Jutta Deckert

SAR650984, A Novel Humanized CD38-Targeting Antibody, Demonstrates Potent Antitumor Activity in Models of Multiple Myeloma and Other CD38+ Hematologic Malignancies

Purpose: The CD38 cell surface antigen is expressed in diverse hematologic malignancies including multiple myeloma, B-cell non-Hodgkin lymphoma (NHL), B-cell chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), and T-cell ALL. Here, we assessed the antitumor activity of the anti-CD38 antibody SAR650984. Experimental Design: Activity of SAR650984 was examined on lymphoma, leukemia and multiple myeloma cell lines, primary multiple myeloma samples, and multiple myeloma xenograft models in immunodeficient mice. Results: We identified a humanized anti-CD38 antibody with strong proapoptotic activity independent of cross-linking agents, and potent effector functions including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis (ADCP), equivalent in vitro to rituximab in CD20+ and CD38+ models. This unique antibody, termed SAR650984, inhibited the ADP-ribosyl cyclase activity of CD38, likely through an allosteric antagonism as suggested by 3D structure analysis of the complex. In vivo, SAR650984 was active in diverse NHL, ALL, and multiple myeloma CD38+ tumor xenograft models. SAR650984 demonstrated single-agent activity comparable with rituximab or cyclophosphamide in Daudi or SU-DHL-8 lymphoma xenograft models with induction of the proapoptotic marker cleaved capase-7. In addition, SAR650984 had more potent antitumor activity than bortezomib in NCI-H929 and Molp-8 multiple myeloma xenograft studies. Consistent with its mode of action, SAR650984 demonstrated potent proapoptotic activity against CD38+ human primary multiple myeloma cells. Conclusion: These results validate CD38 as a therapeutic target and support the current evaluation of this unique CD38-targeting functional antibody in phase I clinical trials in patients with CD38+ B-cell malignancies. Clin Cancer Res; 20(17); 4574–83. ©2014 AACR.

A novel anti-CD37 antibody-drug conjugate with multiple anti-tumor mechanisms for the treatment of B-cell malignancies

CD37 has gathered renewed interest as a therapeutic target in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL); however, CD37-directed antibody-drug conjugates (ADCs) have not been explored. Here, we identified a novel anti-CD37 antibody, K7153A, with potent in vitro activity against B-cell lines through multiple mechanisms including apoptosis induction, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity. The antibody was conjugated to the maytansinoid, DM1, a potent antimicrotubule agent, via the thioether linker, N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and the resulting ADC, IMGN529, retained the intrinsic antibody activities and showed enhanced cytotoxic activity from targeted payload delivery. In lymphoma cell lines, IMGN529 induced G2/M cell cycle arrest after internalization and lysosomal processing to lysine-N(ε)-SMCC-DM1 as the sole intracellular maytansinoid metabolite. IMGN529 was highly active against subcutaneous B-cell tumor xenografts in severe combined immunodeficient mice with comparable or better activity than rituximab, a combination of cyclophosphamide, vincristine, and prednisone, or bendamustine. In human blood cells, CD37 is expressed in B cells at similar levels as CD20, and IMGN529 resulted in potent and specific depletion of normal and CLL B cells. These results support evaluation of the CD37-targeted ADC, IMGN529, in clinical trials in patients with B-cell malignancies including NHL and CLL.

Evaluation of Targets for Maytansinoid ADC Therapy Using a Novel Radiochemical Assay.

