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Robert J. Lutz - One of the best experts on this subject based on the ideXlab platform.

  • Maytansinoid immunoconjugate imgn901 is cytotoxic in a three dimensional culture model of multiple myeloma
    American journal of blood research, 2016
    Co-Authors: Brittany A Nierste, Kathleen R. Whiteman, Robert J. Lutz, Ellen J Gunn, Julia Kirshner
    Abstract:

    Environmental-mediated drug-resistance (EM-DR) presents a major challenge for therapeutic development. Tissue microenvironment in the form of extracellular matrix, soluble factors, and stroma contribute to EM-DR. In multiple myeloma (MM), drug-resistance has hindered treatment success with 5-year survival rates remaining <50%. Here we evaluated IMGN901, a Maytansinoid immunoconjugate, for its ability to overcome EM-DR alone or in combination with lenalidomide or dexamethasone. We show that while adhesion of MM cells to the extracellular matrix reduces potency of IMGN901, it remains cytotoxic with an average LC50=43 nM. However, only a combination of IMGN901, lenalidomide, and dexamethasone was able to overcome drug-resistance arising from the direct contact between MM and stromal cells. We demonstrate that multi-drug resistance protein-1 (MDR-1) was upregulated in MM cells grown in contact with stroma, likely responsible for the observed resistance. This study emphasizes the importance of incorporating the elements of tumor microenvironment during preclinical testing of novel therapeutics.

  • relationship of pharmacokinetics pk toxicity and initial evidence of clinical activity with imgn853 a folate receptor alpha fra targeting antibody drug conjugate in patients pts with epithelial ovarian cancer eoc and other fra positive solid tumors
    Journal of Clinical Oncology, 2014
    Co-Authors: Kathleen N Moore, Robert J. Lutz, David M Omalley, Todd Michael Bauer, Rodrigo Ruizsoto, Michael J Birrer, Joseph Ponte, Patricia Lorusso, Hossein Borghaei, Laeeq Malik
    Abstract:

    5571 Background: IMGN853 is a FRα-targeting ADC that comprises a FRa-binding antibody conjugated with the potent Maytansinoid tubulin inhibitor, DM4. FRa is highly expressed on many solid tumors, p...

  • a novel anti cd37 antibody drug conjugate with multiple anti tumor mechanisms for the treatment of b cell malignancies
    Blood, 2013
    Co-Authors: Jutta Deckert, Christina N Carrigan, Peter U. Park, Robert J. Lutz, Hans K. Erickson, Sharon Chicklas, Katharine C Lai, Michele Mayo, Jan Pinkas, Thomas Chittenden
    Abstract:

    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(e)-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.

  • potent b cell depletion by imgn529 a cd37 targeting antibody Maytansinoid conjugate for the treatment of b cell malignancies
    Blood, 2011
    Co-Authors: Jutta Deckert, Robert J. Lutz, Thomas Chittenden, Sharon Chicklas, Jan Pinkas, Peter U. Park
    Abstract:

    Abstract 3726 CD37 is a B-cell surface antigen which is widely expressed on malignant B cells in non-Hodgkin9s 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, Burkitt9s 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.

  • sar3419 an anti cd19 Maytansinoid immunoconjugate for the treatment of b cell malignancies
    Clinical Cancer Research, 2011
    Co-Authors: Veronique Blanc, Robert J. Lutz, Anne Bousseau, Anne Caron, Chantal Carrez, John M. Lambert
    Abstract:

    SAR3419 is a novel anti-CD19 humanized monoclonal antibody conjugated to a maytansine derivate through a cleavable linker for the treatment of B-cell malignancies. SAR3419 combines the strengths of a high-potency tubulin inhibitor and the exquisite B-cell selectivity of an anti-CD19 antibody. The internalization and processing of SAR3419, following its binding at the surface of CD19-positive human lymphoma cell lines and xenograft models, release active metabolites that trigger cell-cycle arrest and apoptosis, leading to cell death and tumor regression. SAR3419 has also been shown to be active in different lymphoma xenograft models, including aggressive diffuse large B-cell lymphoma, resulting in complete regressions and tumor-free survival. In these models, the activity of SAR3419 compared favorably with rituximab and lymphoma standard of care chemotherapy. Two phase I trials with 2 different schedules of SAR3419 as a single agent were conducted in refractory/relapsed B-cell non-Hodgkin lymphoma. Activity was reported in both schedules, in heavily pretreated patients of both follicular and diffuse large B-cell lymphoma subtypes, with a notable lack of significant hematological toxicity, validating SAR3419 as an effective antibody-drug conjugate and opening opportunities in the future. Numerous B-cell–specific anti-CD19 biologics are available to treat B-cell non-Hodgkin lymphoma, and early phase I results obtained with SAR3419 suggest that it is a promising candidate for further development in this disease. In addition, thanks to the broad expression of CD19, SAR3419 may provide treatment options for B-cell leukemias that are often CD20-negative. Clin Cancer Res; 17(20); 6448–58. ©2011 AACR .

