scholarly journals 854 SGN-B7H4V, a novel, investigational vedotin antibody-drug conjugate directed to the T cell checkpoint ligand B7-H4, shows promising activity in preclinical models

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A895-A895
Author(s):  
Elizabeth Gray ◽  
Angela Epp ◽  
Michelle Ulrich ◽  
Disha Sahetya ◽  
Kelly Hensley ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Immune Checkpoint ◽  
Brentuximab Vedotin ◽  
Preclinical Models ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Tumor Types ◽  
Antibody Drug

BackgroundSGN-B7H4V is a novel, investigational vedotin antibody drug conjugate (ADC) directed to B7-H4, a member of the B7 family of immune checkpoint ligands. B7-H4 expression is elevated on a variety of solid tumors including breast, ovarian, and endometrial tumors.1 SGN-B7H4V is composed of a fully human IgG1 anti-B7-H4 monoclonal antibody (mAb) conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable peptide linker. SGN-B7H4V is designed to bind and internalize the immune checkpoint ligand B7-H4/ADC complex from the surface of malignant cells and release the cytotoxic payload MMAE. This ”vedotin” drug linker system has been clinically validated by multiple ADC programs, including brentuximab vedotin, enfortumab vedotin, and polatuzumab vedotin.2–4 Here, we characterize the target antigen B7-H4 and evaluate SGN-B7H4V activity in preclinical models.MethodsB7-H4 expression was characterized by RNA expression and immunohistochemistry across multiple solid tumor types. The ability of SGN-B7H4V to kill B7-H4-expressing tumor cells in vitro and in vivo in a variety of xenograft tumor models was also evaluated. Finally, the tolerability of SGN-B7H4V was assessed in rodent and non-human primate toxicology studies.ResultsImmunohistochemistry confirmed expression of B7-H4 across multiple solid tumor types, including ovarian and breast tumors. In vitro, upon binding to SGN-B7H4V, the immune checkpoint ligand B7-H4 was rapidly internalized and delivered the cytotoxic payload MMAE. Moreover, SGN-B7H4V killed B7-H4-expressing tumor cells in vitro by MMAE-mediated cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). In vivo, SGN-B7H4V demonstrated strong anti-tumor activity in multiple xenograft models, including ovarian and breast cancer models. Activity was observed in models with both uniformly high and heterogeneous expression of B7-H4, consistent with robust bystander activity of vedotin ADCs. Finally, SGN-B7H4V was tolerated in both rat and non-human primate (NHP) toxicology studies at doses consistent with approved vedotin ADCs.ConclusionsB7-H4 is a promising ADC target expressed by several solid tumor types. SGN-B7H4V demonstrates robust anti-tumor activity in preclinical models through multiple potential mechanisms and is tolerated in rat and NHP toxicity studies. Altogether, these data support further evaluation of SGN-B7H4V in a planned, first-in-human phase 1 clinical study.AcknowledgementsWe would like to thank Kellie Spahr for conjugation support and Martha Anderson for in vivo biology support.ReferencesLeong SR, Liang WC, Wu Y, Crocker L, Cheng E, Sampath D, et al. An anti-B7-H4 antibody-drug conjugate for the treatment of breast cancer. Mol Pharm 2015;12(6):1717–29. Epub 2015/04/09. doi: 10.1021/mp5007745. PubMed PMID: 25853436.Rosenberg JE, O’Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol 2019;37(29):2592–600. Epub 2019/07/30. doi: 10.1200/JCO.19.01140. PubMed PMID: 31356140; PubMed Central PMCID: PMC.Senter PD, Sievers EL. The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nat Biotechnol 2012;30(7):631–7. Epub 2012/07/12. doi: 10.1038/nbt.2289. PubMed PMID: 22781692.Tilly H, Morschhauser F, Bartlett NL, Mehta A, Salles G, Haioun C, et al. Polatuzumab vedotin in combination with immunochemotherapy in patients with previously untreated diffuse large B-cell lymphoma: an open-label, non-randomised, phase 1b-2 study. Lancet Oncol 2019;20(7):998–1010. Epub 2019/05/19. doi: 10.1016/S1470-2045(19)30091–9. PubMed PMID: 31101489.Ethics ApprovalAll animal studies were conducted in accordance with protocols reviewed and approved by the Institutional Animal Care and Use Committee at Seagen or the external testing facility that conducted the studies.