PurposeMany antibody-drug conjugates (ADCs) become active only after antigen-mediated internalization and release of the cytotoxic agent via antibody degradation. Quantifying these processes can provide critical information on the suitability of a particular receptor target or antibody for ADC therapy by providing insight into the amount of cytotoxic agent released. We describe a simple and inexpensive radiolabel assay to monitor this process in cultured cancer cells.MethodsMonoclonal antibodies were trace-labeled at their lysine residues by treatment with the N-hydroxysuccinimide ester of [3H]propionic acid. Human cancer cell cultures were treated with the labeled antibody at concentrations sufficient to saturate the targeted antigen. After washing to remove unbound antibody, cells were incubated and analyzed for antigen expression, conjugate degradation and catabolite formation. Results were compared with data obtained from similar assays run with radiolabeled antibody-[3H]maytansinoid conjugates ([3H]AMCs). To exemplify the method, studies were conducted with a panel of [3H]propionamide-antibodies to evaluate processing efficiency in EGFR-expressing SCCHN cell lines, and in NHL cell lines expressing the B-cell targets CD19, CD20, CD22 and CD37.ResultsUse of the [3H]propionamide-antibody assay yielded cell-mediated processing results similar to those obtained with corresponding maytansinoid ADCs. Further exploration allowed comparison of expression levels, antigen-dependent degradation, and catabolite formation across a panel of EGFR-expressing SCCHN cell lines, and for multiple targets in various B-cell cancer indications.ConclusionsThe [3H]propionamide-antibody assay described here is a sensitive, facile method which enables rapid and robust assessment of relative antibody processing amounts for target, antibody, and cell line evaluation.

Abstract 4735: SAR650984: Characterization of a potent phase I humanized anti-CD38 antibody for the treatment of multiple myeloma and other hematologic malignancies.

SAR650984, a humanized antibody targeting the type II transmembrane glycoprotein CD38 is currently in phase I dose escalation in patients with selected CD38+ hematological malignancies. CD38 is an ectoenzyme which catalyzes the formation of nucleotide metabolites involved in calcium signalling. Nearly 90% of MM patients express CD38 and this expression correlates with poor disease prognosis. The robust multiple mechanisms of action of SAR650984 include antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis induction, leading to in vivo efficacy in different tumor models, as reported previously (AACR 2010 #714; AACR 2009 #859, #2048, #2797; ASH 2008 #2756). Here, we report additional studies aimed to further elucidate the mechanism of action of SAR650984. These studies include solving the crystal structure of the SAR650984/CD38 complex, measuring enzymatic inhibition, testing in vitro activity against human primary MM cells, studying the mechanism of apoptosis induction in vivo and lastly assessing in vivo activity in combination with bortezomib (Velcade®). Fab fragments derived from SAR650984 were co-crystallized with soluble human CD38 to a 1.5 A resolution. Loop H3 of the paratope (residues Asp100, Tyr101, Tyr102, Gly103, Ser104 and Asn105) protrudes out of the SAR650984 Fab structure and is particularly critical for the complex formation. Significant conformational changes are observed in CD38 upon binding of SAR650984 while the configuration of the key residues that are involved in the ADP-ribosyl cyclase activity of CD38 is conserved as well as the access to the catalytic site. SAR650984 shows potent inhibition of the catalytic activity of CD38 (86 % at 10 nM), Taken together this would suggest that SAR650984 is not a direct orthosteric antagonist but more likely an allosteric antagonist of CD38. Consistent with the in vitro activity observed against cell lines, SAR650984 also demonstrated potent pro-apoptotic activity against a panel of CD38+ human primary MM cells. In SCID mice bearing SU-DHL-8 lymphoma, SAR650984 induced apoptosis of tumor cells, evidenced by a robust and sustained induction of cleaved caspase 7. In combination with bortezomib, a standard of care for MM treatment, SAR650984 demonstrated synergy in NCI-H929 MM xenografts in SCID mice. Together with previous reports the humanized anti-CD38 antibody, SAR650984, has demonstrated potent anti-tumor activities including ADCC, CDC and induction of apoptosis which translated into potent in vivo anti-tumor efficacy. These data support the ongoing clinical development of SAR650984 as a promising therapeutic antibody for various CD38+ hematologic malignancies. Citation Format: Marie-Cecile Wetzel, Celine Nicolazzi, Francois Vallee, Jutta Deckert, Charles Dumontet, Adriana Plesa, Aimo Kannt, Vincent Mikol, Marielle Chiron, Loic Vincent, Veronique Blanc. SAR650984: Characterization of a potent phase I humanized anti-CD38 antibody for the treatment of multiple myeloma and other hematologic malignancies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4735. doi:10.1158/1538-7445.AM2013-4735

