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Article ; Online: Considerations for design, manufacture, and delivery for effective and safe T-cell engager therapies.

Arvedson, Tara / Bailis, Julie M / Urbig, Thomas / Stevens, Jennitte L

2022 Volume 78, Page(s) 102799

Abstract: T-cell engager (TCE) molecules provide a targeted immunotherapy approach to treat hematologic malignancies and solid tumors. Since the approval of the CD19-targeted BiTE® (bispecific T-cell engager) molecule blinatumomab, multiple TCE molecules against ... ...

Abstract	T-cell engager (TCE) molecules provide a targeted immunotherapy approach to treat hematologic malignancies and solid tumors. Since the approval of the CD19-targeted BiTE® (bispecific T-cell engager) molecule blinatumomab, multiple TCE molecules against different targets have been developed in several tumor types, with the approval of three additional TCE molecules in 2022. Some of the initial challenges, such as the need for continuous intravenous administration and low productivity, have been addressed in subsequent iterations of the platform by advancing half-life extended, Fc-based molecules. As clinical data from these molecules emerge, additional optimization of formats and manufacturability will be necessary. Ongoing efforts are focused on further improving TCE efficacy, safety, and convenience of administration.
Language	English
Publishing date	2022-09-27
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1052045-4
ISSN	1879-0429 ; 0958-1669
ISSN (online)	1879-0429
ISSN	0958-1669
DOI	10.1016/j.copbio.2022.102799
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Article ; Online: Rhodium Complexes Targeting DNA Mismatches as a Basis for New Therapeutics in Cancers Deficient in Mismatch Repair.

Nano, Adela / Dai, Joanne / Bailis, Julie M / Barton, Jacqueline K

Biochemistry

2021 Volume 60, Issue 26, Page(s) 2055–2063

Abstract: Cancers with microsatellite instability (MSI), which include ≤20% of solid tumors, are characterized by resistance to chemotherapy due to deficiency in the DNA mismatch repair (MMR) pathway. Rhodium metalloinsertors make up a class of compounds that bind ...

Abstract	Cancers with microsatellite instability (MSI), which include ≤20% of solid tumors, are characterized by resistance to chemotherapy due to deficiency in the DNA mismatch repair (MMR) pathway. Rhodium metalloinsertors make up a class of compounds that bind DNA mismatches with high specificity and show selective cytotoxicity in MSI cancer cells. We determined that rhodium complexes with an N∧O coordination showed significantly increased cell potency compared with that of N∧N-coordinated compounds, and we identified [Rh(chrysi)(phen)(PPO)]
MeSH term(s)	Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/metabolism ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Coordination Complexes/chemistry ; Coordination Complexes/metabolism ; Coordination Complexes/pharmacology ; Coordination Complexes/therapeutic use ; DNA/metabolism ; DNA Mismatch Repair/drug effects ; Humans ; Molecular Structure ; Necrosis/chemically induced ; Neoplasms/drug therapy ; Rhodium/chemistry
Chemical Substances	Antineoplastic Agents ; Coordination Complexes ; DNA (9007-49-2) ; Rhodium (DMK383DSAC)
Language	English
Publishing date	2021-06-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.1c00302
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Article: Considerations for design, manufacture, and delivery for effective and safe T-cell engager therapies

Arvedson, Tara / Bailis, Julie M / Urbig, Thomas / Stevens, Jennitte

Current opinion in biotechnology. 2022,

2022

Abstract: T-cell engager (TCE) molecules provide a targeted immunotherapy approach to treat hematologic malignancies and solid tumors. Since the approval of the CD19-targeted bispecific T-cell engager molecule blinatumomab, multiple TCE molecules against different ...

