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David M. Goldenberg - One of the best experts on this subject based on the ideXlab platform.
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targeting lgr5 cells with an Antibody Drug Conjugate for the treatment of colon cancer
Science Translational Medicine, 2015Co-Authors: Melissa R Junttila, David M. Goldenberg, Xi Wang, Bu Er Wang, Thinh S Pham, John A Flygare, Shang Fan Yu, Carter Fields, Jeffrey Easthamanderson, Mallika SinghAbstract:Cancer stem cells (CSCs) are hypothesized to actively maintain tumors similarly to how their normal counterparts replenish differentiated cell types within tissues, making them an attractive therapeutic target for the treatment of cancer. Because most CSC markers also label normal tissue stem cells, it is unclear how to selectively target them without compromising normal tissue homeostasis. We evaluated a strategy that targets the cell surface leucine-rich repeat–containing G protein–coupled receptor 5 (LGR5), a well-characterized tissue stem cell and CSC marker, with an Antibody Conjugated to distinct cytotoxic Drugs. One Antibody-Drug Conjugate (ADC) demonstrated potent tumor efficacy and safety in vivo. Furthermore, the ADC decreased tumor size and proliferation, translating to improved survival in a genetically engineered model of intestinal tumorigenesis. These data demonstrate that ADCs can be leveraged to exploit differences between normal and cancer stem cells to successfully target gastrointestinal cancers.
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sacituzumab govitecan immu 132 an anti trop 2 sn 38 Antibody Drug Conjugate characterization and efficacy in pancreatic gastric and other cancers
Bioconjugate Chemistry, 2015Co-Authors: Thomas M Cardillo, Serengulam V Govindan, Robert M Sharkey, Preeti Trisal, Roberto Arrojo, Edmund A Rossi, Chienhsing Chang, David M. GoldenbergAbstract:Sacituzumab govitecan (IMMU-132) is an Antibody–Drug Conjugate (ADC) made from a humanized anti-Trop-2 monoclonal Antibody (hRS7) Conjugated with the active metabolite of irinotecan, SN-38. In addition to its further characterization, as the clinical utility of IMMU-132 expands to an ever-widening range of Trop-2-expressing solid tumor types, its efficacy in new disease models needs to be explored in a nonclinical setting. Unlike most ADCs that use ultratoxic Drugs and stable linkers, IMMU-132 uses a moderately toxic Drug with a moderately stable carbonate bond between SN-38 and the linker. Flow cytometry and immunohistochemistry disclosed that Trop-2 is expressed in a wide range of tumor types, including gastric, pancreatic, triple-negative breast (TNBC), colonic, prostate, and lung. While cell-binding experiments reveal no significant differences between IMMU-132 and parental hRS7 Antibody, surface plasmon resonance analysis using a Trop-2 CM5 chip shows a significant binding advantage for IMMU-132 over...
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epratuzumab sn 38 a new Antibody Drug Conjugate for the therapy of hematologic malignancies
Molecular Cancer Therapeutics, 2012Co-Authors: Robert M Sharkey, Thomas M Cardillo, Serengulam V Govindan, David M. GoldenbergAbstract:We previously found that slowly internalizing antibodies Conjugated with SN-38 could be used successfully when prepared with a linker that allows approximately 50% of the IgG-bound SN-38 to dissociate in serum every 24 hours. In this study, the efficacy of SN-38 Conjugates prepared with epratuzumab (rapidly internalizing) and veltuzumab (slowly internalizing), humanized anti-CD22 and anti-CD20 IgG, respectively, was examined for the treatment of B-cell malignancies. Both Antibody–Drug Conjugates had similar nanomolar activity against a variety of human lymphoma/leukemia cell lines, but slow release of SN-38 compromised potency discrimination in vitro even against an irrelevant Conjugate. When SN-38 was stably linked to the anti-CD22 Conjugate, its potency was reduced 40- to 55-fold. Therefore, further studies were conducted only with the less stable, slowly dissociating linker. In vivo , similar antitumor activity was found between CD22 and CD20 Antibody–Drug Conjugate in mice-bearing Ramos xenografts, even though Ramos expressed 15-fold more CD20 than CD22, suggesting that the internalization of the epratuzumab–SN-38 Conjugate (Emab–SN-38) enhanced its activity. Emab–SN-38 was more efficacious than a nonbinding, irrelevant IgG–SN-38 Conjugate in vivo , eliminating a majority of well-established Ramos xenografts at nontoxic doses. In vitro and in vivo studies showed that Emab–SN-38 could be combined with unConjugated veltuzumab for a more effective treatment. Thus, Emab–SN-38 is active in lymphoma and leukemia at doses well below toxic levels and therefore represents a new promising agent with therapeutic potential alone or combined with anti-CD20 Antibody therapy. Mol Cancer Ther; 11(1); 224–34. ©2011 AACR .