Abstract 2830: Antibody and linker selection for the anti-CD37 antibody-maytansinoid conjugate IMGN529 for the treatment of B-cell malignancies

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL CD37 represents an attractive target for an antibody-maytansinoid conjugate (AMC) due to its prevalence in B-cell malignancies, such as non-Hodgkins lymphoma (NHL) and chronic lymphocytic leukemia (CLL), and its restricted expression on normal tissue, where it is mainly found on B-cells in blood and lymphoid tissues. Additionally, since antibodies to CD37 have been described to have anti-tumor activity, this target has potential for the development of an AMC containing a functional antibody. To select the antibody for this AMC, a large panel of anti-CD37 antibodies was generated by immunizing mice with CD37+ cells. Anti-CD37 antibodies were selected based on their superior ability to induce apoptosis in Ramos and Raji cells in comparison to the anti-CD20 antibody, rituximab, and the anti-CD37 SMIP, TRU-016. Surprisingly, unlike TRU-016, these antibodies had potent apoptotic activity in the absence of cross-linking agent. After humanization by variable domain re-surfacing, the selected antibodies retained high affinity binding to CD37+ B-cells with an EC50 of < 1 nM. They had much stronger pro-apoptotic activity than rituximab against Ramos cells, with the K7153A antibody among those with the best EC50. They all had antibody-dependent cell-mediated cytotoxicity (ADCC) activity, with K7153A having the most potent activity against Daudi cells. When SMCC-DM1 conjugates of humanized antibodies were compared, the K7153A-SMCC-DM1 conjugate had the most potent specific cytotoxicity against Daudi and Granta-519 cells in vitro. Therefore, the K7153A anti-CD37 antibody provided the best overall anti-tumor activity in terms of its direct pro-apoptotic activity, effector function and potency when used in an AMC. To determine the most effective linker design, maytansinoid conjugates of K7153A were prepared with either hindered disulfide (SPP-DM1) or thioether (SMCC-DM1) linker chemistries. Both conjugates were highly active against lymphoma cells in vitro, with the SMCC-DM1 conjugate being somewhat more potent. In vivo, a single dose of either 10 mg/kg of K7153A-SMCC-DM1 or 5 mg/kg of K7153A-SPP-DM1 was highly active against established SU-DHL-4 sc xenograft tumors. Both treatments resulted in >50% tumor-free survivors at study end. Similarly, the same treatment dose and schedule resulted in good efficacy with both conjugates in a BJAB sc xenograft model. Thus, the K7153A-SMCC-DM1 conjugate was highly active against lymphoma xenograft tumors and, based on preclinical experience, is expected to have comparable, if not better, therapeutic index to that of the SPP-linked conjugate. Taken together, these data support the selection of the K7153A antibody and the SMCC-DM1 design as the optimal anti-CD37 antibody-maytansinoid conjugate for clinical development (designated IMGN529). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2830. doi:10.1158/1538-7445.AM2011-2830

Abstract 4565: IMGN529: A therapeutic maytansinoid conjugate of an anti-CD37 antibody with multiple mechanisms of action for B-cell lymphoma and leukemia