Abstract	T-cell engager (TCE) molecules provide a targeted immunotherapy approach to treat hematologic malignancies and solid tumors. Since the approval of the CD19-targeted bispecific T-cell engager molecule blinatumomab, multiple TCE molecules against different targets have been developed in several tumor types, with the approval of two additional TCE molecules in 2022. Some of the initial challenges, such as the need for continuous intravenous administration and low productivity, have been addressed in subsequent iterations of the platform by advancing half-life-extended, Fc-based molecules. As clinical data from these molecules emerge, additional optimization of formats and manufacturability will be necessary. Ongoing efforts are focused on further improving TCE efficacy, safety, and convenience of administration.
Keywords	T-lymphocytes ; biotechnology ; half life ; immunotherapy ; intravenous injection ; manufacturing ; neoplasms
Language	English
Publishing place	Elsevier Ltd
Document type	Article
Note	Pre-press version
ZDB-ID	1052045-4
ISSN	1879-0429 ; 0958-1669
ISSN (online)	1879-0429
ISSN	0958-1669
DOI	10.1016/j.copbio.2022.102799
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Article ; Online: Emerging therapies targeting the delta-like ligand 3 (DLL3) in small cell lung cancer.

Rudin, Charles M / Reck, Martin / Johnson, Melissa L / Blackhall, Fiona / Hann, Christine L / Yang, James Chih-Hsin / Bailis, Julie M / Bebb, Gwyn / Goldrick, Amanda / Umejiego, John / Paz-Ares, Luis

Journal of hematology & oncology

2023 Volume 16, Issue 1, Page(s) 66

Abstract: Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a poor prognosis. Initial responses to standard-of-care chemo-immunotherapy are, unfortunately, followed by rapid disease recurrence in most patients. Current treatment options ... ...

Abstract	Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a poor prognosis. Initial responses to standard-of-care chemo-immunotherapy are, unfortunately, followed by rapid disease recurrence in most patients. Current treatment options are limited, with no therapies specifically approved as third-line or beyond. Delta-like ligand 3 (DLL3), a Notch inhibitory ligand, is an attractive therapeutic target because it is overexpressed on the surface of SCLC cells with minimal to no expression on normal cells. Several DLL3-targeted therapies are being developed for the treatment of SCLC and other neuroendocrine carcinomas, including antibody-drug conjugates (ADCs), T-cell engager (TCE) molecules, and chimeric antigen receptor (CAR) therapies. First, we discuss the clinical experience with rovalpituzumab tesirine (Rova-T), a DLL3-targeting ADC, the development of which was halted due to a lack of efficacy in phase 3 studies, with a view to understanding the lessons that can be garnered for the rapidly evolving therapeutic landscape in SCLC. We then review preclinical and clinical data for several DLL3-targeting agents that are currently in development, including the TCE molecules-tarlatamab (formerly known as AMG 757), BI 764532, and HPN328-and the CAR T-cell therapy AMG 119. We conclude with a discussion of the future challenges and opportunities for DLL3-targeting therapies, including the utility of DLL3 as a biomarker for patient selection and disease progression, and the potential of rational combinatorial approaches that can enhance efficacy.
MeSH term(s)	Humans ; Small Cell Lung Carcinoma/drug therapy ; Small Cell Lung Carcinoma/metabolism ; Lung Neoplasms/drug therapy ; Lung Neoplasms/metabolism ; Ligands ; Neoplasm Recurrence, Local/drug therapy ; Membrane Proteins ; Intracellular Signaling Peptides and Proteins
Chemical Substances	AMG 757 ; Ligands ; DLL3 protein, human ; Membrane Proteins ; Intracellular Signaling Peptides and Proteins
Language	English
Publishing date	2023-06-24
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2429631-4
ISSN	1756-8722 ; 1756-8722
ISSN (online)	1756-8722
ISSN	1756-8722
DOI	10.1186/s13045-023-01464-y
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Control of gene expression through the nonsense-mediated RNA decay pathway.

Nickless, Andrew / Bailis, Julie M / You, Zhongsheng

Cell & bioscience

2017 Volume 7, Page(s) 26

Abstract: Nonsense-mediated RNA decay (NMD) was originally discovered as a cellular surveillance pathway that safeguards the quality of mRNA transcripts in eukaryotic cells. In its canonical function, NMD prevents translation of mutant mRNAs harboring premature ... ...

