ALBERT

Description: Key Points An anti-CD37 antibody-drug conjugate can kill B-lymphoma cells via direct inhibition, effector function, and payload delivery. Targeting CD37 with an antibody-drug conjugate results in selective depletion of malignant human B cells.

Description: Introduction: Relapsed/refractory B-cell NHL remains an area of significant medical need. CD37 is highly expressed in many B-cell malignancies, including NHL, making it an ideal target for ADC-based therapy. IMGN529 is a CD37-targeting ADC consisting of a CD37-binding antibody conjugated to the maytansinoid anti-mitotic, DM1. IMGN529 has been shown to have potent, targeted activity against NHL cell lines and xenograft models via antibody-mediated direct cell-killing, effector function and the anti-mitotic activity of the DM1 payload. IMGN529 has shown early signs of clinical activity at tolerable doses in an ongoing phase I trial in adult patients with relapsed/refractory NHL (R/R-NHL) (NCT01534715) (Blood 2014 124:1760). Rituximab, an anti-CD20 monoclonal antibody, is widely used for NHL therapy and remains a component of both front-line (with chemotherapy combinations) and late-line (both as a monotherapy and in combination) regimens. We have previously shown data from an in vitro synergy screen which identified strong anti-NHL synergy for IMGN529 used in combination with anti-CD20 antibodies (Hematol Oncol 2015; 33: 181-243). Methods: The activity and mechanism-of-action of IMGN529 in combination with rituximab was further evaluated in clinically relevant preclinical models of NHL: Cell viability in response to single agents and combinations was tested using the WST-8 assay. In vivo combination studies were carried out using human xenograft models of DLBCL implanted in SCID mice. Induction of apoptosis was measured via Annexin-V flow cytometry and caspase 3/7 cleavage assays. Changes in molecular signaling in response to treatment were measured using western blotting and ELISA. Results: Combination of IMGN529 and the anti-CD20 antibodies rituximab, obinutuzumab and ofatumumab resulted in high synergy scores, identifying a potential class-effect of synergy between IMGN529 and anti-CD20 antibodies. The notable activity of an IMGN529/ rituximab combination was confirmed both in vitro and in vivo using cell line viability and xenograft models of DLBCL (both ABC and GCB subtypes). In these models, the activity of the IMGN529/ rituximab combination was consistently greater than either agent administered as a monotherapy. We examined whether this synergistic reduction in cell viability was due to a reduction in cell growth or an induction of cell death. In multiple NHL cell lines, we found that the combination of IMGN529 and rituximab induced significantly higher levels of Annexin-V positivity and caspase 3/7 activity than either single agent alone, consistent with the pro-apoptotic mechanism of action proposed for IMGN529. To further elucidate the mechanisms underlying the synergy of the combination, we are monitoring the effect on key components of upstream signaling pathways responsible for cell survival and induction of apoptosis, including: the apoptotic inhibitors Bcl-2, Bcl-xL and Mcl-1; MAP-kinase signaling, and the NF-kB and AKT/mTOR axes, all of which have been linked to treatment sensitization by rituximab in NHL cell lines. Conclusions: IMGN529 demonstrates synergistic activity in combination with CD20-targeting antibodies including rituximab. In in vitro and in vivo models of NHL, the combination of IMGN529 and rituximab is more active than either agent alone, and this enhanced activity is associated with an increase in the induction of apoptosis and apoptotic signaling pathways. These results support clinical assessment of IMGN529 in combination with rituximab, and a phase II trial assessing safety and efficacy in R/R-NHL is planned. Disclosures Deckert: ImmunoGen, Inc.: Employment, Equity Ownership. Sloss:ImmunoGen, Inc.: Employment, Equity Ownership. O'Callaghan:ImmunoGen, Inc.: Employment, Equity Ownership. Tsui:ImmunoGen, Inc.: Employment, Equity Ownership. Dawra:ImmunoGen, Inc.: Employment, Equity Ownership. Yi:ImmunoGen, Inc.: Employment, Equity Ownership. Coccia:ImmunoGen, Inc.: Employment, Equity Ownership. Lanieri:ImmunoGen, Inc.: Employment, Equity Ownership. Chicklas:ImmunoGen, Inc.: Employment, Equity Ownership. Romanelli:ImmunoGen, Inc.: Employment, Equity Ownership.