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL CD37 is a B-cell surface antigen that is an attractive target for antibody and antibody-drug conjugate mediated therapies due to its restricted expression profile. It is expressed on malignant B-cells in NHL and CLL, but on normal tissue its expression is highly restricted to B-cells present in blood and lymphoid tissues. A large panel of anti-CD37 murine monoclonal antibodies were generated and screened for their specific CD37 binding affinity, direct anti-proliferative activity and pro-apoptotic activity against lymphoma cell lines. Selected antibodies were humanized by variable domain resurfacing and one antibody, designated K7153A, demonstrated the best overall activity in terms of direct antibody activity as well as effector function. K7153A demonstrated much stronger pro-apoptotic activity against Ramos and Raji cells than either of two reference compounds, the anti-CD37 SMIP TRU-016 or the anti-CD20 antibody rituximab, and did not require cross-linking to achieve this effect. The antibody-maytansinoid conjugate, IMGN529, was produced by conjugation of K7153A with the potent maytansinoid, DM1, via the non-cleavable linker, SMCC. IMGN529 retains the high specific binding affinity of the K7153A antibody, with an EC50 of 0.5 nM. IMGN529 also demonstrated the same strong pro-apoptotic activity as the K7153A antibody against Ramos cells, with an EC50 of 0.1 nM. Antibody-dependent cell-mediated cytotoxicity (ADCC) assays, using purified human NK cells as effector cells, showed that K7153A and IMGN529 have similar potent ADCC activity against Ramos and Daudi cells with an EC50 of less than 10 pM. In addition, both K7153A and IMGN529 demonstrated comparable complement-dependent cytotoxicity (CDC) in the presence of human complement against Ramos cells. These results indicate that IMGN529 retains the intrinsic functions of the K7153A antibody. IMGN529 was highly cytotoxic in vitro against NHL cell lines such as Daudi, BJAB, Namalwa and SU-DHL-4 with a greater degree of cell killing and lower EC50 value (19 – 36 pM) than the K7153 antibody alone. In contrast, TRU-016 showed no effect on any of these cell lines and rituximab was only active against SU-DHL-4 cells. In vivo, IMGN529 showed markedly higher efficacy against established SU-DHL-4 and BJAB xenograft tumors than the K7153A antibody alone, with significant anti-tumor activity at single doses of 5 mg/kg or lower. Together, these results demonstrate that IMGN529 combines the strong pro-apoptotic activity, CDC and ADCC activity of its anti-CD37 antibody component with the potent cytotoxic activity provided by the targeted delivery of its maytansinoid payload. IMGN529 is a highly active antibody-drug conjugate with a unique combination of anti-tumor activities and is therefore a promising therapeutic candidate for the treatment of CD37-positive lymphomas and leukemias. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4565. doi:10.1158/1538-7445.AM2011-4565

Structural characterization of a potent humanized anti-CD38 antibody in phase I

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.

Abstract 4324: Maytansinoid conjugates of a novel type III anti-CD20 antibody with potent antitumor activity.

