cells have been developed and, remarkably, show improved efficacy compared to targeting either receptor alone. Bispecific antibodies that co-engage CD33 on AML cells with CD3 on T cells [27,28] or CD16 on natural killer (NK) cells [29] have also shown promising results in pre-clinical and early phase clinical trials (Table 1).…”