Description: CD38 is a promising target for antibody therapeutics for the treatment of various hematological malignancies, including multiple myeloma as well as non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, and chronic myeloid leukemia. CD38 is a type II transmembrane glycoprotein with ectozyme activity that has been implicated in Ca2+ mobilization. CD38 expression correlates with the poor disease prognosis in some hematological malignancies. It has been proposed that rituximab, a well-established anti-CD20 antibody for the treatment of non-Hodgkin’s lymphoma, works by several mechanisms, including antibodydependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. A panel of murine anti-CD38 antibodies was first screened for their ability to induce apoptosis, as measured by Annexin V staining, in various lymphoma, leukemia, and multiple myeloma cell lines. Chimeric human IgG1 versions of the selected murine antibodies with potent apopototic activity were then produced and screened for ADCC and CDC activities. Among the screened antibodies, a chimeric version of SAR650984, a humanized anti-CD38 antibody, had the best overall activities. SAR650984 induced potent apoptosis in Daudi, Raji, Ramos, and SU-DHL-8 lymphoma cells, as well as MOLP-8 multiple myeloma (MM) cells and DND-41 acute T lymphocytic leukemia (T-ALL) cells, which like most, if not, all MM and T-ALL cells, express CD38, but not CD20. SAR650984 also induced potent ADCC and CDC in these tumor cells. When the activities of SAR650984 and rituximab were directly compared in Daudi and Raji lymphoma cells that express similar levels of CD38 and CD20, SAR650984 had similar ADCC and CDC activities as rituximab, and, in addition, SAR650984 induced a greater percentage of lymphoma cells to undergo apoptosis than did rituximab. SAR650984 and rituximab showed similar efficacy in a SCID disseminated survival model with Daudi lymphoma cells. Groups of 10 mice were intravenously injected with 5 × 106 Daudi cells on day 0 and then treated with 40 mg/kg SAR650984, 40 mg/kg rituximab, or PBS control on days 7, 11, 14, 18, 21 and 25. The median survival (range) was 28 days (26–30 days) for the PBS-treated group, 47 days (40–51 days) for the SAR650984-treated group and 42.5 days (40–51 days) for the rituximab-treated group. SAR650984 also showed strong anti-tumor activity in a subcutaneous xenograft SCID model with CD38+ CD20− NCI-H929 multiple myeloma cells. Groups of 10 mice were subcutaneously injected with 106 NCI-H929 cells on day 0, and then treated with 40 mg/kg SAR650984, 40 mg/kg rituximab (non-binding IgG1 control), or PBS control twice weekly for three weeks starting on day 6 when the tumors were palpable. A mean tumor volume of 1000 mm3 was reached by PBS-treated group on day 89 and rituximab-treated group on day 84 (70–80% tumor take rate for NCI-H929). SAR650984 treatment completely prevented the tumor growth in all 10 mice (tumor free at the end of study on day 128). In summary, the humanized anti-CD38 antibody, SAR650984, has potent ADCC, CDC, and apoptotic activities in vitro and anti-tumor activity in vivo. SAR650984 is a promising therapeutic antibody candidate for various hematological malignancies, especially in diseases such as multiple myeloma, where rituximab is inactive.