Robert M Sharkey - One of the best experts on this subject based on the ideXlab platform.
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efficacy of sacituzumab govitecan anti trop 2 sn 38 Antibody Drug Conjugate for treatment refractory hormone receptor positive hr her2 metastatic breast cancer mbc
Journal of Clinical Oncology, 2018Co-Authors: Aditya Bardia, Jennifer R Diamond, Rebecca Moroose, Ingrid A Mayer, Vandana G Abramson, Dejan Juric, Sara M. Tolaney, Linda T Vahdat, Joyce Oshaughnessy, Robert M SharkeyAbstract:1004Background: Sacituzumab govitecan is a novel Antibody-Drug Conjugate consisting of SN-38, the active metabolite of irinotecan, Conjugated to a humanized mAb targeting Trop-2 (trophoblastic anti...
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efficacy of sacituzumab govitecan anti trop 2 sn 38 Antibody Drug Conjugate for treatment refractory hormone receptor positive hr her2 metastatic breast cancer mbc
Journal of Clinical Oncology, 2018Co-Authors: Aditya Bardia, Jennifer R Diamond, Rebecca Moroose, Ingrid A Mayer, Vandana G Abramson, Dejan Juric, Sara M. Tolaney, Linda T Vahdat, Joyce Oshaughnessy, Robert M SharkeyAbstract:1004Background: Sacituzumab govitecan is a novel Antibody-Drug Conjugate consisting of SN-38, the active metabolite of irinotecan, Conjugated to a humanized mAb targeting Trop-2 (trophoblastic antigen-2), which is highly expressed in many epithelial cancers. A phase I/II basket trial (NCT01631552) investigated its activity in patients (pts) with advanced cancers, and we previously reported on pts with triple-negative mBC. Results in HR+/ HER2 negative (as per ASCO/CAP guidelines) mBC pts who had ≥ 1 prior hormonal therapy are presented here. Methods: Pts received sacituzumab govitecan at a dose of 10 mg/kg on days 1 & 8 of a 21-day cycle until progression or unacceptable toxicity. Eligibility included ≥ 1 prior line of standard therapy for metastatic disease, measurable disease by CT or MRI. Efficacy was assessed locally by RECIST 1.1. Adverse events (AE) were evaluated according to CTCAE v4.0, Results: Fifty-four pts with HR+/HER2- mBC (all female; median age 54 yrs, range 33-79) were accrued between 2/2...
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sacituzumab govitecan immu 132 an anti trop 2 sn 38 Antibody Drug Conjugate characterization and efficacy in pancreatic gastric and other cancers
Bioconjugate Chemistry, 2015Co-Authors: Thomas M Cardillo, Serengulam V Govindan, Robert M Sharkey, Preeti Trisal, Roberto Arrojo, Edmund A Rossi, Chienhsing Chang, David M. GoldenbergAbstract:Sacituzumab govitecan (IMMU-132) is an Antibody–Drug Conjugate (ADC) made from a humanized anti-Trop-2 monoclonal Antibody (hRS7) Conjugated with the active metabolite of irinotecan, SN-38. In addition to its further characterization, as the clinical utility of IMMU-132 expands to an ever-widening range of Trop-2-expressing solid tumor types, its efficacy in new disease models needs to be explored in a nonclinical setting. Unlike most ADCs that use ultratoxic Drugs and stable linkers, IMMU-132 uses a moderately toxic Drug with a moderately stable carbonate bond between SN-38 and the linker. Flow cytometry and immunohistochemistry disclosed that Trop-2 is expressed in a wide range of tumor types, including gastric, pancreatic, triple-negative breast (TNBC), colonic, prostate, and lung. While cell-binding experiments reveal no significant differences between IMMU-132 and parental hRS7 Antibody, surface plasmon resonance analysis using a Trop-2 CM5 chip shows a significant binding advantage for IMMU-132 over...