Ravi V J Chari - One of the best experts on this subject based on the ideXlab platform.

  • abstract 538 lc ms based catabolite identification study of an adc with dm21 c a novel Maytansinoid linker payload
    Cancer Research, 2019
    Co-Authors: Janet Lau, Wayne C. Widdison, Ravi V J Chari, Stuart W Hicks, Juliet Costoplus, Paulin Salomon, Nicholas C Yoder, Kerstin Sinkevicius, Megan Fuller, Thomas A Keating
    Abstract:

    ImmunoGen’s newest antibody-drug conjugate (ADC) design uses the novel Maytansinoid linker-payload, DM21-C that bears a peptidase/protease cleavable linker. These ADCs show good bystander killing of proximal antigen negative cells, suggesting the generation of cell-permeable catabolites. The goal of this study was to identify the catabolites generated upon incubation in antigen-positive cancer cells (both cell pellet and media), in mouse plasma, as well as in in vitro catabolic systems. Upon incubation with a cysteine-conjugated DM21-C ADC, the small molecule fraction was extracted with an organic solvent and analyzed by high resolution mass spectrometry after chromatographic separation. Through comparison to reference standards, mass spectral signal extraction of possible products, and database search of unknown peaks, the potential in vitro catabolite products of DM21-C conjugate were identified. Information on linker-payload stability in these model systems, including plasma stability, in vitro metabolism of the ADC, and catabolic products that were both retained and effluxed from cancer cells was obtained. As a result, we identified DM51 (the thiol- resulting from self-immolation of the cleaved linker-payload) as a major catabolite of the DM21-C ADC. Citation Format: Janet Lau, Paulin Salomon, Kerstin Sinkevicius, Juliet Costoplus, Megan Fuller, Raymond Xu, Stuart Hicks, Ravi Chari, Wayne Widdison, Nicholas Yoder, Thomas Keating. LC-MS based catabolite identification study of an ADC with DM21-C, a novel Maytansinoid linker-payload [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 538.

  • abstract 2186 peptide cleavable Maytansinoid adcs induce high bystander killing leading to improved anti tumor activityin vivo
    Cancer Research, 2017
    Co-Authors: Wayne C. Widdison, Jose F Ponte, Leanne Lanieri, Yelena Kovtun, Juliet Costoplus, Yulius Setiady, Ling Dong, Anna Skaletskaya, Qifeng Qiu, Ravi V J Chari
    Abstract:

    Antibodies targeting surface antigens on cancer cells typically have progressively lower access to tumor cells that are further removed from blood vessels. Also, the antibody will not bind to cells in the tumor mass that do not express antigen, including stromal cells of the tumor, many of which reportedly aid in the survival or metastasis of cancer cells. ADCs can bind to antigen positive cancer cells, after which they are internalized and catabolized to release one or more cytotoxic metabolite(s) that can kill the targeted cell. Metabolites that are membrane permeable may also diffuse into and kill neighboring cells, often called bystander cells, that would normally be less accessible. The goal of this work was to design ADCs that would have increased bystander activity, which could result in greater killing of cancer cells and stromal cells in the tumor environment. We have prepared a new type of peptide-cleavable immolative ADC (PCI-ADC) that efficiently releases membrane permeable cytotoxic Maytansinoid metabolites upon cleavage of the peptide linker, followed by immolation. Several PCI-ADCs were prepared that release metabolites having different degrees of hydrophobicity. As the hydrophobicity of the metabolite increased, the PCI-ADCs’ bystander activity also increased. The lead PCI-ADC generally displayed a similar degree of in vitro cytotoxicity as Maytansinoid ADCs that utilize disulfide linkers, however the PCI-ADC induced significantly more bystander killing. In mice bearing large tumor xenografts (250 mm3) or tumor xenografts that express the target antigen heterogeneously, PCI-ADCs were found to be more efficacious than Maytansinoid ADCs that use disulfide linkers, as well as our recently reported peptide-para-anilino Maytansinoid ADCs. The nature of the amino acid residues in the peptide linker of the PCI-ADC was also altered so that the tolerability of the ADCs in mice could be increased without impeding efficacy. In conclusion, we have developed a promising new type of Maytansinoid ADC, one that provides a high degree of bystander killing, improved activity in homogeneous and heterogeneous tumor models in vivo, and has a different mechanism of metabolite release than current Maytansinoid based ADCs. Citation Format: Wayne C. Widdison, Juliet A. Costoplus, Jose F. Ponte, Leanne Lanieri, Yulius Setiady, Ling Dong, Anna Skaletskaya, Rui Wu, Qifeng Qiu, Yelena Kovtun, Ravi V. Chari. Peptide-cleavable Maytansinoid (ADCs) induce high bystander killing leading to improved anti-tumor activity in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2186. doi:10.1158/1538-7445.AM2017-2186

