525O A phase I dose escalation study of PRS-343, a HER2/4-1BB bispecific molecule, in patients with HER2-positive malignancies

Ku, Geoffrey Yuyat; Bendell, J.C.; Tolcher, A. W.; Hurvitz, Sara A.; Krishnamurthy, Anuradha; El-Khoueiry, Anthony B.; Patnaik, Amita; Shroff, Rachna T.; Noonan, Anne M.; Hahn, Noah M.; Matrana, Marc; Zettl, Markus; Aviano, Kayti; Mar, Lynn; Jolicoeur, P.; Olwill, Shane A.; Bruns, Ingmar; Piha‐Paul, Sarina A.

doi:10.1016/j.annonc.2020.08.639

Cited by 23 publications

(19 citation statements)

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“…Strikingly, there was also no CRS nor toxicities in central nervous system reported which highlighted a further advantage of CD137-targeting versus CD3-targeting bispecific compounds [ 74 ]. PRS-343 in clinical combination with atezolizumab was also reported but the combination appears to be lack of additive effects [ 75 ]. Biomarker data of PRS-343 showed an increase of CD8 + T cells in tumor as well as sCD137 in serum in a dose dependent manner.…”

Section: Technological Advances To Mitigate Hepatotoxicity For Cd137 Targeting Moleculesmentioning

confidence: 99%

“…CD137 targeting bispecific molecules are attractive agents with less safety concerns for CRS than CD3 targeting bispecific molecules and may be able to provide prolonged efficacy of T cell activation even a TAA is lost. Previous clinical studies of HPN424 and RO7122290 showed the potential of combination studies with PD-L1 inhibitors [ 75 , 80 ]. Utomilumab in combination with pembrolizumab was assessed in 33 patients with solid tumors and the combination achieved a 26% ORR including 1 CR, however, the effect of the combination compared with pembrolizumab monotherapy is unclear [ 60 ].…”

Section: Potential Combination Partners For Cd137 Targeting Moleculesmentioning

confidence: 99%

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CD137 as an Attractive T Cell Co-Stimulatory Target in the TNFRSF for Immuno-Oncology Drug Development

Hashimoto¹

2021

Cancers

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Immune checkpoint inhibitors have altered the treatment landscape significantly in several cancers, yet not enough for many cancer patients. T cell costimulatory receptors have been pursued as targets for the next generation of cancer immunotherapies, however, sufficient clinical efficacy has not yet been achieved. CD137 (TNFRSF9, 4-1BB) provides co-stimulatory signals and activates cytotoxic effects of CD8+ T cells and helps to form memory T cells. In addition, CD137 signalling can activate NK cells and dendritic cells which further supports cytotoxic T cell activation. An agonistic monoclonal antibody to CD137, urelumab, provided promising clinical efficacy signals but the responses were achieved above the maximum tolerated dose. Utomilumab is another CD137 monoclonal antibody to CD137 but is not as potent as urelumab. Recent advances in antibody engineering technologies have enabled mitigation of the hepato-toxicity that hampered clinical application of urelumab and have enabled to maintain similar potency to urelumab. Next generation CD137 targeting molecules currently in clinical trials support T cell and NK cell expansion in patient samples. CD137 targeting molecules in combination with checkpoint inhibitors or ADCC-enhancing monoclonal antibodies have been sought to improve both clinical safety and efficacy. Further investigation on patient samples will be required to provide insights to understand compensating pathways for future combination strategies involving CD137 targeting agents to optimize and maintain the T cell activation status in tumors.