SYD985, a novel HER2-targeting antibody-drug conjugate in preclinical models for USC, both in vitro and in vivo.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. e16527-e16527 ◽  
Author(s):  
Jonathan Black ◽  
Salvatore Lopez ◽  
Emiliano Cocco ◽  
Stefania Bellone ◽  
Elena Bonazzoli ◽  
...  
Keyword(s):  
Preclinical Models ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

scholarly journals Combination of Camidanlumab Tesirine, a CD25-Targeted ADC, with Gemcitabine Elicits Synergistic Anti-Tumor Activity in Preclinical Tumor Models

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 31-32
Author(s):  
Asma Jabeen ◽  
Shiran Huang ◽  
John A. Hartley ◽  
Patrick H Van Berkel ◽  
Francesca Zammarchi
Keyword(s):  
Solid Tumor ◽  
Synergistic Activity ◽  
Publicly Traded ◽  
Tumor Models ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Anti Tumor Activity ◽  
Antibody Drug

Camidanlumab tesirine (ADCT-301) is an antibody-drug conjugate (ADC) comprised of HuMax®-TAC, a monoclonal antibody directed against human CD25, conjugated to the pyrrolobenzodiazepine dimer payload tesirine[1]. Currently, camidanlumab tesirine is being evaluated in a pivotal Phase 2 clinical trial in patients with relapsed or refractory Hodgkin lymphoma (HL) (NCT04052997) and in a Phase 1b clinical trial in patients with advanced solid tumors (NCT03621982). In pre-clinical studies, camidanlumab tesirine demonstrated strong and durable single agent activity in CD25-expressing lymphoma xenograft models[1] and in vitro it synergised with selected targeted agents[2]. Moreover, CD25-ADC, a mouse CD25 cross-reactive surrogate of camidanlumab tesirine, induced potent anti-tumor immunity against established syngeneic solid tumor models by depleting CD25-positive tumor-infiltrating T regulatory cells (Tregs) and it showed synergistic activity when combined with PD-1 blockade[3]. Here, we investigated the in vitro and in vivo anti-tumor activity of camidanlumab tesirine combined with gemcitabine, a common standard-of-care chemotherapeutic agent used both in a hematological and solid tumor clinical setting. In vitro, the combination of camidanlumab tesirine and gemcitabine was evaluated in three human-derived cancer cell lines (two HL and one anaplastic large cell lymphoma, ALCL) and resulted in synergistic activity as determined by the Chou-Talalay method. In vivo, camidanlumab tesirine was tested either alone (0.05 or 0.1 mg/kg, single dose) or in combination with gemcitabine (80 mg/kg, q3dx4) in the CD25-expressing ALCL Karpas299 xenograft model. At both ADC dose levels, combination with gemcitabine resulted in synergistic anti-tumor activity (coefficient of drug interaction (CDI) 0.51 and 0.17, respectively), better response rates and increased survival compared to monotherapy with camidanlumab tesirine. In order to extend the investigation to solid tumor models, CD25-ADC was tested in the CT26 syngeneic model, a colorectal cancer model with CD25-expressing tumor-infiltrating Tregs. CD25-ADC was administered either alone (0.1, 0.5 or 1 mg/kg, single dose) or in combination with gemcitabine (80 mg/kg, q3dx4). At the 0.1 mg/kg dose of CD25-ADC, combination with gemcitabine resulted in synergistic anti-tumor activity (CDI 0.68). Moreover, at 0.5 and 1 mg/kg, the combination of CD25-ADC and gemcitabine resulted in more durable anti-tumor activity and better response rates compared to both monotherapy treatments. In conclusion, the combination of camidanlumab tesirine and gemcitabine was synergistic both in vitro and in vivo in lymphoma preclinical models. Synergistic anti-tumor activity was also demonstrated in a colorectal cancer model using CD25-ADC, a mouse-cross-reactive version of camidanlumab tesirine, in combination with gemcitabine. Altogether, these novel pre-clinical data warrant translation of the combination between camidanlumab tesirine and gemcitabine into the clinic. 1.Flynn, M.J., et al., ADCT-301, a Pyrrolobenzodiazepine (PBD) Dimer-Containing Antibody-Drug Conjugate (ADC) Targeting CD25-Expressing Hematological Malignancies. Mol Cancer Ther, 2016. 15(11): p. 2709-2721. 2.Spriano, F., et al., The anti-CD25 antibody-drug conjugate camidanlumab tesirine (ADCT-301) presents a strong preclinical activity both as single agent and in combination in lymphoma cell lines. Hematological Oncology, 2019. 37(S2): p. 323-324. 3.Zammarchi, F., et al., A CD25-targeted antibody-drug conjugate depletes regulatory T cells and eliminates established syngeneic tumors via antitumor immunity. Journal for ImmunoTherapy of Cancer, 2020. In press. Disclosures Jabeen: ADC Therapeutics: Current Employment. Hartley:ADC Therapeutics: Consultancy, Current equity holder in publicly-traded company, Research Funding. Van Berkel:ADC-Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zammarchi:ADC-Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Abstract 2651: A novel CD19 targeting antibody-drug conjugate, huB4-DGN462, shows promising in vitro and in vivo activity in CD19-positive lymphoma models