Description: Abstract 188 BACKGROUND: Introduction of the anti-CD20 antibody rituximab has led to remarkable progress in the development of targeted therapies for CLL and other B-cell malignancies. Despite prolonging patient survival, therapies targeting CD20 have not been curative. In recent years, alternative targets for therapeutic antibodies have emerged. One of the most promising targets has been CD37, which is highly expressed on malignant B-cells in chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma. The recent interest in this target has led to the generation of novel anti-CD37 therapeutics that could benefit from more extensive preclinical evaluation. However, preclinical development of these agents has been limited by the absence of appropriate leukemia animal models that provide targets expressing human CD37 (hCD37). Here we describe the development and characterization of a transgenic mouse where CLL-like leukemic B-cells express hCD37 and aggressively transplant into syngenic hosts. We demonstrate the utility of this unique mouse model by evaluating the in vivo efficacy of IMGN529, a novel antibody-drug conjugate targeting hCD37 that consists of the CD37-targeting K7153A antibody linked to the maytansinoid DM1 via the thioether SMCC linker. METHODS: The hCD37 transgenic mouse (hCD37-Tg) founder lines were generated by conventional methodology at the OSU Transgenic Facility. B-cell specific expression of hCD37 is driven by immunoglobulin heavy chain promoter and Ig-μ enhancer elements. Founder lines were evaluated by RT-PCR and flow cytometry to confirm RNA and protein expression, respectively. These lines were then crossed with the EμTCL1 mouse model of CLL to generate hCD37xTCL1 mice that develop CD5+CD19+hCD37+ leukemia. For in vivo studies, splenocytes from a leukemic hCD37xTCL1 donor were injected i.v. into healthy hCD37-Tg mice. Mice were randomly assigned to the following treatment groups (n=8–10 per group): IMGN529 conjugate, its K7153A antibody component, or negative controls (isotype antibody-DM1 conjugate or trastuzumab). Upon diagnosis of leukemia, a 10 mg/kg dose was administered i.p. and repeat doses were given 2 times per week for 3 weeks (70 mg/kg total). Peripheral blood disease was monitored by flow cytometry, using counting beads to obtain the absolute number of leukemic CD5+CD19+ B-cells. CD37 expression levels were determined by quantitative flow cytometry. In vitro cytotoxicity was evaluated after 24 hour incubation by flow cytometry with Annexin V and propidium iodide staining. RESULTS: IMGN529 and its K7153A antibody component demonstrated comparable in vitro activity against freshly isolated human CLL cells even in the absence of cross-linking agents (mean IMGN529 cytotoxicity=50.04% vs. 48.85% for K7153A; p=0.175; n=9). Both compounds also demonstrated cytotoxicity against hCD37 Tg B-cells ex vivo in a cross-linking dependent manner, and while expression of hCD37 in hCD37-Tg animals was B-cell specific, the expression levels were substantially lower than those observed in human CLL cells. In vivo studies with transferred hCD37xTCL1 splenocytes demonstrated rapid and complete depletion of CD5+CD19+ leukemic B-cells in response to IMGN529 conjugate, but not K7153A antibody treatment. After 1 week of IMGN529 treatment, peripheral blood leukemia was nearly undetectable and previously detected massive splenomegaly was no longer palpable. In contrast, leukemic counts and spleen sizes continued to increase in control cohorts. CONCLUSIONS: In summary, our group has generated a mouse model that develops a transplantable CD5+CD19+ leukemia expressing hCD37. We demonstrate the utility of this model for both in vitro and in vivo testing of therapeutics targeting hCD37. In addition, preclinical mouse studies expose the robust anti-leukemic effects of IMGN529 in this in vivo model of aggressive B-cell malignancy, despite the relatively low expression of hCD37 on the leukemic B-cells. Our engraftment model shows that IMGN529 is capable of eliminating widespread and highly proliferative mouse leukemia by a mechanism that is both CD37 antigen and conjugate dependent. Therefore, we propose that this novel therapeutic may also exhibit substantial efficacy in a wide range of human B-cell malignancies, even those with relatively low CD37 expression. [This work was supported by NIH (NM, JCB), LLS (NM, JCB) and Pelotonia (KAB)]. Disclosures: Deckert: ImmunoGen Inc.: Employment.