  • metabolites of antibody Maytansinoid conjugates characteristics and in vitro potencies
    Molecular Pharmaceutics, 2015
    Co-Authors: Wayne C. Widdison, Barbara A. Leece, Yelena Kovtun, Sharon Wilhelm, Laura M Bartle, Juliet Costoplus, Charlene Audette, Karen Veale, Gregory T Jones, Ravi V J Chari
    Abstract:

    Several antibody–Maytansinoid conjugates (AMCs) are in clinical trials for the treatment of various cancers. Each of these conjugates can be metabolized by tumor cells to give cytotoxic Maytansinoid metabolites that can kill targeted cells. In preclinical studies in mice, the cytotoxic metabolites initially formed in vivo are further processed in the mouse liver to give several oxidized metabolic species. In this work, the primary AMC metabolites were synthesized and incubated with human liver microsomes (HLMs) to determine if human liver would likely give the same metabolites as those formed in mouse liver. The results of these HLM metabolism studies as well as the subsequent syntheses of the resulting HLM oxidation products are presented. Syntheses of the minor impurities formed during the conjugation of AMCs were also conducted to determine their cytotoxicities and to establish how these impurities would be metabolized by HLM.

  • evaluation of targets for Maytansinoid adc therapy using a novel radiochemical assay
    Pharmaceutical Research, 2015
    Co-Authors: Katharine C Lai, Ravi V J Chari, Lintao Wang, Jutta Deckert, Yulius Setiady, Prerak Shah, John M. Lambert
    Abstract:

    Many 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. Monoclonal 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. Use 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. The [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.

  • ado trastuzumab emtansine t dm1 an antibody drug conjugate adc for her2 positive breast cancer
    Journal of Medicinal Chemistry, 2014
    Co-Authors: John M. Lambert, Ravi V J Chari
    Abstract:

    Ado-trastuzumab emtansine (T-DM1) is an antibody–drug conjugate that combines the antitumor properties of the humanized anti-human epidermal growth factor receptor 2 (HER2) antibody, trastuzumab, with the Maytansinoid, DM1, a potent microtubule-disrupting agent, joined by a stable linker. Upon binding to HER2, the conjugate is internalized via receptor-mediated endocytosis, and an active derivative of DM1 is subsequently released by proteolytic degradation of the antibody moiety within the lysosome. Initial clinical evaluation led to a phase III trial in advanced HER2-positive breast cancer patients who had relapsed after prior treatment with trastuzumab and a taxane, which showed that T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine. In 2013, T-DM1 received FDA approval for the treatment of patients with HER2-positive metastatic breast cancer who had previously received trastuzumab and a taxane, separately or in combination, the first...

John M. Lambert - One of the best experts on this subject based on the ideXlab platform.

  • evaluation of targets for Maytansinoid adc therapy using a novel radiochemical assay
    Pharmaceutical Research, 2015
    Co-Authors: Katharine C Lai, Ravi V J Chari, Lintao Wang, Jutta Deckert, Yulius Setiady, Prerak Shah, John M. Lambert
    Abstract:

    Many 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. Monoclonal 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. Use 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. The [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.

  • ado trastuzumab emtansine t dm1 an antibody drug conjugate adc for her2 positive breast cancer
    Journal of Medicinal Chemistry, 2014
    Co-Authors: John M. Lambert, Ravi V J Chari
    Abstract:

    Ado-trastuzumab emtansine (T-DM1) is an antibody–drug conjugate that combines the antitumor properties of the humanized anti-human epidermal growth factor receptor 2 (HER2) antibody, trastuzumab, with the Maytansinoid, DM1, a potent microtubule-disrupting agent, joined by a stable linker. Upon binding to HER2, the conjugate is internalized via receptor-mediated endocytosis, and an active derivative of DM1 is subsequently released by proteolytic degradation of the antibody moiety within the lysosome. Initial clinical evaluation led to a phase III trial in advanced HER2-positive breast cancer patients who had relapsed after prior treatment with trastuzumab and a taxane, which showed that T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine. In 2013, T-DM1 received FDA approval for the treatment of patients with HER2-positive metastatic breast cancer who had previously received trastuzumab and a taxane, separately or in combination, the first...