2017 ◽  
Author(s):  
Eugenio Gaudio ◽  
Chiara Tarantelli ◽  
Alberto J. Arribas ◽  
Roberta Pittau Bordone ◽  
Andrea Rinaldi ◽  
...  
Keyword(s):  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

In vitro and in vivo catabolism of TAK-164, a gcc-targeted antibody-drug conjugate

2019 ◽  
Vol 34 (1) ◽  
pp. S20-S21
Author(s):  
Jayaprakasam Bolleddula ◽  
Mohammad Shadid ◽  
Abhi Shah ◽  
Afrand Kamali ◽  
Mike Smith ◽  
...  
Keyword(s):  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

scholarly journals 783 SGN-PDL1V, a novel, investigational PD-L1-directed antibody-drug conjugate for the treatment of solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A818-A818
Author(s):  
Byron Kwan ◽  
Megan Ramirez ◽  
Steven Jin ◽  
Changpu Yu ◽  
Serena Wo ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Safety Profile ◽  
Cell Lymphoma ◽  
Brentuximab Vedotin ◽  
Programmed Death ◽  
Xenograft Models ◽  
Human Primate ◽  
Antibody Drug

BackgroundPD-1/PD-L1 immune checkpoint inhibitors have transformed oncology, but a significant unmet need persists for patients with relapsed/refractory tumors following PD-1/PD-L1 treatment. PD-L1 is expressed in patients across a broad spectrum of tumor types and displays limited normal tissue expression, highlighting the potential of PD-L1 as a target for antibody-drug conjugates (ADCs) in addition to its role as an immune checkpoint. SGN-PDL1V is a PD-L1-directed ADC currently under preclinical investigation, which is comprised of an anti-PD-L1 antibody conjugated to the vedotin drug-linker. The vedotin drug-linker, consists of the microtubule disrupting agent, monomethyl auristatin E (MMAE), and a protease-cleavable peptide linker, which has been clinically validated in multiple ADC programs including brentuximab vedotin, enfortumab vedotin and polatuzumab vedotin.1–3 The proposed SGN-PDL1V primary mechanism of action is direct cytotoxicity against PD-L1-expressing malignant cells through delivery of the MMAE payload. Additionally, MMAE induces immunogenic cell death, leading to subsequent immune activation in the tumor microenvironment.4 Here, we characterize the preclinical activity and tolerability of SGN-PDL1V.MethodsSGN-PDL1V cytotoxicity was evaluated using PD-L1 expressing tumor cell lines in vitro and xenograft tumor models in vivo. Inhibition of the PD-1/PD-L1 immune checkpoint was assessed in a luminescent reporter system in vitro and a syngeneic tumor model in vivo. The tolerability and safety profile of SGN-PDL1V was determined in a non-human primate study.ResultsIn vitro, SGN-PDL1V demonstrated internalization