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Section: Technological Advances To Mitigate Hepatotoxicity For Cd137 Targeting Moleculesmentioning

confidence: 99%

Section: Potential Combination Partners For Cd137 Targeting Moleculesmentioning

confidence: 99%

CD137 as an Attractive T Cell Co-Stimulatory Target in the TNFRSF for Immuno-Oncology Drug Development

Hashimoto¹

2021

Cancers

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“…One example is PRS-343 (HER2 × 4-1BB), composed of an Fc-silenced HER2 mAb fused with a 4-1BB-agonistic anticalin [ 38 ]. This BsAb is in phase I/II clinical development and has shown a clinical benefit and safety in HER2 + cancer patients [ 105 ]. Other examples are RG7827 (FAP × 4-1BBL) and RG6076 (CD19 × 4-1BBL), which are fusion proteins composed of trimeric 4-1BBL in one arm, and FAP or CD19-targeting Fab in the other arm.…”

Section: Tumor-targeted Immunomodulatorsmentioning

confidence: 99%

Bispecific Antibodies: A Smart Arsenal for Cancer Immunotherapies

et al. 2021

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Following the clinical success of cancer immunotherapies such as immune checkpoint inhibitors blocking B7/CTLA-4 or PD-1/PD-L1 signaling and ongoing numerous combination therapies in the clinic,3 bispecific antibodies (BsAbs) are now emerging as a growing class of immunotherapies with the potential to improve clinical efficacy and safety further. Here, we describe four classes of BsAbs: (a) immune effector cell redirectors; (b) tumor-targeted immunomodulators; (c) dual immunomodulators; and (d) dual tumor-targeting BsAbs. This review describes each of these classes of BsAbs and presents examples of BsAbs in development. We reviewed the biological rationales and characteristics of BsAbs and summarized the current status and limitations of clinical development of BsAbs and strategies to overcome limitations. The field of BsAb-based cancer immunotherapy is growing, and more data from clinical trials are accumulating. Thus, BsAbs could be the next generation of new treatment options for cancer patients.

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“…Cinrebafusp alfa (PRS-343) is a bispecific fusion protein targeting both HER2/4-1BB on tumour cells and T cells, respectively. Seventy patients with HER2-positive tumors received cinrebafusp alfa in a phase I clinical trial (NCT03330561) [ 65 ]. This drug was well tolerated and, for doses at/above 8 mg/kg, ORR was 40% and DCR was 70%.…”

Section: Immune Cell Engagers In Solid Tumorsmentioning

confidence: 99%

Research and Clinical Landscape of Bispecific Antibodies for the Treatment of Solid Malignancies

et al. 2021

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Solid tumors adopt multiple mechanisms to grow, evade immune responses, and to withstand therapeutic approaches. A major breakthrough in the armamentarium of anti-cancer agents has been the introduction of monoclonal antibodies (mAbs), able to inhibit aberrantly activated pathways and/or to unleash antigen (Ag)-specific immune responses. Nonetheless, mAb-mediated targeted pressure often fails due to escape mechanisms, mainly Ag loss/downregulation, ultimately providing therapy resistance. Hence, in order to target multiple Ag at the same time, and to facilitate cancer-immune cells interactions, bispecific antibodies (bsAbs) have been developed and are being tested in clinical trials, yielding variable safety/efficacy results based on target selection and their structure. While in hematologic cancers the bsAb blinatumomab recently reached the Food and Drug Administration (FDA)-approval for B Cell Acute Lymphoblastic Leukemia, bsAbs use in solid tumors faces considerable challenges, such as target Ag selection, biodistribution, and the presence of an immune-suppressive tumor microenvironment (TME). This review will focus on the state-of-the art, the design, and the exploitation of bsAbs against solid malignancies, delineating their mechanisms of action, major pitfalls, and future directions.

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525O A phase I dose escalation study of PRS-343, a HER2/4-1BB bispecific molecule, in patients with HER2-positive malignancies

Abstract: Initial results of a phase I study of MK-4830, a first-in-class antie immunoglobulin-like transcript 4 (ILT4) myeloid-specific antibody in patients (pts) with advanced solid tumours

Cited by 23 publications

References 0 publications

CD137 as an Attractive T Cell Co-Stimulatory Target in the TNFRSF for Immuno-Oncology Drug Development

CD137 as an Attractive T Cell Co-Stimulatory Target in the TNFRSF for Immuno-Oncology Drug Development

Bispecific Antibodies: A Smart Arsenal for Cancer Immunotherapies

Research and Clinical Landscape of Bispecific Antibodies for the Treatment of Solid Malignancies

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