  • adme of antibody Maytansinoid conjugates
    Aaps Journal, 2012
    Co-Authors: Hans K. Erickson, John M. Lambert
    Abstract:

    The concept of treating cancer with antibody-drug conjugates (ADCs) has gained momentum with the favorable activity and safety of trastuzumab emtansine (T-DM1), SAR3419, and lorvotuzumab mertansine (IMGN901). All three ADCs utilize Maytansinoid cell-killing agents which target tubulin and suppress microtubule dynamics. Each ADC utilizes a different optimized chemical linker to attach the Maytansinoid to the antibody. Characterizing the absorption, distribution, metabolism, and excretion (ADME) of these ADCs in preclinical animal models is important to understanding their efficacy and safety profiles. The ADME properties of these ADCs in rodents were inferred from studies with radio-labeled ADCs prepared with nonbinding antibodies since T-DM1, SAR3419, IMGN901 all lack cross-reactivity with rodent antigens. For studies exploring tumor localization and activation in tumor-bearing mice, tritium-labeled T-DM1, SAR3419, and IMGN901 were utilized. The chemical nature of the linker was found to have a significant impact on the ADME properties of these ADCs—particularly on the plasma pharmacokinetics and observed catabolites in tumor and liver tissues. Despite these differences, T-DM1, SAR3419, and IMGN901 were all found to facilitate efficient deliveries of active Maytansinoid catabolites to the tumor tissue in mouse xenograft models. In addition, all three ADCs were effectively detoxified during hepatobiliary elimination in rodents.

  • sar3419 an anti cd19 Maytansinoid immunoconjugate for the treatment of b cell malignancies
    Clinical Cancer Research, 2011
    Co-Authors: Veronique Blanc, Robert J. Lutz, Anne Bousseau, Anne Caron, Chantal Carrez, John M. Lambert
    Abstract:

    SAR3419 is a novel anti-CD19 humanized monoclonal antibody conjugated to a maytansine derivate through a cleavable linker for the treatment of B-cell malignancies. SAR3419 combines the strengths of a high-potency tubulin inhibitor and the exquisite B-cell selectivity of an anti-CD19 antibody. The internalization and processing of SAR3419, following its binding at the surface of CD19-positive human lymphoma cell lines and xenograft models, release active metabolites that trigger cell-cycle arrest and apoptosis, leading to cell death and tumor regression. SAR3419 has also been shown to be active in different lymphoma xenograft models, including aggressive diffuse large B-cell lymphoma, resulting in complete regressions and tumor-free survival. In these models, the activity of SAR3419 compared favorably with rituximab and lymphoma standard of care chemotherapy. Two phase I trials with 2 different schedules of SAR3419 as a single agent were conducted in refractory/relapsed B-cell non-Hodgkin lymphoma. Activity was reported in both schedules, in heavily pretreated patients of both follicular and diffuse large B-cell lymphoma subtypes, with a notable lack of significant hematological toxicity, validating SAR3419 as an effective antibody-drug conjugate and opening opportunities in the future. Numerous B-cell–specific anti-CD19 biologics are available to treat B-cell non-Hodgkin lymphoma, and early phase I results obtained with SAR3419 suggest that it is a promising candidate for further development in this disease. In addition, thanks to the broad expression of CD19, SAR3419 may provide treatment options for B-cell leukemias that are often CD20-negative. Clin Cancer Res; 17(20); 6448–58. ©2011 AACR .

  • sar3419 an anti cd19 Maytansinoid immunoconjugate for the treatment of b cell malignancies
    Clinical Cancer Research, 2011
    Co-Authors: Veronique Blanc, Robert J. Lutz, Anne Bousseau, Anne Caron, Chantal Carrez, John M. Lambert
    Abstract:

    SAR3419 is a novel anti-CD19 humanized monoclonal antibody conjugated to a maytansine derivate through a cleavable linker for the treatment of B-cell malignancies. SAR3419 combines the strengths of a high-potency tubulin inhibitor and the exquisite B-cell selectivity of an anti-CD19 antibody. The internalization and processing of SAR3419, following its binding at the surface of CD19-positive human lymphoma cell lines and xenograft models, release active metabolites that trigger cell-cycle arrest and apoptosis, leading to cell death and tumor regression. SAR3419 has also been shown to be active in different lymphoma xenograft models, including aggressive diffuse large B-cell lymphoma, resulting in complete regressions and tumor-free survival. In these models, the activity of SAR3419 compared favorably with rituximab and lymphoma standard of care chemotherapy. Two phase I trials with 2 different schedules of SAR3419 as a single agent were conducted in refractory/relapsed B-cell non-Hodgkin lymphoma. Activity was reported in both schedules, in heavily pretreated patients of both follicular and diffuse large B-cell lymphoma subtypes, with a notable lack of significant hematological toxicity, validating SAR3419 as an effective antibody-drug conjugate and opening opportunities in the future. Numerous B-cell-specific anti-CD19 biologics are available to treat B-cell non-Hodgkin lymphoma, and early phase I results obtained with SAR3419 suggest that it is a promising candidate for further development in this disease. In addition, thanks to the broad expression of CD19, SAR3419 may provide treatment options for B-cell leukemias that are often CD20-negative.

Wayne C. Widdison - One of the best experts on this subject based on the ideXlab platform.