and potent cytotoxic activity against PD-L1 expressing tumor cells. In vivo, SGN-PDL1V achieved tumor regressions in multiple tumor xenograft models at doses as low as 1 mg/kg when dosed weekly for a total of three doses. This activity was observed in immunocompromised mice, which lack responses to PD-1/PD-L1 inhibition. Notably, activity was observed even in xenograft models with low, heterogeneous PD-L1 expression, supporting the possibility to treat patients across a wide range of PD-L1 expression levels. Additionally, SGN-PDL1V exhibited potential to inhibit the PD-1/PD-L1 checkpoint in vitro and in vivo. The tolerability and safety profile of SGN-PDL1V were assessed in a non-human primate study and found to be comparable to other FDA-approved vedotin ADCs.ConclusionsSGN-PDL1V is a promising PD-L1 directed ADC with a unique cytotoxic mechanism of action among other PD-L1-targeted therapeutics. SGN-PDL1V demonstrated robust activity in multiple preclinical models and comparable tolerability and safety profile to other vedotin ADCs in non-human primates. Collectively, these data support further evaluation of SGN-PDL1V in a planned, first-in-human Phase 1 study.AcknowledgementsWe would like to thank Kerry Klussman for assay support and Jamie Mitchell for conjugation support.Trial RegistrationN/AReferencesSenter PD, Sievers EL. The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nat Biotechnol 2012;30(7):631–7. Epub 2012/07/12. doi: 10.1038/nbt.2289. PubMed PMID: 22781692.Rosenberg JE, O'Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/Programmed death ligand 1 therapy. J Clin Oncol 2019;37(29):2592–600. Epub 2019/07/30. doi: 10.1200/JCO.19.01140. PubMed PMID: 31356140; PubMed Central PMCID: PMC6784850.Tilly H, Morschhauser F, Bartlett NL, Mehta A, Salles G, Haioun C, et al. Polatuzumab vedotin in combination with immunochemotherapy in patients with previously untreated diffuse large B-cell lymphoma: an open-label, non-randomised, phase 1b-2 study. Lancet Oncol 2019;20(7):998–1010. Epub 2019/05/19. doi: 10.1016/S1470-2045(19)30091-9. PubMed PMID: 31101489.Klussman K, Tenn E, Higgins S, Mazahreh R, Snead K, Hamilton J, Grogan B, Sigurjonsson J, Cao A, Gardai S, Liu B. 618 Vedotin ADCs induce ER stress and elicit hallmarks of ICD across multiple cancer indications. J Immunother Cancer 2020;8(Suppl 3):A372. DOI:10.1136/jitc-2020-SITC2020.0618.Ethics ApprovalAll animal studies were conducted in accordance with protocols reviewed and approved by the Institutional Animal Care and Use Committee at Seagen or the external testing facility that conducted the studies.