Description: CD37 is a surface antigen widely expressed on malignant B cells in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). In normal tissues, CD37 expression is restricted to lymphoid tissues and blood cells, with high levels of expression on B lymphocytes and low levels on non-B lymphoid and myeloid cells. IMGN529 is a CD37-targeting ADC currently in a Phase I clinical study in adult patients with relapsed or refractory NHL (NCT01534715). This ADC uniquely combines the intrinsic pro-apoptotic and immune effector activities of its anti-CD37 antibody component with the potent cytotoxic mechanism provided by targeted delivery of its maytansinoid payload, DM1. In the Phase I study, IMGN529 has demonstrated early evidence of clinical activity. A reduction in lymphocyte counts was also observed in the majority of patients after dosing, consistent with the proposed mechanism of action of a CD37-targeted therapy. However, in the initial dose-escalation phase, some patients experienced transient, early-onset neutropenia. To investigate the potential mechanisms of this transient neutropenia observed in patients, different pre-clinical models were considered and utilized to recapitulate clinical findings. In vitro studies with peripheral blood cells from normal human donors demonstrated that incubation with IMGN529 for 1 hour or 24 hours resulted in significant B-cell depletion with no apparent neutrophil depletion detected, similar to observations after rituximab treatment. In contrast, alemtuzumab treatment in vitro resulted in both B-cell and neutrophil depletion. This is consistent with the high level of CD37 expression on target B cells and the relatively low CD37 expression level on other blood cells. Analysis of cytokine release by normal human donor peripheral blood cells incubated with IMGN529 revealed increased levels of IL-8, CCL2 (MCP-1) and CCL4 (MIP-1β), but not IL-6 or TNF, to a similar extent as rituximab but less pronounced than alemtuzumab. An anti-murine CD37 antibody was identified to enable in vivo studies in a murine model and characterize CD37 expression on murine blood cells. Similar to the expression profile of CD37 in human peripheral blood cells, CD37 expression on murine peripheral blood cells was highest in B cells, with much lower expression seen on T cells and granulocytes. In vivo activity of the anti-muCD37 antibody and the corresponding ADC, with the same SMCC-DM1 linker-payload combination as IMGN529, was evaluated to discern antibody and payload-mediated events in comparison to the classic cytotoxic cyclophosphamide (CPA). Treatment of C57/B6 mice with 1-10 mg/kg of anti-muCD37 antibody or anti-muCD37 ADC resulted in a significant decrease in absolute lymphocyte counts (ALC) lasting greater than 7 days and a transient decrease in absolute neutrophil counts (ANC) lasting 1-2 days. A non-targeted control SMCC-DM1 ADC had no effect on ALC or ANC counts, suggesting the decrease is a CD37-mediated effect. In contrast, treatment with CPA resulted in an ALC decrease with similar kinetics but a more pronounced ANC decline. No impact on bone marrow lymphocyte, myeloid or erythroid precursor cell counts was observed in response to the anti-muCD37 antibody or anti-muCD37 ADC, whereas CPA treatment caused reduced cellularity with a decrease in the percentage of mature myeloid precursors and neutrophils in bone marrow. Elevated levels of CCL2 and CCL4 chemokines were detected in mouse plasma after anti-muCD37 ADC treatment, which may contribute to a redistribution of circulating neutrophils into peripheral tissues. Studies are currently underway to assess neutrophil distribution in murine tissues post anti-muCD37 ADC treatment. Current preclinical studies provide no clear evidence for direct IMGN529-mediated depletion of normal human neutrophils in the context of B-cell depletion in vitro. In vivo studies with an anti-muCD37 ADC recapitulate transient peripheral lymphopenia and neutropenia with no impact on bone marrow precursors observed, indicative of a different mechanism than classic chemotherapy-induced bone marrow myelosuppression. These preliminary results suggest a role for chemokine-mediated neutrophil redistribution following CD37 engagement, which is the subject of further studies. Disclosures Deckert: ImmunoGen, Inc.: Employment, Equity Ownership. Ponte:ImmunoGen, Inc.: Employment, Equity Ownership. Coccia:ImmunoGen, Inc.: Employment, Equity Ownership. Lanieri:ImmunoGen, Inc.: Employment, Equity Ownership. Chicklas:ImmunoGen, Inc.: Employment, Equity Ownership. Yi:ImmunoGen, Inc.: Employment, Equity Ownership. Watkins:ImmunoGen, Inc.: Employment, Equity Ownership. Ruiz-Soto:ImmunoGen, Inc.: Employment, Equity Ownership; sanofi: Employment. Romanelli:ImmunoGen, Inc.: Employment, Equity Ownership; sanofi: Employment. Lutz:ImmunoGen, Inc.: Employment, Equity Ownership.

