- |||||||||| mirzotamab clezutoclax (ABBV-155) / AbbVie
Targeted delivery of BCL-Xl selective inhibitors alleviates on-target toxicity of systemically dosed inhibitors in preclinical models (In-person; Room 356 (Ernest N. Morial Convention Center)) - Mar 12, 2024 - Abstract #ACSSp2024ACS_Sp_6589;
To overcome this liability, antibody-drug conjugates were developed using novel BCL-X L inhibitors, unique linker technologies and targeting antibodies. Although a novel BCL-X L -mediated toxicity was uncovered in monkey kidneys upon repeat dosing of ADC, this toxicity was mitigated by modification of a drug-linker that has been incorporated into mirzotamab clezutoclax, the first BCL-X L selective agent to enter human clinical trials.
- |||||||||| mirzotamab clezutoclax (ABBV-155) / AbbVie
Trial completion date, Trial primary completion date, Combination therapy: A Study With ABBV-155 Alone and in Combination With Taxane Therapy in Adults With Relapsed and/or Refractory Solid Tumors (clinicaltrials.gov) - Oct 30, 2023
P1, N=169, Active, not recruiting,
Although a novel BCL-X L -mediated toxicity was uncovered in monkey kidneys upon repeat dosing of ADC, this toxicity was mitigated by modification of a drug-linker that has been incorporated into mirzotamab clezutoclax, the first BCL-X L selective agent to enter human clinical trials. Trial completion date: Nov 2023 --> Mar 2024 | Trial primary completion date: Nov 2023 --> Mar 2024
- |||||||||| mirzotamab clezutoclax (ABBV-155) / AbbVie
Enrollment closed, Combination therapy: A Study With ABBV-155 Alone and in Combination With Taxane Therapy in Adults With Relapsed and/or Refractory Solid Tumors (clinicaltrials.gov) - Jan 17, 2023
P1, N=168, Active, not recruiting,
In the dose expansion phase of the Phase 1 study, patients were treated as follows: (i) R/R small cell lung cancer (SCLC) with Mirzo-C monotherapy, (ii) non-small cell lung cancer (NSCLC) with Mirzo-C + docetaxel, and (iii) hormone positive, Her2 negative, post Recruiting --> Active, not recruiting
- |||||||||| Journal, IO biomarker: Strategies to reduce the On-target Platelet Toxicity of Bcl-xL Inhibitors: PROTACs, SNIPERs and Prodrug-based approaches. (Pubmed Central) - Jun 23, 2022
This paper also discussed the approaches that utilized the concept of the prodrugs, such as antibody-drug conjugates, phosphate prodrugs, dendrimer conjugate, and glycosylated conjugate. Various studies such as in vitro , in vivo , structure-activity relationship, and biophysical characterization of each inhibitor retrieved from these strategies are timely discussed in the paper.
- |||||||||| mirzotamab clezutoclax (ABBV-155) / AbbVie
ED016. Novel Antibody Drug Conjugates (La Nouvelle Orleans A-B, Convention Center) - Jan 28, 2022 - Abstract #AACR2022AACR_961;
The second talk will discuss BCL-XL inhibitors as warheads for ADCs, including the development of ABBV-155, a BCL-XL inhibitor linked to an anti-B7H3 targeting antibody. The final speaker will address the challenges and opportunities with selecting patients for ADC therapeutics, including how such approaches may differ when ADCs with non-chemotherapy payloads are administered.