  • a case study comparing heterogeneous lysine and site specific cysteine conjugated Maytansinoid antibody drug conjugates adcs illustrates the benefits of lysine conjugation
    Molecular Pharmaceutics, 2019
    Co-Authors: Nicholas C Yoder, Sharon D Wilhelm, Olga Ab, Wayne C. Widdison, Kathleen R. Whiteman, Erin K. Maloney, Molly A Mcshea, Daniel Tavares, Alan Wilhelm, Lintao Wang
    Abstract:

    Antibody-drug conjugates are an emerging class of cancer therapeutics constructed from monoclonal antibodies conjugated with small molecule effectors. First-generation molecules of this class often employed heterogeneous conjugation chemistry, but many site-specifically conjugated ADCs have been described recently. Here, we undertake a systematic comparison of ADCs made with the same antibody and the same macrocyclic Maytansinoid effector but conjugated either heterogeneously at lysine residues or site-specifically at cysteine residues. Characterization of these ADCs in vitro reveals generally similar properties, including a similar catabolite profile, a key element in making a meaningful comparison of conjugation chemistries. In a mouse model of cervical cancer, the lysine-conjugated ADC affords greater efficacy on a molar payload basis. Rather than making general conclusions about ADCs conjugated by a particular chemistry, we interpret these results as highlighting the complexity of ADCs and the interpl...

  • a case study comparing heterogeneous lysine and site specific cysteine conjugated Maytansinoid antibody drug conjugates adcs illustrates the benefits of lysine conjugation
    Molecular Pharmaceutics, 2019
    Co-Authors: Nicholas C Yoder, Sharon D Wilhelm, Wayne C. Widdison, Kathleen R. Whiteman, Erin K. Maloney, Molly A Mcshea, Chen Bai, Daniel Tavares, Alan Wilhelm, Lintao Wang
    Abstract:

    Antibody-drug conjugates are an emerging class of cancer therapeutics constructed from monoclonal antibodies conjugated with small molecule effectors. First-generation molecules of this class often employed heterogeneous conjugation chemistry, but many site-specifically conjugated ADCs have been described recently. Here, we undertake a systematic comparison of ADCs made with the same antibody and the same macrocyclic Maytansinoid effector but conjugated either heterogeneously at lysine residues or site-specifically at cysteine residues. Characterization of these ADCs in vitro reveals generally similar properties, including a similar catabolite profile, a key element in making a meaningful comparison of conjugation chemistries. In a mouse model of cervical cancer, the lysine-conjugated ADC affords greater efficacy on a molar payload basis. Rather than making general conclusions about ADCs conjugated by a particular chemistry, we interpret these results as highlighting the complexity of ADCs and the interplay between payload class, linker chemistry, target antigen, and other variables that determine efficacy in a given setting.

  • abstract 3898 preclinical evaluation of dm21 a next generation Maytansinoid payload with a stable peptide linker
    Cancer Research, 2019
    Co-Authors: Wayne Deats, Wayne C. Widdison, Laura M Bartle, Juliet Costoplus, Bahar Matin, Nicole Mcbrine, Richard Gregory, Jan Pinkas
    Abstract:

    Antibody drug conjugates (ADCs) are designed to target surface antigen(s) expressed at higher levels on cancer cells compared to normal cells. ADCs are internalized and the antibody component is subsequently degraded in catabolic vesicles to release cytotoxic metabolites that can kill the cell. Membrane permeable metabolites can also diffuse into and kill neighboring cells (also called bystander cells) via a mechanism known as bystander killing, resulting in greater tumor cell killing. Non-antigen-mediated mechanisms of antibody and ADC uptake are also known to occur, and the maximum tolerated dose for most ADCs is driven by target independent delivery. DM21 is a peptide-cleavable immolative Maytansinoid payload that was designed to allow ADCs to efficiently release hydrophobic metabolites better than conjugates utilizing the disulfide linked Maytansinoid DM4. DM21 ADCs typically have similar direct in vitro cytotoxicity as DM4 ADCs against antigen positive cells, but have much greater bystander killing activity in assays where antigen positive cells are mixed with antigen negative cells. To evaluate the toxicity of DM21 as an ADC, it was conjugated to the non-targeting, chimeric anti-soybean trypsin inhibitor antibody (chKTI), and administered to cynomolgus monkeys. Two groups of 5 male cynomolgus monkeys received a single intravenous dose of chKTI-DM21 at dose levels of 11 and 22 mg/kg (204 and 408 µg/kg DM21), while a concurrent group of 5 male monkeys was administered the formulation buffer as a control group. Three monkeys/group were sacrificed on Day 5 (terminal necropsy) to assess acute toxicity, and the remaining two monkeys/group were sacrificed on Day 29 (recovery necropsy) to assess the recovery, persistence, or progression of any effects. Toxicity was determined based upon clinical observations, body weights, ophthalmic examinations, and clinical and anatomic pathology. Plasma and serum samples were also collected to evaluate the toxicokinetic (TK) profile. chKTI-DM21 was well tolerated at both doses. There was no effect on body weight gain, and clinical observations were limited to reddened/darkened skin, scabbing, and soft/liquid feces. Effects noted on clinical pathology parameters included alterations in erythroid and leukocyte parameters, increased platelet counts and fibrinogen, and transient increases in ALT and AST without histopathologic correlates. The target organ noted at the terminal necropsy was the large intestine (cecum, colon, and rectum), but all findings were resolved by the recovery necropsy indicating reversibility. Toxicokinetic analysis of the samples showed that chKTI-DM21 has dose proportional exposure and apparent stability of the peptide linkage in cynomolgus plasma. In conclusion, DM21 is a promising Maytansinoid payload with a high-degree of bystander activity and a favorable toxicity profile. Citation Format: Wayne Deats, Wayne Widdison, Juliet Costoplus, Bahar Matin, Nicole McBrine, Laura Bartle, Olga Ab, Richard Gregory, Jan Pinkas. Preclinical evaluation of DM21, a next-generation Maytansinoid payload with a stable peptide linker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3898.