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epratuzumab sn 38 a new Antibody Drug Conjugate for the therapy of hematologic malignancies
Molecular Cancer Therapeutics, 2012Co-Authors: Robert M Sharkey, Thomas M Cardillo, Serengulam V Govindan, David M. GoldenbergAbstract:We previously found that slowly internalizing antibodies Conjugated with SN-38 could be used successfully when prepared with a linker that allows approximately 50% of the IgG-bound SN-38 to dissociate in serum every 24 hours. In this study, the efficacy of SN-38 Conjugates prepared with epratuzumab (rapidly internalizing) and veltuzumab (slowly internalizing), humanized anti-CD22 and anti-CD20 IgG, respectively, was examined for the treatment of B-cell malignancies. Both Antibody–Drug Conjugates had similar nanomolar activity against a variety of human lymphoma/leukemia cell lines, but slow release of SN-38 compromised potency discrimination in vitro even against an irrelevant Conjugate. When SN-38 was stably linked to the anti-CD22 Conjugate, its potency was reduced 40- to 55-fold. Therefore, further studies were conducted only with the less stable, slowly dissociating linker. In vivo , similar antitumor activity was found between CD22 and CD20 Antibody–Drug Conjugate in mice-bearing Ramos xenografts, even though Ramos expressed 15-fold more CD20 than CD22, suggesting that the internalization of the epratuzumab–SN-38 Conjugate (Emab–SN-38) enhanced its activity. Emab–SN-38 was more efficacious than a nonbinding, irrelevant IgG–SN-38 Conjugate in vivo , eliminating a majority of well-established Ramos xenografts at nontoxic doses. In vitro and in vivo studies showed that Emab–SN-38 could be combined with unConjugated veltuzumab for a more effective treatment. Thus, Emab–SN-38 is active in lymphoma and leukemia at doses well below toxic levels and therefore represents a new promising agent with therapeutic potential alone or combined with anti-CD20 Antibody therapy. Mol Cancer Ther; 11(1); 224–34. ©2011 AACR .
Qing Sheng - One of the best experts on this subject based on the ideXlab platform.
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abstract 4743 using genome wide crispr screen to understand resistance mechanisms to pca062 a p cadherin targeting Antibody Drug Conjugate
Cancer Research, 2019Co-Authors: Mark Zambrowski, Katherine Seiss, Tinya Abrams, Giordano Caponigro, William R Tschantz, Tony Dalessio, Jennifer Campbell, Qing ShengAbstract:P-cadherin (PCAD) is a member of the cadherin family that mediates calcium dependent cell-cell contacts in adherens-type junctions of epithelium. Expression of P-cadherin is high in malignant tumors of epithelial origin, such as breast, esophagus, head and neck cancers, but low in normal tissues. This expression pattern makes P-cadherin a potential good target for Antibody-Drug Conjugates (ADCs). PCA062 is a first-in-class Antibody Drug Conjugate targeting P-cadherin. PCA062 consists of a fully human anti-P-cadherin Antibody of the IgG1/κ subtype, a non-cleavable bi-functional linker (SMCC) and a maytansine-derived cytotoxic payload (DM1, with a target average Drug to Antibody ratio (DAR) of 3.8). PCA062 activity was examined in a collection of cell lines expressing high level of PCAD. A subset of these PCAD high cell lines are resistant to PCA062 treatment while they remain sensitive to DM1, suggesting defects in the process of PCA062 uptake or the processing and release of DM1 into the cytoplasmic compartment. PCA062 internalization rate was measured by the uptake of a fluorescent dye labeled anti-PCAD Antibody (CQY684, the Ab portion of PCA062) in both PCA062 sensitive and resistant lines. PCA062 resistant lines show slower CQY684 internalization as compared to PCA062 sensitive lines, indicating a defect in ADC internalization may contribute to PCA062 resistance. To explore additional resistance mechanisms to PCA062 as well as to find critical components for PCA062 internalization, a genome wide CRISPR screen was performed in