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(BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia Sarah E.M

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(BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia Sarah E.M Published OnlineFirst November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-0463 Cancer Therapy: Preclinical Clinical Cancer Research The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia Sarah E.M. Herman1, Arnau Montraveta1,2, Carsten U. Niemann1,3, Helena Mora-Jensen1, Michael Gulrajani4, Fanny Krantz4, Rose Mantel5, Lisa L. Smith5, Fabienne McClanahan5, Bonnie K. Harrington5, Dolors Colomer2,ToddCovey4, John C. Byrd5, Raquel Izumi4, Allard Kaptein4, Roger Ulrich4, Amy J. Johnson5, Brian J. Lannutti4,6, Adrian Wiestner1, and Jennifer A. Woyach5 Abstract Purpose: Acalabrutinib (ACP-196) is a novel, potent, and bition of CLL cell proliferation. Furthermore, tumor burden in the highly selective Bruton tyrosine kinase (BTK) inhibitor, which spleen of the mice treated with acalabrutinib was significantly binds covalently to Cys481 in the ATP-binding pocket of BTK. We decreased compared with vehicle-treated mice. Similarly, in the sought to evaluate the antitumor effects of acalabrutinib treat- TCL1 adoptive transfer model, decreased phosphorylation of ment in two established mouse models of chronic lymphocytic BTK, PLCg2, and S6 was observed. Most notably, treatment with leukemia (CLL). acalabrutinib resulted in a significant increase in survival com- Experimental Design: Two distinct mouse models were used, pared with mice receiving vehicle. the TCL1 adoptive transfer model where leukemic cells from Conclusions: Treatment with acalabrutinib potently inhibits Em-TCL1 transgenic mice are transplanted into C57BL/6 mice, BTK in vivo, leading to on-target decreases in the activation of key and the human NSG primary CLL xenograft model. Mice received signaling molecules (including BTK, PLCg2, S6, and ERK). In two either vehicle or acalabrutinib formulated into the drinking water. complementary mouse models of CLL, acalabrutinib significantly Results: Utilizing biochemical assays, we demonstrate that reduced tumor burden and increased survival compared with acalabrutinib is a highly selective BTK inhibitor as compared with vehicle treatment. Overall, acalabrutinib showed increased BTK ibrutinib. In the human CLL NSG xenograft model, treatment selectivity compared with ibrutinib while demonstrating signif- with acalabrutinib demonstrated on-target effects, including icant antitumor efficacy in vivo on par with ibrutinib. Clin Cancer decreased phosphorylation of PLCg2, ERK, and significant inhi- Res; 1–11. Ó2016 AACR. 1Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland. 2Experimental Therapeutics in Lymphoid Malignancies Group, Institut Introduction d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Bruton tyrosine kinase (BTK), a member of the TEC family of 3Department of Hematology, Rigshospitalet, Copenhagen, Denmark. 4Acerta Pharma, Redwood City, California. 5Division of Hematology, Department of kinases, is a key node in the B-cell receptor (BCR) signaling Internal Medicine, College of Medicine, The Ohio State University, Columbus, pathway and is essential for normal B-cell development (1, 2). Ohio. 6Oncternal Therapeutics, San Diego, California. BTK functions as a bridge between the BCR and the activation of Note: Supplementary data for this article are available at Clinical Cancer key downstream survival signals, including NF-kB. Expression of Research Online (http://clincancerres.aacrjournals.org/). BTK is limited to cells of the hematopoietic lineage, excluding T cells, and is upregulated in chronic lymphocytic leukemia (CLL) Current address for B.J. Lannutti: Oncternal Therapeutics, San Diego, California. cells compared with normal B cells (3). Mutation of BTK in S.E.M. Herman, A. Montraveta, A. Wiestner, and J.A. Woyach contributed equally humans results in the development of X-linked agammaglobu- to this article. linemia, characterized by a block in B-cell development resulting S.E.M. Herman and A. Montraveta are co-first authors of this article. in the absence of mature B cells. In a subset of B-cell malignancies, A. Wiestner, and J.A. Woyach are co-senior authors of this article. BTK is also essential for proliferation and survival (4, 5). In Corresponding Authors: Jennifer A. Woyach, The Ohio State University, 410 particular, knockdown of BTK induces tumor cell death in primary West 12th Avenue, Columbus, OH 43210. Phone: 614-685-5667; Fax: 614-293- CLL cells and lymphoma cell lines that are dependent on BCR 7484; E-mail: [email protected]; and Adrian Wiestner, Hematology signaling (6, 7). Furthermore, genetic ablation of BTK inhibits Branch, National Heart, Lung, and Blood Institute, NIH, Bldg. 10, CRC 3-5140, 10 disease progression in mouse models of CLL, indicating its Center Drive, 20892-1202 Bethesda, MD. Phone: 301-594-6855; Fax: 301-496- continued importance for B-cell malignancies (7, 8). 