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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-07, Vol.78 (13_Supplement), p.3780-3780
• Main Authors: Dulos, John, Driessen, Lilian, Zandvoort, Peter van, Crommert, Jos van de, Nair, Nitya, Randlev, Britta, Cock, Eduard de, Schaap, Jeroen Elassaiss, Eenennaam, Hans van, Elsas, Andrea van
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-3780

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