PCA062 sensitive HCC1954 and in PCA062 resistant KYSE510 cell line in the presence and absence of PCA062 and DM1 to look for genes that when knocked out may specifically modulate PCA062 sensitivity. The multi-Drug resistant gene MRP1 is a strong hit for PCA062 sensitization in both PCA062 resistant KYSE510 and PCA062 sensitive HCC1954 cells. Lysosomal transporter SLC46A3 and Saga transcription complex components are strong rescue hits for PCA062 in HCC1954. These data suggest that in addition to target expression level and cell intrinsic sensitivity to payload, genes involved in ADC internalization and payload cytoplasmic accumulation will also impact tumor cell sensitivity to ADCs. Citation Format: Angela Tam, Mark Zambrowski, Katherine Seiss, Si-Qi Liu, Tinya Abrams, Giordano Caponigro, William Tschantz, Jennifer Campbell, Tony DAlessio, Qing Sheng. Using genome-wide CRISPR screen to understand resistance mechanisms to PCA062, a P-cadherin targeting Antibody-Drug Conjugate [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 4743.
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abstract 4743 using genome wide crispr screen to understand resistance mechanisms to pca062 a p cadherin targeting Antibody Drug Conjugate
Cancer Research, 2019Co-Authors: Mark Zambrowski, Katherine Seiss, Tinya Abrams, Giordano Caponigro, William R Tschantz, Tony Dalessio, Jennifer Campbell, Qing ShengAbstract:P-cadherin (PCAD) is a member of the cadherin family that mediates calcium dependent cell-cell contacts in adherens-type junctions of epithelium. Expression of P-cadherin is high in malignant tumors of epithelial origin, such as breast, esophagus, head and neck cancers, but low in normal tissues. This expression pattern makes P-cadherin a potential good target for Antibody-Drug Conjugates (ADCs). PCA062 is a first-in-class Antibody Drug Conjugate targeting P-cadherin. PCA062 consists of a fully human anti-P-cadherin Antibody of the IgG1/κ subtype, a non-cleavable bi-functional linker (SMCC) and a maytansine-derived cytotoxic payload (DM1, with a target average Drug to Antibody ratio (DAR) of 3.8). PCA062 activity was examined in a collection of cell lines expressing high level of PCAD. A subset of these PCAD high cell lines are resistant to PCA062 treatment while they remain sensitive to DM1, suggesting defects in the process of PCA062 uptake or the processing and release of DM1 into the cytoplasmic compartment. PCA062 internalization rate was measured by the uptake of a fluorescent dye labeled anti-PCAD Antibody (CQY684, the Ab portion of PCA062) in both PCA062 sensitive and resistant lines. PCA062 resistant lines show slower CQY684 internalization as compared to PCA062 sensitive lines, indicating a defect in ADC internalization may contribute to PCA062 resistance. To explore additional resistance mechanisms to PCA062 as well as to find critical components for PCA062 internalization, a genome wide CRISPR screen was performed in PCA062 sensitive HCC1954 and in PCA062 resistant KYSE510 cell line in the presence and absence of PCA062 and DM1 to look for genes that when knocked out may specifically modulate PCA062 sensitivity. The multi-Drug resistant gene MRP1 is a strong hit for PCA062 sensitization in both PCA062 resistant KYSE510 and PCA062 sensitive HCC1954 cells. Lysosomal transporter SLC46A3 and Saga transcription complex components are strong rescue hits for PCA062 in HCC1954. These data suggest that in addition to target expression level and cell intrinsic sensitivity to payload, genes involved in ADC internalization and payload cytoplasmic accumulation will also impact tumor cell sensitivity to ADCs. Citation Format: Angela Tam, Mark Zambrowski, Katherine Seiss, Si-Qi Liu, Tinya Abrams, Giordano Caponigro, William Tschantz, Jennifer Campbell, Tony DAlessio, Qing Sheng. Using genome-wide CRISPR screen to understand resistance mechanisms to PCA062, a P-cadherin targeting Antibody-Drug Conjugate [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 4743.