Description: Introduction: Relapsed/refractory B-cell NHL remains an area of significant medical need. CD19 is broadly expressed on B-cell malignancies making it an ideal target for antibody-drug conjugate (ADC) based therapy. Coltuximab ravtansine is a CD19-targeting ADC consisting of a CD19-targeting antibody conjugated to the maytansinoid anti-mitotic DM4. In preclinical studies, coltuximab ravtansine has shown potent, targeted activity against NHL cell lines and xenograft models. In early clinical trials, it has been well tolerated and has shown promising signs of efficacy as both a single agent and in combination with rituximab. In the STARLYTE Phase 2 trial coltuximab ravtansine monotherapy resulted in an ORR of 44% in R/R-DLBCL that included an ORR of 21% in hard-to-treat primary refractory patients (NCT01472887). Here we describe studies aimed at the identification of combination partners for coltuximab ravtansine to further optimize clinical benefit to R/R-NHL patients. We are employing a dual approach where we investigate combination of coltuximab ravtansine with multiple, novel targeted therapy partners whilst in parallel also investigating the combination of coltuximab ravtansine with chemotherapies commonly used in the late stage R/R-NHL setting. Methods: Coltuximab ravtansine and the DM4 payload were evaluated in a high throughput screen both as single agents and in combination with a selection of novel, emerging targeted agents across a panel of twenty NHL cell lines. The combinations were evaluated in a dose-response matrix and a statistical method was used to identify combination synergies significantly superseding baseline additivity values. The in vivo efficacy of coltuximab ravtansine was additionally assessed in combination with various clinically relevant chemotherapy agents in subcutaneous xenograft models of NHL. Results: Coltuximab ravtansine and DM4 both showed potent single agent activity against the entire panel of NHL cell lines with median GI50's of 770pM and 100pM, respectively. We observed a significant correlation in the cell line sensitivity of the two compounds suggesting that sensitivity to coltuximab ravtansine is driven, at least in part, by inherent sensitivity of cells to the cytotoxic effects of the DM4 payload. In vitro combination studies for coltuximab ravtansine were performed to identify targets or pathways that result in the most prominent combination effects across the cell line panel. Analysis of the in vitro combination dose-matrix revealed particularly strong synergy between coltuximab ravtansine and various inhibitors of the PI3K/AKT/mTOR axis. Studies to examine the synergism between coltuximab ravtansine and PI3K inhibitors in in vivo models of NHL are ongoing. In order to further determine the utility of coltuximab ravtansine as part of a potential combination regimen for the treatment of R/R-NHL, we assessed the combination of coltuximab ravtansine with the chemotherapy agents bendamustine and gemcitabine in vivo. As gemcitabine is typically used in combination we assessed the efficacy of a coltuximab ravtansine with rituximab and gemcitabine in vivo. In both cases the combination with coltuximab ravtansine was significantly more efficacious than the standard-of-care alone arms. Conclusions: Coltuximab ravtansine demonstrates synergistic activity in combination with multiple PI3K pathway inhibitors across a large panel of NHL cell lines. Additionally, we have shown that combination of coltuximab ravtansine with clinically relevant late stage treatments such as bendamustine and rituximab + gemcitabine is more efficacious than the chemotherapy regimens alone. These results support the continued development of coltuximab ravtansine in R/R-NHL in combination with chemotherapy regimens and suggest that a combination of coltuximab ravtansine with PI3K inhibitors may also be of interest in the clinical setting. Disclosures Sloss: ImmunoGen, Inc.: Employment, Equity Ownership. O'Callaghan:ImmunoGen, Inc.: Employment, Equity Ownership. Deckert:ImmunoGen, Inc.: Employment, Equity Ownership. Tsui:ImmunoGen, Inc.: Employment, Equity Ownership. Lanieri:ImmunoGen, Inc.: Employment, Equity Ownership. Romanelli:ImmunoGen, Inc.: Employment, Equity Ownership.

