A Case of Sustained Tumor Regression With MP0274, a Novel DARPin Therapeutic Targeting Human Epidermal Growth Factor Receptor 2 Signaling, in Metastatic Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer After Prior Trastuzumab and Pertuzumab

Fischer, Stefanie; Götze, T.O.; Omlin, Aurelius; Baird, Richard D.; Dawson, Keith M.; Zitt, Christof; Arany, Zita; Tresch, Gaby; Fiedler, Ulrike; Jeger, Simone; Fung, Samson; Legenne, Philippe; Leupin, Nicolas; Schneeweiß, Andreas; Fremd, Carlo

doi:10.1200/po.22.00006

Cited by 5 publications

(3 citation statements)

References 14 publications

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“…In a Phase I study in patients with HER2-positive solid tumors, MP0274 showed good exposure and a favorable safety profile. 25 A metastatic breast cancer patient previously treated with both trastuzumab and pertuzumab showed a sustained response to MP0274, establishing clinical proof of concept. Retrospective biomarker analysis revealed this patient to be the only one harboring a HER2-positive, PI3K wild-type genetic signature with the highest dose level, suggesting that patient selection could result in higher response rates given good exposure to MP0274.…”

Section: Moas Of Bpabsmentioning

confidence: 81%

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Biparatopic antibodies: therapeutic applications and prospects

Niquille,

Fitzgerald,

Gera

2024

mAbs

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Biparatopic antibodies (bpAbs) bind distinct, non-overlapping epitopes on an antigen. This unique binding mode enables new mechanisms of action beyond monospecific and bispecific antibodies (bsAbs) that can make bpAbs effective therapeutics for various indications, including oncology and infectious diseases. Biparatopic binding can lead to superior affinity and specificity, promote antagonism, lock target conformation, and result in higher-order target clustering. Such antibody-target complexes can elicit strong agonism, increase immune effector function, or result in rapid target downregulation and lysosomal trafficking. These are not only attractive properties for therapeutic antibodies but are increasingly being explored for other modalities such as antibody-drug conjugates, T-cell engagers and chimeric antigen receptors. Recent advances in bpAb engineering have enabled the construction of ever more sophisticated formats that are starting to show promise in the clinic.

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Section: Moas Of Bpabsmentioning

confidence: 81%

“…Beyond the immunoglobulin fold, a biparatopic designed ankyrin repeat protein (DARPin), MP0274, highlights the potential of alternative scaffolds. 25 A comprehensive review of all bispecific formats is covered by Labrijn et al. 26 …”

Section: Biparatopic Formatsmentioning

confidence: 99%

Biparatopic antibodies: therapeutic applications and prospects

Niquille,

Fitzgerald,

Gera

2024

mAbs

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“…Notably, the wild-type PI3K signaling pathway plays a vital role in the efficacy of MP0274. [ 134 ] Trastuzumab biosimilars are biologic products sourced from living cells, showcasing comparable pharmacokinetic and pharmacological characteristics to the original reference medication. Notably, trastuzumab-dkst achieved the distinction of being the initial FDA-approved trastuzumab biosimilar.…”

Section: Drugs Targeting the Her2–akt Pathwaymentioning

confidence: 99%

HER2/PI3K/AKT pathway in HER2-positive breast cancer: A review

Pan,

Li,

et al. 2024

Medicine

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Breast cancer is currently the most commonly occurring cancer globally. Among breast cancer cases, the human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for 15% to 20% and is a crucial focus in the treatment of breast cancer. Common HER2-targeted drugs approved for treating early and/or advanced breast cancer include trastuzumab and pertuzumab, which effectively improve patient prognosis. However, despite treatment, most patients with terminal HER2-positive breast cancer ultimately suffer death from the disease due to primary or acquired drug resistance. The prevalence of aberrantly activated the protein kinase B (AKT) signaling in HER2-positive breast cancer was already observed in previous studies. It is well known that p-AKT expression is linked to an unfavorable prognosis, and the phosphatidylinositol-3-kinase (PI3K)/AKT pathway, as the most common mutated pathway in breast cancer, plays a major role in the mechanism of drug resistance. Therefore, in the current review, we summarize the molecular alterations present in HER2-positive breast cancer, elucidate the relationships between HER2 overexpression and alterations in the PI3K/AKT signaling pathway and the pathways of the alterations in breast cancer, and summarize the resistant mechanism of drugs targeting the HER2–AKT pathway, which will provide an adjunctive therapeutic rationale for subsequent resistance to directed therapy in the future.

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