Joohee Yi - One of the best experts on this subject based on the ideXlab platform.
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population pharmacokinetics of trastuzumab emtansine t dm1 a her2 targeted Antibody Drug Conjugate in patients with her2 positive metastatic breast cancer clinical implications of the effect of covariates
Cancer Chemotherapy and Pharmacology, 2014Co-Authors: Dan Lu, Sandhya Girish, Ellie Guardino, Meghna Samant, Mothaffar F. Rimawi, Melody A Cobleigh, Joohee Yi, Bei Wang, Pierfranco ConteAbstract:Purpose Trastuzumab emtansine (T-DM1) is an Antibody–Drug Conjugate comprising the humanized monoclonal Antibody trastuzumab linked to DM1, a highly potent cytotoxic agent. A population pharmacokinetic (PK) analysis was performed to estimate typical values and interindividual variability of T-DM1 PK parameters and the effects of clinically relevant covariates.
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clinical pharmacology of trastuzumab emtansine t dm1 an Antibody Drug Conjugate in development for the treatment of her2 positive cancer
Cancer Chemotherapy and Pharmacology, 2012Co-Authors: Sandhya Girish, Ian E Krop, Charles L Vogel, Howard A Burris, Dan Lu, Bei Wang, Manish Gupta, Joohee YiAbstract:Purpose Trastuzumab emtansine (T-DM1) is an Antibody–Drug Conjugate comprising trastuzumab and DM1, a microtubule polymerization inhibitor, covalently bound via a stable thioether linker. To characterize the pharmacokinetics (PK) of T-DM1 in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, data from four studies (TDM3569g, TDM4258g, TDM4374g, and TDM4688g) of single-agent T-DM1 administered at 3.6 mg/kg every 3 weeks (q3w) were assessed in aggregate.
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phase i study of trastuzumab dm1 an her2 Antibody Drug Conjugate given every 3 weeks to patients with her2 positive metastatic breast cancer
Journal of Clinical Oncology, 2010Co-Authors: M Beeram, Sandhya Girish, S N Holden, Joohee Yi, Jay Tibbitts, Shanu Modi, Suzanne F Jones, Wei Yu, Mark X SliwkowskiAbstract:Purpose Trastuzumab-DM1 (T-DM1) is an Antibody-Drug Conjugate that uses trastuzumab to specifically deliver the maytansinoid antimicrotubule agent DM1 to HER2-positive cells. This first-in-human study of T-DM1 evaluated safety, pharmacokinetics, and preliminary activity of T-DM1 in patients with advanced HER2-positive breast cancer. Patients and Methods Successive cohorts of patients who had progressed on trastuzumab-based therapy received escalating doses of T-DM1. Outcomes were assessed by standard solid-tumor phase I methods. Results Twenty-four patients who had received a median of four prior chemotherapeutic agents for metastatic disease received T-DM1 at 0.3 mg/kg to 4.8 mg/kg on an every-3-weeks schedule. Transient thrombocytopenia was dose-limiting at 4.8 mg/kg; the maximum-tolerated dose (MTD) was 3.6 mg/kg. The half-life of T-DM1 at the MTD was 3.5 days, with peak DM1 levels < 10 ng/mL. Clearance at doses < 1.2 mg/kg was faster than at higher doses. Common Drug-related adverse events (AEs) inclu...
Toshimi Takano - One of the best experts on this subject based on the ideXlab platform.
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single agent activity of u3 1402 a her3 targeting Antibody Drug Conjugate in breast cancer patients phase 1 dose escalation study
Journal of Clinical Oncology, 2018Co-Authors: Takahiro Kogawa, Kan Yonemori, Norikazu Masuda, Shunji Takahashi, Masato Takahashi, Hirotaka Iwase, Takahiro Nakayama, Toshiaki Saeki, Tatsuya Toyama, Toshimi TakanoAbstract:2512Background: U3-1402 is a human epidermal growth factor receptor 3 (HER3)-targeting Antibody-Drug Conjugate (ADC) of high Drug-to-Antibody-ratio (DAR: 7 to 8) with a novel linker and topoisomera...