Safety and Efficacy of Engineered Toxin Body MT-3724 in Relapsed or Refractory B-cell Non-Hodgkin's Lymphomas and Diffuse Large B-cell Lymphoma

Abstract

PURPOSE: MT-3724, a novel engineered toxin body comprised of an anti-CD20 single-chain variable fragment genetically fused to Shiga-like Toxin A subunit, is capable of binding to and internalizing against CD20, inducing cell killing via permanent ribosomal inactivation. This study evaluated MT-3724 in patients with relapsed/refractory B-cell Non-Hodgkin lymphoma (r/rNHL). METHODS: This open-label, multiple-dose Phase 1a/b trial included a dose escalation in patients with r/rNHL according to a standard 3+3 design. Primary objectives were to determine the maximum tolerated dose (MTD) and pharmacokinetics/pharmacodynamics. In a dose expansion study at MTD in serum rituximab-negative patients with diffuse large B-cell lymphoma (DLBCL), primary objectives were safety, tolerability, and pharmacokinetics/pharmacodynamics. RESULTS: Twenty-seven patients enrolled. MTD was 50 µg/kg/dose with 6000 µg/dose cap. Thirteen patients experienced at least one Grade ≥3 treatment-related adverse events; the most common Grade ≥3 event was myalgia (11.1%). Two patients (75 µg/kg/dose) experienced Grade 2 treatment-related capillary leak syndrome. Overall objective response rate was 21.7%. In serum rituximab-negative patients with DLBCL or composite DLBCL (n=12), overall response rate was 41.7% (complete response, n=2; partial response, n=3). In patients with detectable baseline peripheral B-cells, treatment resulted in dose-dependent B-cell depletion. The proportion of patients with anti-drug antibodies (ADAs) increased during treatment and the majority appeared to be neutralizing based on an in vitro assay; nevertheless, tumor regression and responses were observed. CONCLUSIONS: MT-3724 demonstrated efficacy at the MTD in this population of previously treated patients with r/rDLBCL, with mild-to-moderate immunogenic safety events.

The progress of novel strategies on immune-based therapy in relapsed or refractory diffuse large B-cell lymphoma

“…The median DOR, PFS, and OS were 13.4, 5.6, and 20.1 months, respectively [28]. In R/R DLBCL patients of auto-SCT ineligible, although the Pola-BR group had higher rates of grade 3-4 neutropenia, anemia, and thrombocytopenia (but similar rates of grade Other ADCs, such as anti-CD19 [35], anti-CD20 [36], anti-CD22 [28], anti-CD25, anti-CD37, and anti-CD70, had been investigated previously. Among these, MT-3724, capable of binding to and internalizing against CD20, is a novel engineered toxin body [36].…”

“…Other ADCs, such as anti-CD19 [ 35 ], anti-CD20 [ 36 ], anti-CD22 [ 28 ], anti‑CD25, anti‑CD37, and anti‑CD70, had been investigated previously. Among these, MT-3724, capable of binding to and internalizing against CD20, is a novel engineered toxin body [ 36 ]. In a phase Ia/b trial, MT-3724 showed an ORR of 41.7% in R/R DLBCLs with serum rituximab negative [ 36 ].…”

“…Among these, MT-3724, capable of binding to and internalizing against CD20, is a novel engineered toxin body [ 36 ]. In a phase Ia/b trial, MT-3724 showed an ORR of 41.7% in R/R DLBCLs with serum rituximab negative [ 36 ]. However, others were limited to further use because of the high rate of adverse events [ 28 , 37 , 38 ].…”

Advancements in cancer immunotherapies targeting CD20: from pioneering monoclonal antibodies to chimeric antigen receptor-modified T cells

“…Due to the relatively poor internalization of CD20, few ADCs and immunotoxins were developed. A single-chain variable fragment-based targeting CD20 and conjugated with Shiga-like toxin A subunit, MT-3724, presented promising preclinical and early clinical results, but its development was ceased by the manufacturer ( 38 ). Another strategy that does not require CD20 internalization for direct and targeted cell killing is the use of radio-immunoconjugates.…”

“…The majority of mAbs are characterized as type I, which exhibit the ability to cluster CD20 into membrane lipid rafts, which is associated with potent induction of CDC. On the other hand, type I antibodies display a higher rate of internalization, which can limit their therapeutic efficacy (36). Type II mAbs do not stabilize CD20 in lipid rafts and are weak inducers of CDC, but they potently evoke direct cell death (37).…”