Description: Abstract 3726 CD37 is a B-cell surface antigen which is widely expressed on malignant B cells in non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). In normal tissues CD37 expression is limited to blood cells and lymphoid tissues. This restricted expression profile makes CD37 an attractive therapeutic target for antibodies and antibody-drug conjugates. We developed a novel anti-CD37 antibody, K7153A, which provides a unique combination of functional properties: it demonstrated strong pro-apoptotic and direct cell killing activity against NHL cell lines and could mediate effector activity such as CDC and ADCC. The antibody-maytansinoid conjugate, IMGN529, was produced by conjugation of K7153A with the potent maytansinoid, DM1, via the non-cleavable linker, SMCC. The direct cytotoxic potency of the K7153A antibody was superior to that of the CD20-directed rituximab and was further enhanced with maytansinoid conjugation in IMGN529. In vivo, IMGN529 demonstrated better anti-tumor activity than the K7153A antibody in established subcutaneous follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and CLL xenograft models in SCID mice. A single administration of IMGN529 showed similar or improved efficacy compared to anti-CD20 antibodies or standard chemotherapy where tested. Immunohistochemical (IHC) staining of formalin fixed paraffin-embedded (FFPE) NHL tissue sections was performed to evaluate CD37 expression. CD37 exhibited a similar prevalence to CD20 in subtypes of NHL such as FL, DLBCL, Burkitt's lymphoma (BL) and mantle cell lymphoma (MCL). B-cell depletion is an important measure of efficacy for targeted therapies, such as CD20-directed antibodies, in B-cell malignancies. CD37 expression in blood cells from healthy human donors was measured by quantitative flow cytometry in comparison to CD20. The greatest CD37 expression was found in B cells at approximately 77,000 antibodies bound per cell (ABC), which was similar to CD20 expression in B cells at 95,000 ABC. In other blood cell types CD37 staining was seen at low levels, about 2,000 – 5,000 ABC, in monocytes, NK cells and T cells. In vitro depletion experiments were performed with purified peripheral blood mononuclear cells (PBMCs) and with whole blood, both derived from several healthy donors. Cells were incubated for 1 hr with 10 μg/mL of either K7153A, IMGN529, CD37-targeting TRU-016, rituximab or the anti-CD52 antibody alemtuzumab, with cell depletion determined relative to counting beads by flow cytometry. The K7153A antibody and the IMGN529 conjugate efficiently and specifically depleted B-cells in a dose-dependent manner in the context of purified PBMCs and whole blood. With purified PBMCs, both K7153A and IMGN529 caused 50–60% depletion of B cells, with little to no depletion of T cells or monocytes. IMGN529 was more potent than rituximab, which led to 30–40% B-cell depletion, or TRU-016, which caused 20–30% B-cell depletion. IMGN529 also was more specific than alemtuzumab, which depleted T-cells and monocytes as well as B cells. With whole blood samples, both K7153A and IMGN529 resulted in 30–40% B-cell depletion with no effect on T cells, NK cells or monocytes. IMGN529 was again more potent than rituximab or TRU-016, which caused approximately 10% B-cell depletion, and was more specific than alemtuzumab, which depleted the majority of T cells in addition to 40% of B cells. IMGN529 embodies a unique B-cell targeted agent as it combines the intrinsic pro-apoptotic, CDC and ADCC activities of its anti-CD37 antibody component with the potent cytotoxic mechanism provided by the targeted delivery of its maytansinoid payload. It is highly active in vitro and in vivo against B-cell lymphoma and CLL cell lines. In addition, it mediates specific B-cell depletion in vitro that is greater than B-cell depletion by CD20-directed rituximab. Together, these findings indicate that IMGN529 is a promising therapeutic candidate for the treatment of B-cell malignancies. Disclosures: Deckert: ImmunoGen, Inc.: Employment. Chicklas:ImmunoGen, Inc.: Employment. Yi:ImmunoGen, Inc.: Employment. Li:ImmunoGen, Inc.: Employment. Pinkas:ImmunoGen, Inc.: Employment. Chittenden:ImmunoGen, Inc.: Employment. Lutz:ImmunoGen, Inc.: Employment. Park:ImmunoGen, Inc.: Employment.

Description: CD38 is a type II transmembrane glycoprotein with both ADP-rybosyl cyclase and glycohydrolase activities. CD38 is highly expressed at the surface of malignant plasma cells of multiple myeloma. SAR650984 is a humanized IgG1 antibody targeting CD38 in early clinical developement that is acting through several potential mechanisms including ADCC, CDC and pro-apoptotic activity. Here we report further preclinical characterization of SAR650984 with a high resolution structure of Fab-SAR650984 in complex with CD38 allowing an epitope mapping. The crystal structure of SAR650984-Fab/huCD38 complex shows that SAR650984 neither blocks the access nor alters the configuration of the ADPRC catalytic site of CD38 although in vitro assays have demonstrated that SAR650984 behaves as a strong inhibitor of the ADPRC activity of CD38. These results suggest that SAR650984 is likely an allosteric antagonist of CD38 that alters the dynamics of enzyme upon binding.