Delving into the Latest Updates on BMS-986148 with Synapse

Overview

Basic Info

Drug Type

Antibody drug conjugate (ADC)

Synonyms

Mesothelin-ADC

Target

MSLN x Tubulin

Mechanism

MSLN inhibitors(Mesothelin inhibitors), Tubulin inhibitors

Therapeutic Areas

Neoplasms

Active Indication-

Inactive Indication

Advanced cancerAdvanced Malignant Solid NeoplasmMetastatic Solid Tumor

Originator Organization

Bristol Myers Squibb Co.

Active Organization-

Inactive Organization

Bristol Myers Squibb Co.

Drug Highest PhaseDiscontinuedPhase 1/2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC11H22N4O4

InChIKeyAGGWFDNPHKLBBV-YUMQZZPRSA-N

CAS Registry159858-33-0

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Gene Sequence

Sequence Code 58051H

Sequence Code 58069L

Subsets of tumor-produced cell surface and secreted proteins can bind to IgG1 type antibodies and suppress their immune-effector activities. As they affect antibody and complement-mediated immunity, we call these proteins humoral immuno-oncology (HIO) factors. Antibody-drug conjugates (ADCs) use antibody targeting to bind cell surface antigens, internalize into the cell, then kill target cells upon liberation of the cytotoxic payload. Binding of the ADC antibody component by a HIO factor may potentially hamper ADC efficacy due to reduced internalization. To determine the potential effects of HIO factor ADC suppression, we evaluated the efficacy of a HIO-refractory, mesothelin-directed ADC (NAV-001) and a HIO-bound, mesothelin-directed ADC (SS1). The HIO factor MUC16/CA125 binding to SS1 ADC was shown to have a negative effect on internalization and tumor cell killing. The MUC16/CA125 refractory NAV-001 ADC was shown to have robust killing of MUC16/CA125 expressing and non-expressing tumor cells in vitro and in vivo at single, sub-mg/kg dosing. Moreover, NAV-001-PNU, which contains the PNU-159682 topoisomerase II inhibitor, demonstrated good stability in vitro and in vivo as well as robust bystander activity of resident cells while maintaining a tolerable safety profile in vivo. Single-dose NAV-001-PNU demonstrated robust tumor regression of a number of patient-derived xenografts from different tumor types regardless of MUC16/CA125 expression. These findings suggest that identification of HIO-refractory antibodies to be used in ADC format may improve therapeutic efficacy as observed by NAV-001 and warrants NAV-001-PNU's advancement to human clinical trials as a monotherapy to treat mesothelin-positive cancers.

01 Jan 2022·Clinical Cancer Research

Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody–drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors

Article

Author: Rottey, Sylvie ; Vezina, Heather ; Duca, Matteo ; Clarke, Jeffrey ; Santoro, Armando ; Koyama, Takafumi ; Lolkema, Martijn ; de Souza, Paul ; Aung, Kyaw ; Curigliano, Giuseppe ; Heinhuis, Kimberley M. ; Machiels, Jean-Pascal ; Brown, Michelle ; Markman, Ben ; Millward, Michael ; Chu, Quincy Siu-Chung ; Patel, Sandip Pravin ; He, Chunsheng

AbstractPurpose:To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody–drug conjugate (ADC) ± nivolumab, in patients with selected tumors.Patients and Methods:In an international phase I/IIa study [NCT02341625 (CA008-002)], patients received BMS-986148 monotherapy (0.1–1.6 mg/kg intravenously (i.v.) every 3 weeks or 0.4 or 0.6 mg/kg i.v. once weekly; n = 96) or BMS-986148 0.8 mg/kg + nivolumab 360 mg i.v. every 3 weeks (n = 30). The primary endpoint was safety and tolerability.Results:In CA008-002, the most common (≥ 10%) treatment-related adverse events (TRAEs) included increased aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 every 3 weeks monotherapy, three (25%) receiving BMS-986148 once-weekly monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab every 3 weeks. Overall, 17 of 126 patients (13%) discontinued because of a TRAE. The MTD of BMS-986148 was 1.2 mg/kg i.v. every 3 weeks. The safety profile of BMS-986148 + nivolumab was similar to that of BMS-986148 monotherapy (0.8 mg/kg). Active ADC exposures increased in a dose-proportional manner with both dosing regimens (every 3 weeks and once weekly). Preliminary clinical activity was observed with BMS-986148 ± nivolumab. No association between mesothelin expression and response was detected.Conclusions:BMS-986148 ± nivolumab demonstrated a clinically manageable safety profile and preliminary evidence of clinical activity, supporting additional studies combining directed cytotoxic therapies with checkpoint inhibitors as potential multimodal therapeutic strategies in patients with advanced solid tumors.