- |||||||||| mirzotamab clezutoclax (ABBV-155) / AbbVie
[VIRTUAL] A First-in-human Study of Mirzotamab Clezutoclax as Monotherapy & in Combination with Taxane Therapy in Relapsed/Refractory Solid Tumors () - Sep 23, 2021 - Abstract #ADCUSA2021ADC_USA_40;
The final speaker will address the challenges and opportunities with selecting patients for ADC therapeutics, including how such approaches may differ when ADCs with non-chemotherapy payloads are administered. Mirzotamab clezutoclax is a first-in-class antibody-drug conjugate targeting the intrinsic apoptosis pathway Reviewing how Mirzotamab clezutoclax as monotherapy and with paclitaxel demonstrates a tolerable safety profile; monotherapy MTD not reached Presenting on the anti-tumor activity seen with objective responses (by RECIST 1.1) in combination with taxane
- |||||||||| mirzotamab clezutoclax (ABBV-155) / AbbVie
[VIRTUAL] Looking at BCL-XL Inhibitor Antibody Drug Conjugates: A Novel Approach to Increase the Therapeutic Index of ADCs () - Sep 23, 2021 - Abstract #ADCUSA2021ADC_USA_8;
Mirzotamab clezutoclax is a first-in-class antibody-drug conjugate targeting the intrinsic apoptosis pathway Reviewing how Mirzotamab clezutoclax as monotherapy and with paclitaxel demonstrates a tolerable safety profile; monotherapy MTD not reached Presenting on the anti-tumor activity seen with objective responses (by RECIST 1.1) in combination with taxane Reviewing the narrow therapeutic index of cytotoxic-based ADCs placing limits on their clinical utility Describing the preclinical development and characterization of BCL-XL inhibitor ADCs and how they expand TI Evaluating preclinical characterization and status of the lead program mirzotamab clezutoclax (ABBV-155)
- |||||||||| [VIRTUAL] New Targetable Pathways in Chronic Lymphocytic Leukemia (CLL) () - Sep 6, 2021 - Abstract #SOHO2021SOHO_385;
P1/2
We and others reported that preclinical efficacy of AZ5576, a selective inhibitor of CDK9, and its clinical congener AZD4573 in lymphoid tumors depended on rapid downmodulation of MCL1, BFL1, and MYC.19–21 CDK9 inhibition can increase efficacy of BH3-mimetics, but safety of this combination will need to be explored.22,23 CDK9 inhibitors in development, in addition to AZD4573, include VIP152, CYC065, and voruciclib...Navitoclax is a small-molecule inhibitor of BCL2, BCLX, and BCL2L2; however, its use in CLL has been plagued by thrombocytopenia.24 AZD4320 is an alternative agent that co-targets BCL2/X...ABBV-155, an antibody-drug conjugate targeting BCLX, where BCLX is being used as a payload to avoid “off-tumor” effects, demonstrated promise in solid tumor models.26 Finally, as many microenvironment-driven pro-survival pathways converge on NFB, leading to induction of chemokines, cell cycle regulators, and BCL2 family proteins themselves, this transcription factor continues to be an attractive target in CLL...When combined with ibrutinib in murine CLL models, VAY-736 produced prolonged survival compared with either therapy alone.28 Alternative targets for therapeutic antibodies include ROR1 (cirmtuzumab), CD19 (tafasitamab), and others.29 As resistance to novel agents is becoming an unmet need in CLL, exploration of novel targets is of paramount importance...Multiple CDK inhibitors are currently being explored and have anti-tumor effects not restricted to MCL1 inhibition. CAR T cells and bi-specific antibodies have exceptional efficacy in lymphoid malignancies and thus are of high relevance in CLL.
- |||||||||| mirzotamab clezutoclax (ABBV-155) / AbbVie
Trial completion date, Trial primary completion date, Combination therapy: A Study With ABBV-155 Alone and in Combination With Taxane Therapy in Adults With Relapsed and/or Refractory Solid Tumors (clinicaltrials.gov) - Nov 11, 2019
P1, N=152, Recruiting,
Further investigation in prospectively-selected B7H3 positive tumors as monoTx in pts with R/R small cell lung cancer and with paclitaxel in pts with R/R breast cancer and docetaxel in pts with R/R non-small cell lung cancer in the dose expansion phase is ongoing. Trial completion date: Apr 2021 --> Dec 2021 | Trial primary completion date: Apr 2021 --> Dec 2021
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