Abstract	Nonsense-mediated RNA decay (NMD) was originally discovered as a cellular surveillance pathway that safeguards the quality of mRNA transcripts in eukaryotic cells. In its canonical function, NMD prevents translation of mutant mRNAs harboring premature termination codons (PTCs) by targeting them for degradation. However, recent studies have shown that NMD has a much broader role in gene expression by regulating the stability of many normal transcripts. In this review, we discuss the function of NMD in normal physiological processes, its dynamic regulation by developmental and environmental cues, and its association with human disease.
Language	English
Publishing date	2017-05-19
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2593367-X
ISSN	2045-3701
ISSN	2045-3701
DOI	10.1186/s13578-017-0153-7
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Article: Rhodium Complexes Targeting DNA Mismatches as a Basis for New Therapeutics in Cancers Deficient in Mismatch Repair

Nano, Adela / Dai, Joanne / Bailis, Julie M. / Barton, Jacqueline K.

Biochemistry. 2021 June 11, v. 60, no. 26

2021

Abstract	Cancers with microsatellite instability (MSI), which include ≤20% of solid tumors, are characterized by resistance to chemotherapy due to deficiency in the DNA mismatch repair (MMR) pathway. Rhodium metalloinsertors make up a class of compounds that bind DNA mismatches with high specificity and show selective cytotoxicity in MSI cancer cells. We determined that rhodium complexes with an N∧O coordination showed significantly increased cell potency compared with that of N∧N-coordinated compounds, and we identified [Rh(chrysi)(phen)(PPO)]²⁺ (RhPPO) as the most potent, selective compound in this class. Using matched cell lines that are MMR-deficient (HCT116O) and MMR-proficient (HCT116N), we demonstrated that RhPPO preferentially activates the DNA damage response and inhibits DNA replication and cell proliferation in HCT116O cells, leading to cell death by necrosis. Using a fluorescent conjugate of RhPPO, we established that the metalloinsertor localizes to DNA mismatches in the cell nucleus and causes DNA double-strand breaks at or near the mismatch sites. Evaluation of RhPPO across MMR-deficient and MMR-proficient cell lines confirmed the broad potential for RhPPO to target MSI cancers, with cell potency significantly higher than that of platinum complexes used broadly as chemotherapeutics. Moreover, in a mouse xenograft model of MSI cancer, RhPPO shows promising antitumor activity and increased survival. Thus, our studies indicate that RhPPO is a novel DNA-targeted therapy with improved potency and selectivity over standard-of-care platinum-based chemotherapy and, importantly, that DNA mismatches offer a critical new target in the design of chemotherapeutics for MSI cancers.
Keywords	DNA ; DNA damage ; DNA repair ; DNA replication ; antineoplastic activity ; cell death ; cell nucleus ; cell proliferation ; cytotoxicity ; drug therapy ; fluorescence ; mice ; microsatellite repeats ; models ; necrosis ; platinum ; rhodium ; xenotransplantation
Language	English
Dates of publication	2021-0611
Size	p. 2055-2063.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.1c00302
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Rhodium metalloinsertor binding generates a lesion with selective cytotoxicity for mismatch repair-deficient cells.

Bailis, Julie M / Weidmann, Alyson G / Mariano, Natalie F / Barton, Jacqueline K

Proceedings of the National Academy of Sciences of the United States of America

2017 Volume 114, Issue 27, Page(s) 6948–6953

Abstract: The DNA mismatch repair (MMR) pathway recognizes and repairs errors in base pairing and acts to maintain genome stability. Cancers that have lost MMR function are common and comprise an important clinical subtype that is resistant to many standard of ... ...

Abstract	The DNA mismatch repair (MMR) pathway recognizes and repairs errors in base pairing and acts to maintain genome stability. Cancers that have lost MMR function are common and comprise an important clinical subtype that is resistant to many standard of care chemotherapeutics such as cisplatin. We have identified a family of rhodium metalloinsertors that bind DNA mismatches with high specificity and are preferentially cytotoxic to MMR-deficient cells. Here, we characterize the cellular mechanism of action of the most potent and selective complex in this family, [Rh(chrysi)(phen)(PPO)]
Language	English
Publishing date	2017-07-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1706665114
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Article ; Online: Control of gene expression through the nonsense-mediated RNA decay pathway

Andrew Nickless / Julie M. Bailis / Zhongsheng You

Cell & Bioscience, Vol 7, Iss 1, Pp 1-

2017 Volume 12

Abstract: Abstract Nonsense-mediated RNA decay (NMD) was originally discovered as a cellular surveillance pathway that safeguards the quality of mRNA transcripts in eukaryotic cells. In its canonical function, NMD prevents translation of mutant mRNAs harboring ... ...