  • abstract 538 lc ms based catabolite identification study of an adc with dm21 c a novel Maytansinoid linker payload
    Cancer Research, 2019
    Co-Authors: Janet Lau, Wayne C. Widdison, Ravi V J Chari, Stuart W Hicks, Juliet Costoplus, Paulin Salomon, Nicholas C Yoder, Kerstin Sinkevicius, Megan Fuller, Thomas A Keating
    Abstract:

    ImmunoGen’s newest antibody-drug conjugate (ADC) design uses the novel Maytansinoid linker-payload, DM21-C that bears a peptidase/protease cleavable linker. These ADCs show good bystander killing of proximal antigen negative cells, suggesting the generation of cell-permeable catabolites. The goal of this study was to identify the catabolites generated upon incubation in antigen-positive cancer cells (both cell pellet and media), in mouse plasma, as well as in in vitro catabolic systems. Upon incubation with a cysteine-conjugated DM21-C ADC, the small molecule fraction was extracted with an organic solvent and analyzed by high resolution mass spectrometry after chromatographic separation. Through comparison to reference standards, mass spectral signal extraction of possible products, and database search of unknown peaks, the potential in vitro catabolite products of DM21-C conjugate were identified. Information on linker-payload stability in these model systems, including plasma stability, in vitro metabolism of the ADC, and catabolic products that were both retained and effluxed from cancer cells was obtained. As a result, we identified DM51 (the thiol- resulting from self-immolation of the cleaved linker-payload) as a major catabolite of the DM21-C ADC. Citation Format: Janet Lau, Paulin Salomon, Kerstin Sinkevicius, Juliet Costoplus, Megan Fuller, Raymond Xu, Stuart Hicks, Ravi Chari, Wayne Widdison, Nicholas Yoder, Thomas Keating. LC-MS based catabolite identification study of an ADC with DM21-C, a novel Maytansinoid linker-payload [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 538.

  • abstract 2186 peptide cleavable Maytansinoid adcs induce high bystander killing leading to improved anti tumor activityin vivo
    Cancer Research, 2017
    Co-Authors: Wayne C. Widdison, Jose F Ponte, Leanne Lanieri, Yelena Kovtun, Juliet Costoplus, Yulius Setiady, Ling Dong, Anna Skaletskaya, Qifeng Qiu, Ravi V J Chari
    Abstract:

    Antibodies targeting surface antigens on cancer cells typically have progressively lower access to tumor cells that are further removed from blood vessels. Also, the antibody will not bind to cells in the tumor mass that do not express antigen, including stromal cells of the tumor, many of which reportedly aid in the survival or metastasis of cancer cells. ADCs can bind to antigen positive cancer cells, after which they are internalized and catabolized to release one or more cytotoxic metabolite(s) that can kill the targeted cell. Metabolites that are membrane permeable may also diffuse into and kill neighboring cells, often called bystander cells, that would normally be less accessible. The goal of this work was to design ADCs that would have increased bystander activity, which could result in greater killing of cancer cells and stromal cells in the tumor environment. We have prepared a new type of peptide-cleavable immolative ADC (PCI-ADC) that efficiently releases membrane permeable cytotoxic Maytansinoid metabolites upon cleavage of the peptide linker, followed by immolation. Several PCI-ADCs were prepared that release metabolites having different degrees of hydrophobicity. As the hydrophobicity of the metabolite increased, the PCI-ADCs’ bystander activity also increased. The lead PCI-ADC generally displayed a similar degree of in vitro cytotoxicity as Maytansinoid ADCs that utilize disulfide linkers, however the PCI-ADC induced significantly more bystander killing. In mice bearing large tumor xenografts (250 mm3) or tumor xenografts that express the target antigen heterogeneously, PCI-ADCs were found to be more efficacious than Maytansinoid ADCs that use disulfide linkers, as well as our recently reported peptide-para-anilino Maytansinoid ADCs. The nature of the amino acid residues in the peptide linker of the PCI-ADC was also altered so that the tolerability of the ADCs in mice could be increased without impeding efficacy. In conclusion, we have developed a promising new type of Maytansinoid ADC, one that provides a high degree of bystander killing, improved activity in homogeneous and heterogeneous tumor models in vivo, and has a different mechanism of metabolite release than current Maytansinoid based ADCs. Citation Format: Wayne C. Widdison, Juliet A. Costoplus, Jose F. Ponte, Leanne Lanieri, Yulius Setiady, Ling Dong, Anna Skaletskaya, Rui Wu, Qifeng Qiu, Yelena Kovtun, Ravi V. Chari. Peptide-cleavable Maytansinoid (ADCs) induce high bystander killing leading to improved anti-tumor activity in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2186. doi:10.1158/1538-7445.AM2017-2186