In vitro and in vivo activity of DHES0815A, an antibody-drug conjugate targeting HER2/neu in uterine serous carcinoma

2021 ◽  
Vol 162 ◽  
pp. S186-S187
Author(s):  
Joan Tymon-Rosario ◽  
Elena Bonazzoli ◽  
Adele Guglielmi ◽  
Stefania Bellone ◽  
Nupur Nagarkatti ◽  
...  
Keyword(s):  
Serous Carcinoma ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Uterine Serous Carcinoma ◽  
Antibody Drug

scholarly journals Antibody–Drug Conjugate to Treat Meningiomas

2021 ◽  
Vol 14 (5) ◽  
pp. 427
Author(s):  
Kai Chen ◽  
Yingnan Si ◽  
Jianfa Ou ◽  
Jia-Shiung Guan ◽  
Seulhee Kim ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Imaging System ◽  
Somatostatin Receptor ◽  
Antibody Drug Conjugate ◽  
Primary Tumors ◽  
Drug Conjugate ◽  
Binding Rate ◽  
Antibody Drug

Meningiomas are primary tumors of the central nervous system with high recurrence. It has been reported that somatostatin receptor 2 (SSTR2) is highly expressed in most meningiomas, but there is no effective targeted therapy approved to control meningiomas. This study aimed to develop and evaluate an anti-SSTR2 antibody–drug conjugate (ADC) to target and treat meningiomas. The meningioma targeting, circulation stability, toxicity, and anti-tumor efficacy of SSTR2 ADC were evaluated using cell lines and/or an intracranial xenograft mouse model. The flow cytometry analysis showed that the anti-SSTR2 mAb had a high binding rate of >98% to meningioma CH157-MN cells but a low binding rate of <5% to the normal arachnoidal AC07 cells. The In Vivo Imaging System (IVIS) imaging demonstrated that the Cy5.5-labeled ADC targeted and accumulated in meningioma xenograft but not in normal organs. The pharmacokinetics study and histological analysis confirmed the stability and minimal toxicity. In vitro anti-cancer cytotoxicity indicated a high potency of ADC with an IC50 value of <10 nM. In vivo anti-tumor efficacy showed that the anti-SSTR2 ADC with doses of 8 and 16 mg/kg body weight effectively inhibited tumor growth. This study demonstrated that the anti-SSTR2 ADC can target meningioma and reduce the tumor growth.

scholarly journals ABBV-176, a PRLR antibody drug conjugate with a potent DNA-damaging PBD cytotoxin and enhanced activity with PARP inhibition

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mark G. Anderson ◽  
Qian Zhang ◽  
Luis E. Rodriguez ◽  
Claudie M. Hecquet ◽  
Cherrie K. Donawho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Parp Inhibition ◽  
Breast Cancers ◽  
Dna Breaks ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Patient Derived Xenograft ◽  
Antibody Drug

Abstract Background Prolactin receptor (PRLR) is an attractive antibody therapeutic target with expression across a broad population of breast cancers. Antibody efficacy, however, may be limited to subtypes with either PRLR overexpression and/or those where estradiol no longer functions as a mitogen and are, therefore, reliant on PRLR signaling for growth. In contrast a potent PRLR antibody-drug conjugate (ADC) may provide improved therapeutic outcomes extending beyond either PRLR overexpressing or estradiol-insensitive breast cancer populations. Methods We derived a novel ADC targeting PRLR, ABBV-176, that delivers a pyrrolobenzodiazepine (PBD) dimer cytotoxin, an emerging class of warheads with enhanced potency and broader anticancer activity than the clinically validated auristatin or maytansine derivatives. This agent was tested in vitro and in vivo cell lines and patient derived xenograft models. Results In both in vitro and in vivo assays, ABBV-176 exhibits potent cytotoxicity against multiple cell line and patient-derived xenograft breast tumor models, including triple negative and low PRLR expressing models insensitive to monomethyl auristatin (MMAE) based PRLR ADCs. ABBV-176, which cross links DNA and causes DNA breaks by virtue of its PBD warhead, also demonstrates enhanced anti-tumor activity in several breast cancer models when combined with a poly-ADP ribose polymerase (PARP) inhibitor, a potentiator of DNA damage. Conclusions Collectively the efficacy and safety profile of ABBV-176 suggest it may be an effective therapy across a broad range of breast cancers and other cancer types where PRLR is expressed with the potential to combine with other therapeutics including PARP inhibitors.

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