Abstract 3780: Preclinical pharmacokinetics, pharmacodynamics and safety of BION-1301, a first-in-class antibody targeting APRIL for the treatment of multiple myeloma

Autor: Peter van Zandvoort, Nitya Nair, Lilian Driessen, Eduard de Cock, Britta Randlev, Jos van de Crommert, Jeroen Elassaiss Schaap, Andrea van Elsas, John Dulos, Hans van Eenennaam
Rok vydání: 2018
Předmět:
Zdroj: Cancer Research. 78:3780-3780
ISSN: 1538-7445
0008-5472
Popis: APRIL critically triggers BCMA to drive proliferation and survival of human multiple myeloma (MM) cells. Importantly, APRIL induces resistance to lenalidomide, bortezomib and other standard-of-care drugs. Furthermore, APRIL drives expression of PD-L1, IL-10, VEGF and TGFβ forcing an immunosuppressive phenotype on BCMA+ cells. MM survival, resistance to treatment and the immunosuppressive phenotype can be blocked by BION-1301, the first-in class humanized antibody neutralizing APRIL. BION-1301 blocks APRIL binding to the MM relevant receptors BCMA and TACI in contrast with anti-BCMA bispecifics, ADC and CAR T-cells which use only BCMA for MM cell killing. In addition, BION-1301 inhibits immune suppressive effects of regulatory T-cells via TACI which differentiates it from BCMA targeting cytotoxic approaches. In vivo, BION-1301 was shown to suppress T cell-independent B cell responses to NP-Ficoll. Furthermore, APRIL blockade demonstrated single agent anti-MM activity in a humanized SCID model confirming its activity in vivo targeting MM cells in the tumor-protective bone marrow microenvironment. Here, we report on the preclinical pharmacokinetics (PK)/ pharmacodynamics (PD) relationship and safety analysis of BION-1301. A single-dose non-human primate (NHP) study administering intravenous BION-1301 at 0.3, 3 and 30 mg/kg, yielded PK parameters typical for IgG4 class antibodies and absence of tolerability issues. PD analysis showed a statistically significant reduction in total IgA and IgM in a dose-dependent fashion. Another measure of target modulation by BION-1301 was provided by co-injection of the hapten TNP-Ficoll (T-cell independent antigen) in different dose groups. Consistent with previous observations in hAPRIL transgenic mice, BION-1301 reduced in a dose-dependent fashion, TNP-specific IgA and IgM. Using a weekly dosing regimen, a 4-week repeat-dose toxicity study was conducted at doses of 10, 30 and 100 mg/kg, demonstrating that BION-1301 had no effect on vital organs and other toxicology related factors examined, at any dose level up to 100 mg/kg. Chronic exposure to BION-1301 led to significantly reduced levels of IgA, IgG and IgM observed at all dose levels. To determine target engagement of BION-1301, quantitative assays were developed to detect free APRIL and BION-1301. BION-1301 reduced free APRIL levels in serum in a dose-dependent manner following single and multiple dose administrations. Using a MABEL approach, PK/PD modeling informed a proposed human starting dose of 50 mg. In summary, BION-1301 showed no toxicity in NHP and binding of APRIL resulted in decreased IgA, IgG and IgM levels. PK and target engagement biomarkers predict the first in human dose using PK/PD pharmacometric modeling. A first-in-human study is ongoing to characterize safety and PK/PD of BION-1301 in heavily pretreated MM patients. Citation Format: John Dulos, Lilian Driessen, Peter van Zandvoort, Jos van de Crommert, Nitya Nair, Britta Randlev, Eduard de Cock, Jeroen Elassaiss Schaap, Hans van Eenennaam, Andrea van Elsas. Preclinical pharmacokinetics, pharmacodynamics and safety of BION-1301, a first-in-class antibody targeting APRIL for the treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3780.
Databáze: OpenAIRE
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