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  • a case study comparing heterogeneous lysine and site specific cysteine conjugated Maytansinoid antibody drug conjugates adcs illustrates the benefits of lysine conjugation
    Molecular Pharmaceutics, 2019
    Co-Authors: Nicholas C Yoder, Sharon D Wilhelm, Wayne C. Widdison, Kathleen R. Whiteman, Erin K. Maloney, Molly A Mcshea, Chen Bai, Daniel Tavares, Alan Wilhelm, Lintao Wang
    Abstract:

    Antibody-drug conjugates are an emerging class of cancer therapeutics constructed from monoclonal antibodies conjugated with small molecule effectors. First-generation molecules of this class often employed heterogeneous conjugation chemistry, but many site-specifically conjugated ADCs have been described recently. Here, we undertake a systematic comparison of ADCs made with the same antibody and the same macrocyclic Maytansinoid effector but conjugated either heterogeneously at lysine residues or site-specifically at cysteine residues. Characterization of these ADCs in vitro reveals generally similar properties, including a similar catabolite profile, a key element in making a meaningful comparison of conjugation chemistries. In a mouse model of cervical cancer, the lysine-conjugated ADC affords greater efficacy on a molar payload basis. Rather than making general conclusions about ADCs conjugated by a particular chemistry, we interpret these results as highlighting the complexity of ADCs and the interplay between payload class, linker chemistry, target antigen, and other variables that determine efficacy in a given setting.

  • a case study comparing heterogeneous lysine and site specific cysteine conjugated Maytansinoid antibody drug conjugates adcs illustrates the benefits of lysine conjugation
    Molecular Pharmaceutics, 2019
    Co-Authors: Nicholas C Yoder, Sharon D Wilhelm, Olga Ab, Wayne C. Widdison, Kathleen R. Whiteman, Erin K. Maloney, Molly A Mcshea, Daniel Tavares, Alan Wilhelm, Lintao Wang
    Abstract:

    Antibody-drug conjugates are an emerging class of cancer therapeutics constructed from monoclonal antibodies conjugated with small molecule effectors. First-generation molecules of this class often employed heterogeneous conjugation chemistry, but many site-specifically conjugated ADCs have been described recently. Here, we undertake a systematic comparison of ADCs made with the same antibody and the same macrocyclic Maytansinoid effector but conjugated either heterogeneously at lysine residues or site-specifically at cysteine residues. Characterization of these ADCs in vitro reveals generally similar properties, including a similar catabolite profile, a key element in making a meaningful comparison of conjugation chemistries. In a mouse model of cervical cancer, the lysine-conjugated ADC affords greater efficacy on a molar payload basis. Rather than making general conclusions about ADCs conjugated by a particular chemistry, we interpret these results as highlighting the complexity of ADCs and the interpl...

  • effects of drug antibody ratio on pharmacokinetics biodistribution efficacy and tolerability of antibody Maytansinoid conjugates
    Bioconjugate Chemistry, 2017
    Co-Authors: Xiuxia Sun, Jose F Ponte, Jennifer Coccia, Leanne Lanieri, Megan Bogalhas, Rassol Laleau, Qifeng Qiu, Nicholas C Yoder, Erica Hong, Lintao Wang
    Abstract:

    Antibody–drug conjugates (ADCs) are being actively pursued as a treatment option for cancer following the regulatory approval of brentuximab vedotin (Adcetris) and ado-trastuzumab emtansine (Kadcyla). ADCs consist of a cytotoxic agent conjugated to a targeting antibody through a linker. The two approved ADCs (and most ADCs now in the clinic that use a microtubule disrupting agent as the payload) are heterogeneous conjugates with an average drug-to-antibody ratio (DAR) of 3–4 (potentially ranging from 0 to 8 for individual species). Ado-trastuzumab emtansine employs DM1, a semisynthetic cytotoxic payload of the Maytansinoid class, which is conjugated via lysine residues of the antibody to an average DAR of 3.5. To understand the effect of DAR on the preclinical properties of ADCs using Maytansinoid cytotoxic agents, we prepared a series of conjugates with a cleavable linker (M9346A–sulfo-SPDB–DM4 targeting folate receptor α (FRα)) or an uncleavable linker (J2898A–SMCC–DM1 targeting the epidermal growth fac...