Abstract	Abstract Nonsense-mediated RNA decay (NMD) was originally discovered as a cellular surveillance pathway that safeguards the quality of mRNA transcripts in eukaryotic cells. In its canonical function, NMD prevents translation of mutant mRNAs harboring premature termination codons (PTCs) by targeting them for degradation. However, recent studies have shown that NMD has a much broader role in gene expression by regulating the stability of many normal transcripts. In this review, we discuss the function of NMD in normal physiological processes, its dynamic regulation by developmental and environmental cues, and its association with human disease.
Keywords	Nonsense-mediated decay ; RNA surveillance ; Gene expression ; Human disease ; Biotechnology ; TP248.13-248.65 ; Biology (General) ; QH301-705.5 ; Biochemistry ; QD415-436
Language	English
Publishing date	2017-05-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cell-Selective Cytotoxicity of a Fluorescent Rhodium Metalloinsertor Conjugate Results from Irreversible DNA Damage at Base Pair Mismatches.

Nano, Adela / Bailis, Julie M / Mariano, Natalie F / Pham, Elizabeth D / Threatt, Stephanie D / Barton, Jacqueline K

Biochemistry

2020 Volume 59, Issue 5, Page(s) 717–726

Abstract: Up to 20% of solid tumors are characterized by DNA mismatch repair (MMR) deficiency and microsatellite instability that confer resistance to standard of care chemotherapy. MMR-deficient cancers have an increased mutation rate, and DNA mismatches ... ...

Abstract	Up to 20% of solid tumors are characterized by DNA mismatch repair (MMR) deficiency and microsatellite instability that confer resistance to standard of care chemotherapy. MMR-deficient cancers have an increased mutation rate, and DNA mismatches accumulate as part of these cancers. We previously described a class of compounds, rhodium metalloinsertors, that bind DNA mismatches with high specificity and selectivity and have potential as targeted therapy. [Rh(chrysi)(phen)(PPO)]
MeSH term(s)	Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Carbocyanines/chemistry ; Carbocyanines/pharmacology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Coordination Complexes/chemical synthesis ; Coordination Complexes/chemistry ; Coordination Complexes/pharmacology ; DNA Damage ; DNA Mismatch Repair/drug effects ; Fluorescent Dyes/chemical synthesis ; Fluorescent Dyes/chemistry ; Fluorescent Dyes/pharmacology ; HCT116 Cells ; Humans ; Molecular Structure ; Optical Imaging ; Rhodium/chemistry ; Rhodium/pharmacology
Chemical Substances	Antineoplastic Agents ; Carbocyanines ; Coordination Complexes ; Fluorescent Dyes ; cyanine dye 3 ; Rhodium (DMK383DSAC)
Language	English
Publishing date	2020-01-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.9b01037
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Article ; Online: Mesothelin/CD3 half-life extended bispecific T-cell engager molecule shows specific tumor uptake and distributes to mesothelin and CD3 expressing tissues.

Suurs, Frans V / Lorenczewski, Grit / Bailis, Julie M / Stienen, Sabine / Friedrich, Matthias / Lee, Fei / van der Vegt, Bert / de Vries, Elisabeth G E / de Groot, Derk-Jan A / Lub-de Hooge, Marjolijn N

Journal of nuclear medicine : official publication, Society of Nuclear Medicine

2021

Abstract: ... ...

Abstract	BiTE
Language	English
Publishing date	2021-04-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	80272-4
ISSN	1535-5667 ; 0097-9058 ; 0161-5505 ; 0022-3123
ISSN (online)	1535-5667
ISSN	0097-9058 ; 0161-5505 ; 0022-3123
DOI	10.2967/jnumed.120.259036
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