Previously identified anti-CD20 antibodies have been classified as either Type I antibodies with lipid raft and complement-dependent cytotoxicity (CDC) activity or Type II antibodies with strong pro-apoptotic activity, but not both. We describe here a novel anti-CD20 antibody with a unique combination of functional properties that defines a new Type III anti-CD20 antibody classification. In addition, when conjugated to the potent, microtubule-acting maytansinoids DM1 or DM4, it demonstrated enhanced cell-killing activity. Novel anti-CD20 antibodies were generated by immunizing mice with CD20-positive cells. One of these murine monoclonal anti-CD20 antibodies demonstrated very strong pro-apoptotic activity against Ramos and Raji lymphoma cells in the absence of cross-linking agents, similar to the activity of Type II antibodies. The humanized version of the antibody, termed D1302A, had a stronger pro-apoptotic effect against Ramos cells than other CD20 antibodies tested including rituximab, tositumumab (B1) and GA101-NG (non-glycoengineered GA101/afutuzumab). Strikingly, D1302A also induced CD20-redistribution to lipid rafts and showed CDC activity similar to the Type I antibody rituximab, while the Type II antibodies tositumumab and GA101-NG lacked these activities. D1302A, rituximab, and ofatumumab demonstrated comparable antibody-dependent cell mediated cytotoxicity (ADCC) activity on Ramos cells with human natural killer effector cells. In vivo, D1302A showed strong efficacy in an SU-DHL-4 xenograft model (at 1 or 10 mg/kg x3) and was more active than rituximab. D1302A was conjugated to DM1 via the non-cleavable SMCC thioether linker and to DM4 via the sulfo-SPDB disulfide linker. The resulting antibody-drug conjugates retained all the functional activities of the unconjugated antibody including binding affinity, pro-apoptotic, CDC and ADCC activities, and showed enhanced and specific in vitro cytotoxicity against Granta-519 and Farage lymphoma cells. In vivo, single-dose treatment with maytansinoid conjugates of D1302A elicited enhanced activity in Daudi and SU-DHL-4 xenograft models as compared to the antibody alone and showed comparable efficacy as standard of care treatment regimens such as rituximab or rituximab + chemotherapy (R-CHOP). D1302A is a novel Type III anti-CD20 antibody that has the functional properties of both Type I (potent CDC activity) and Type II (strong pro-apoptotic activity) antibodies, together with ADCC activity. Conjugation of D1302A with maytansinoids further increases anticancer activity in vitro and in vivo, combining the potent antibody-produced activities with a fourth cytotoxic mechanism distinct from that of other CD20 targeted agents. Therefore, D1302A-maytansinoid conjugates provide a unique combination of anti-tumor activities and are promising therapeutic candidates for the treatment of CD20+ lymphomas and leukemias. Citation Format: Jutta Deckert, Peter U. Park, Yong Yi, Sharon Chicklas, Min Li, Erin K. Maloney, Rui Wu, Leanne Lanieri, Jennifer A. Coccia, Joe Ponte, Lingyun Rui, Daniel J. Tavares, Jan Pinkas, Thomas Chittenden. Maytansinoid conjugates of a novel type III anti-CD20 antibody with potent antitumor activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4324. doi:10.1158/1538-7445.AM2013-4324

Abstract 4625: IMGN529, a CD37-directed antibody-drug conjugate for the treatment of B-cell malignancies, has a favorable in vitro safety profile

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The B-cell surface antigen CD37 is an attractive target for antibody-drug conjugate (ADC) mediated therapies, as it is widely expressed on malignant B cells in NHL and CLL. In normal human tissues, high CD37 expression is mainly restricted to B cells, with substantially lower expression seen in T cells, NK cells, monocytes and granulocytes. The CD37-targeting K7153A antibody was selected from a panel of antibodies for its potent pro-apoptotic, CDC and ADCC activity against B-cell lymphoma cell lines in vitro. The K7153A antibody was conjugated to the maytansinoid DM1 via the SMCC linker to yield the IMGN529 conjugate, which retained the intrinsic functions of the antibody and demonstrated enhanced in vitro and in vivo activity through targeted delivery of its payload. To complement preclinical in vivo toxicity studies with IMGN529 in animal models, we conducted extensive in vitro safety studies, with the aim of identifying any potential negative effects on normal human blood cells. Depletion of B cells, T cells and monocytes from peripheral blood cells by K7153A, IMGN529, the anti-CD20 antibody rituximab or the anti-CD52 antibody alemtuzumab was determined by flow cytometry. Proliferation of peripheral blood mononuclear cells (PBMCs) in response to K7153A or IMGN529 was evaluated by CFDA staining. Cytokine release of TNF-α, IFN-γ, IL-2, IL-4, IL-6 and IL-10 by normal human PBMCs was measured by ELISpot and cytometric bead array following exposure to compounds in both soluble and immobilized form. K7153A and IMGN529 specifically depleted B cells in a dose-dependent manner, but had no effect on T cells or monocytes, consistent with the much lower CD37 expression levels in these cells. K7153A and IMGN529 were more potent than rituximab and more specific than alemtuzumab, which depleted T cells and monocytes in addition to B cells. Incubation with IMGN529 did not increase the percentage of proliferating cells, while the anti-CD3 control antibody was able to strongly stimulate T cell proliferation. Treatment with K7153A or IMGN529 did not specifically induce cytokine release as compared to non-binding antibody controls, while treatment with the anti-CD3 control antibody resulted in significant cytokine release for all donors. Rituximab treatment caused release of low levels of IFN-γ and TNF in some donors. In contrast, treatment with alemtuzumab resulted in release of IFN-γ, TNF-α and IL-6 for most donors consistent with its potential for cytokine release in patients. In conclusion, the CD37-directed IMGN529 maytansinoid conjugate demonstrated potent in vitro and in vivo efficacy combined with a favorable in vitro safety profile with respect to cytokine release. Our analysis confirmed that the primary target cells of IMGN529 are B cells. Together, these data support the clinical development of this ADC for the treatment of B-cell malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4625. doi:1538-7445.AM2012-4625