  • understanding how the stability of the thiol maleimide linkage impacts the pharmacokinetics of lysine linked antibody Maytansinoid conjugates
    Bioconjugate Chemistry, 2016
    Co-Authors: Jose F Ponte, Xiuxia Sun, Jennifer Coccia, Leanne Lanieri, Megan Bogalhas, Rassol Laleau, Nathan Fishkin, Nathanael C. Yoder, Lintao Wang, Sharon D Wilhelm
    Abstract:

    Antibody-drug conjugates (ADCs) have become a widely investigated modality for cancer therapy, in part due to the clinical findings with ado-trastuzumab emtansine (Kadcyla). Ado-trastuzumab emtansine utilizes the Ab-SMCC-DM1 format, in which the thiol-functionalized Maytansinoid cytotoxic agent, DM1, is linked to the antibody (Ab) via the maleimide moiety of the heterobifunctional SMCC linker. The pharmacokinetic (PK) data for ado-trastuzumab emtansine point to a faster clearance for the ADC than for total antibody. Cytotoxic agent release in plasma has been reported with nonMaytansinoid, cysteine-linked ADCs via thiol-maleimide exchange, for example, brentuximab vedotin. For Ab-SMCC-DM1 ADCs, however, the main catabolite reported is lysine-SMCC-DM1, the expected product of intracellular antibody proteolysis. To understand these observations better, we conducted a series of studies to examine the stability of the thiol-maleimide linkage, utilizing the EGFR-targeting conjugate, J2898A-SMCC-DM1, and compari...

  • Understanding How the Stability of the Thiol-Maleimide Linkage Impacts the Pharmacokinetics of Lysine-Linked Antibody–Maytansinoid Conjugates
    2016
    Co-Authors: Jose F Ponte, Xiuxia Sun, Jennifer Coccia, Leanne Lanieri, Megan Bogalhas, Rassol Laleau, Nathan Fishkin, Nathanael C. Yoder, Lintao Wang, Sharon Wilhelm
    Abstract:

    Antibody-drug conjugates (ADCs) have become a widely investigated modality for cancer therapy, in part due to the clinical findings with ado-trastuzumab emtansine (Kadcyla). Ado-trastuzumab emtansine utilizes the Ab-SMCC-DM1 format, in which the thiol-functionalized Maytansinoid cytotoxic agent, DM1, is linked to the antibody (Ab) via the maleimide moiety of the heterobifunctional SMCC linker. The pharmacokinetic (PK) data for ado-trastuzumab emtansine point to a faster clearance for the ADC than for total antibody. Cytotoxic agent release in plasma has been reported with nonMaytansinoid, cysteine-linked ADCs via thiol-maleimide exchange, for example, brentuximab vedotin. For Ab-SMCC-DM1 ADCs, however, the main catabolite reported is lysine-SMCC-DM1, the expected product of intracellular antibody proteolysis. To understand these observations better, we conducted a series of studies to examine the stability of the thiol-maleimide linkage, utilizing the EGFR-targeting conjugate, J2898A-SMCC-DM1, and comparing it with a control ADC made with a noncleavable linker that lacked a thiol-maleimide adduct (J2898A-(CH2)3-DM). We employed radiolabeled ADCs to directly measure both the antibody and the ADC components in plasma. The PK properties of the conjugated antibody moiety of the two conjugates, J2898A-SMCC-DM1 and J2898A-(CH2)3-DM (each with an average of 3.0 to 3.4 Maytansinoid molecules per antibody), appear to be similar to that of the unconjugated antibody. Clearance values of the intact conjugates were slightly faster than those of the Ab components. Furthermore, J2898A-SMCC-DM1 clears slightly faster than J2898A-(CH2)3-DM, suggesting that there is a fraction of Maytansinoid loss from the SMCC-DM1 ADC, possibly through a thiol-maleimide dependent mechanism. Experiments on ex vivo stability confirm that some loss of Maytansinoid from Ab-SMCC-DM1 conjugates can occur via thiol elimination, but at a slower rate than the corresponding rate of loss reported for thiol-maleimide links formed at thiols derived by reduction of endogenous cysteine residues in antibodies, consistent with expected differences in thiol-maleimide stability related to thiol pKa. These findings inform the design strategy for future ADCs