01 Jan 2017·Molecular Cancer TherapeuticsQ2 · MEDICINE

Preclinical Efficacy of an Antibody–Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET

Q2 · MEDICINE

Article

Author: Scales, Suzie J. ; Vanderbilt, Alexander N. ; Tinianow, Jeff N. ; Ogasawara, Annie ; Williams, Simon-Peter ; Li, Dongwei ; Marik, Jan ; Terwisscha van Scheltinga, Anton G.T. ; Gupta, Nidhi ; Pacheco, Glenn ; Firestein, Ron

AbstractAntibody–drug conjugates (ADC) use monoclonal antibodies (mAb) as vehicles to deliver potent cytotoxic drugs selectively to tumor cells expressing the target. Molecular imaging with zirconium-89 (89Zr)-labeled mAbs recapitulates similar targeting biology and might help predict the efficacy of these ADCs. An anti-mesothelin antibody (AMA, MMOT0530A) was used to make comparisons between its efficacy as an ADC and its tumor uptake as measured by 89Zr immunoPET imaging. Mesothelin-targeted tumor growth inhibition by monomethyl auristatin E (MMAE), ADC AMA-MMAE (DMOT4039A), was measured in mice bearing xenografts of ovarian cancer OVCAR-3×2.1, pancreatic cancers Capan-2, HPAC, AsPC-1, and HPAF-II, or mesothelioma MSTO-211H. Ex vivo analysis of mesothelin expression was performed using immunohistochemistry. AMA-MMAE showed the greatest growth inhibition in OVCAR-3×2.1, Capan-2, and HPAC tumors, which showed target-specific tumor uptake of 89Zr-AMA. The less responsive xenografts (AsPC-1, HPAF-II, and MSTO-211H) did not show 89Zr-AMA uptake despite confirmed mesothelin expression. ImmunoPET can demonstrate the necessary delivery, binding, and internalization of an ADC antibody in vivo and this correlates with the efficacy of mesothelin-targeted ADC in tumors vulnerable to the cytotoxic drug delivered. Mol Cancer Ther; 16(1); 134–42. ©2016 AACR.

1

News (Medical) associated with BMS-986148

15 Dec 2023

·www.fiercebiotech.com

Pfizer finds room for ADC snack after swallowing Seagen, inking deal for mesothelin candidate

Pfizer has identified the candidate as an asset that can realize the potential of mesothelin as an ADC target. Pfizer just swallowed a $43 billion antibody-drug conjugate (ADC) company and still isn’t full. Hours after Pfizer closed the Seagen buyout, Nona Biosciences put out news that the Big Pharma has committed $53 million in upfront and near-term payments for rights to its mesothelin-targeted ADC. The deal with Nona gives Pfizer an exclusive global license to the ADC, dubbed HBM9033, a drug candidate that received FDA clearance for testing in humans earlier this year. Harbor BioMed, Nona’s parent company, created the asset in collaboration with MediLink Therapeutics, pooling technologies to link an anti-mesothelin antibody to a novel topoisomerase inhibitor via a tumor-specific cleavable linker. Pfizer, which is on the hook for up to $1.05 billion in milestones, has identified the candidate as an asset that can realize the potential of mesothelin as an ADC target. A mesothelin ADC candidate that Bayer developed with ImmunoGen and MorphoSys failed a pivotal trial in mesothelioma patients in 2017. Bayer remained interested in the target, inking and then axing a CAR-T pact with Atara Biotherapeutics, and other companies have kept in the hunt across a range of modalities. The activity reflects evidence that mesothelin is overexpressed in multiple tumor types, including mesothelioma and cancers of the ovary, lung, breast and pancreas. The deal further strengthens Pfizer’s position in a modality that CEO Albert Bourla called “one of the hottest” areas of business development in recent months on a call with investors to discuss the closure of the Seagen deal. “Everybody is looking for an ADC and actually the prices that we've seen being paid for ADCs are way, way higher than what we were able to get [Seagen for],” Bourla said. While Massachusetts-based Nona put out news of the deal, Harbor, a company that mostly has offices in China, is behind the project. Harbor set up Nona as a wholly owned subsidiary last year and went on to receive FDA clearance to study.

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100 Deals associated with BMS-986148

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced cancer	Phase 2	CA	Bristol Myers Squibb Co.	19 Jun 2015
Advanced cancer	Phase 2	US	Bristol Myers Squibb Co.	19 Jun 2015
Advanced cancer	Phase 2	BE	Bristol Myers Squibb Co.	19 Jun 2015
Advanced cancer	Phase 2	CA	Bristol Myers Squibb Co.	19 Jun 2015
Advanced cancer	Phase 2	AU	Bristol Myers Squibb Co.	19 Jun 2015
Advanced cancer	Phase 2	BE	Bristol Myers Squibb Co.	19 Jun 2015
Advanced cancer	Phase 2	GB	Bristol Myers Squibb Co.	19 Jun 2015
Advanced cancer	Phase 2	GB	Bristol Myers Squibb Co.	19 Jun 2015
Advanced cancer	Phase 2	AU	Bristol Myers Squibb Co.	19 Jun 2015
Advanced cancer	Phase 2	US	Bristol Myers Squibb Co.	19 Jun 2015