Abstract 2513: Evaluation of CD37 expression by calibrated IHC identifies non-Hodgkin's lymphoma as a therapeutic target for IMGN529, an anti-CD37-maytansinoid conjugate

Background: CD37 is a B-cell surface antigen reported to be widely expressed on malignant B cells in patients with non-Hodgkin9s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Expression of CD37 in normal tissues is mainly restricted to B cells in blood and lymphoid tissues. This suggests that CD37 may be an attractive target for development of a therapeutic antibody drug conjugate (ADC). The antibody maytansinoid conjugate, IMGN529 consists of a CD37-binding monoclonal antibody, K7153A, with the DM1 maytansinoid cytotoxic agent attached via an SMCC linker. IMGN529 has demonstrated potent in vitro and in vivo anti-tumor activities supporting its development as a treatment for CD37-expressing lymphomas and CLL. Objective: The objectives of this study were to assess the potential utility of IMGN529 for treatment of lymphoma patients by: (1) determining the extent of CD37 expression in NHL tissue samples relative to CD20, a well-validated target for antibody-directed therapies against B-cell malignancies; (2) identifying xenograft models with similar CD37 expression as seen in NHL patient samples; and (3) evaluating IMGN529 efficacy in these xenograft models. Methods: CD37 expression in human lymphoma cell lines was determined by quantitative flow cytometry. Cell pellet controls were prepared from human lymphoma cell lines that represented a range of CD37 expression to establish a calibrated IHC method. Using this IHC method, CD37 and CD20 expression levels were evaluated on a panel of FFPE biopsy samples from patients with NHL and from NHL-derived tumor xenograft models. For all stained biopsy samples, the extent and intensity of immunostaining was evaluated and antigen expression levels were estimated by comparing to the quantified cell pellet controls. In vivo efficacy was evaluated in subcutaneous xenograft models in SCID mice. Results: Biopsy samples from patients with B-cell NHL including subtypes such as follicular lymphoma, diffuse large B-cell lymphoma, Burkitt9s lymphoma, and mantle cell lymphoma showed similar prevalence for CD37 and CD20. Most biopsy samples from patients with NHL showed strong and uniform expression levels of the CD37 antigen. As expected, no positive CD37 staining was seen in multiple myeloma and T-cell lymphoma biopsies. IMGN529 was highly active at a single dose of 10 mg/kg in tumor xenografts with CD37 expression levels similar to NHL patient samples. Conclusion: CD37 is expressed widely in B-cell lymphomas, including all major subtypes, which confirms CD37 as target for development of a therapeutic antibody drug conjugate. The CD37-targeting ADC, IMGN529, shows strong in vivo efficacy in lymphoma xenograft models with comparable CD37 expression levels as seen in lymphoma patients. Together these data support the development of IMGN529 for treatment of NHL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2513. doi:1538-7445.AM2012-2513