8396; E-mail: [email protected] Targeting the BCR pathway (through inhibition of SYK, BTK, doi: 10.1158/1078-0432.CCR-16-0463 or PI3K) in patients with CLL has proven very effective (9). Ó2016 American Association for Cancer Research. Activation of BCR and NF-kB signaling in the lymph node www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-0463 Herman et al. chain variable region promoter and enhancer (25). These mice Translational Relevance þ þ spontaneously develop a CD5 /CD19 CLL-like leukemia with B-cell receptor (BCR)-directed kinase inhibitors are chang- unmutated IGHV and have a response to CLL therapies analogous ing treatment paradigms of chronic lymphocytic leukemia to humans (26). To overcome the heterogeneity in presentation (CLL). With the first-in-class Bruton tyrosine kinase (BTK) and the delay of tumor development of the spontaneous model, inhibitor ibrutinib, durable responses are common, but com- leukemic splenic lymphocytes from TCL1 mice can be engrafted plete responses are relatively rare, and some patients develop into SCID or immunocompetent mice. In addition to this trans- resistance. In addition, adverse effects and impaired NK-cell genic mouse model, xenografting of mononuclear cells (MNCs) and platelet function, with implications for combination from patients with CLL into NOD/scid/gcnull (NSG) mice has also therapy and safety, have been attributed to inhibition of been shown to recapitulate the tumor–host interactions encoun- kinases other than BTK. Conversely, it is unclear whether the tered in the diseased human lymph node, including activation of inhibition of additional kinases contributes to clinical efficacy BCR and NF-kB signaling and tumor proliferation (27). of ibrutinib. We therefore investigated the novel, highly selec- We report herein on the potency, selectivity, and on-target tive BTK inhibitor, acalabrutinib, in vivo, utilizing two estab- efficacy of acalabrutinib, a novel, potent and highly selective BTK lished mouse models of CLL. We show that BCR signaling and inhibitor. Acalabrutinib binds covalently to Cys481 in the ATP- proliferation of tumor cells is effectively inhibited in mice binding pocket of BTK, similarly to ibrutinib. It has been shown to treated with acalabrutinib. Acalabrutinib also reduced tumor have improved pharmacologic features, such as rapid oral absorp- burden and increased survival compared with vehicle-treated tion and a short plasma half-life (28). Early results from the mice. Thus, while showing better overall kinase selectivity, ongoing first-in-human phase I–II study demonstrate impressive acalabrutinib exerts potent antitumor effects on par with clinical activity of acalabrutinib in CLL (28). Here, we investigate ibrutinib, supporting the critical role of BTK in CLL. pharmacodynamic properties of acalabrutinib in two comple- mentary murine models of CLL demonstrating on-target effects on BCR signaling, tumor biology, and antileukemic efficacy, further justifying the exploration of this treatment in CLL. microenvironment appears to be a central event in CLL patho- Materials and Methods genesis and disease progression and is effectively disrupted in vivo Kinase-binding selectivity profiling by the BTK inhibitor ibrutinib (10, 11). Ibrutinib, as a single agent, Acalabrutinib and ibrutinib (Acerta Pharma B.V.) were profiled has demonstrated a high rate of durable clinical responses in at 1 mmol/L in an ATP site–dependent competition binding assay patients with CLL, irrespective of adverse prognostic features, for 395 wild-type human kinases at DiscoveRx (29). including very high risk patients with deletion 17p (12–14). Ibrutinib is now approved for the treatment of patients with CLL who have received at least one prior therapy or harbor a 17p Potency and return of B-cell function assay deletion (15). For potency assays, female C57BL/6 mice were administered Despite the impressive clinical results with ibrutinib, most vehicle, acalabrutinib, or ibrutinib via oral gavage. After 3 hours, patients do not experience a complete response and a subset of spleens were extracted, and splenocytes were stimulated with goat patients develops resistance. Resistance develops most commonly anti-mouse IgM (Southern Biotech) at 10 mg/mL for 18 hours in a through mutations in BTK or PLCg2, suggesting that BTK is indeed 37 C, 5% CO2 incubator. For the return of B-cell function experi- a critically important target for ibrutinib (16, 17). In addition, ments,
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