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Identification of a peptide-peptide binding motif in the coating of nab-paclitaxel nanoparticles with clinical antibodies: bevacizumab, rituximab, and trastuzumab.

ABSTRACT: Antibody directed chemotherapy (ADC) takes advantage of the selectivity of the monoclonal antibody to increase the efficacy of the chemotherapeutic agent, while reducing toxicity. Previously we described three nab-paclitaxel (Abraxane) nanoparticles coated with commercial monoclonal antibodies. Identifying the binding sites responsible for these particles could allow reverse engineering of nab-paclitaxel binding antibodies, creating a modular platform for antibody directed chemotherapeutic nanoparticles. Herein, Biacore surface plasmon resonance is used to identify an antibody binding site, HSA Peptide 40, on human serum albumin with nanomolar affinity for all three monoclonal antibodies. This 18-mer peptide, which lies in Subdomain IIIA of human serum albumin, blocks binding of all three antibodies to nab-paclitaxel when added in excess. We furthermore show the complementary binding region on all three monoclonal antibodies to be the CDR H3 loop of the Fab region, and show that they all have nano to micromolar affinity for HSA Peptide 40 and nab-paclitaxel nanoparticles. The presented data identify the nature of the critical protein-protein interaction that enables antibody coating of nab-paclitaxel.

SUBMITTER: Butterfield JT

PROVIDER: S-EPMC5670201 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Identification of a peptide-peptide binding motif in the coating of nab-paclitaxel nanoparticles with clinical antibodies: bevacizumab, rituximab, and trastuzumab.

Butterfield John T JT Kim Hidong H Knauer Daniel J DJ Nevala Wendy K WK Markovic Svetomir N SN

Scientific reports 20171103 1

Antibody directed chemotherapy (ADC) takes advantage of the selectivity of the monoclonal antibody to increase the efficacy of the chemotherapeutic agent, while reducing toxicity. Previously we described three nab-paclitaxel (Abraxane) nanoparticles coated with commercial monoclonal antibodies. Identifying the binding sites responsible for these particles could allow reverse engineering of nab-paclitaxel binding antibodies, creating a modular platform for antibody directed chemotherapeutic nanop ...[more]

PMID: 29101359

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Project description:BackgroundThe anti-tumor activity and acceptable tolerability of pyrotinib plus chemotherapy have been demonstrated in phase III trials in human epidermal growth factor receptor 2-positive metastatic breast cancer (BC). In this study, we assessed the efficacy and safety of neoadjuvant pyrotinib plus trastuzumab and albumin-bound paclitaxel in women with human epidermal growth factor receptor 2-positive early or locally advanced BC.MethodsIn this single-arm exploratory phase II trial, patients with untreated human epidermal growth factor receptor 2-positive BC (stage IIA-IIIC) received pyrotinib 400 mg once daily, trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg once a week, and albumin-bound paclitaxel 125 mg/m2 once a week for four 21-day cycles before surgery. The primary endpoint of the study was total pathological complete response (pCR) rate, defined as no microscopic invasive tumor remnants in the breast and axillary lymph nodes. The secondary endpoints were investigator-assessed objective response rate (ORR) and adverse event profiles.ResultsBetween May 17, 2019 and November 26, 2019, a total of 21 patients were enrolled. The total pCR rate was 57.1% (12/21), whereas 23.8% (5/21) and 19.0% (4/21) of patients had minimal and moderate residual disease (RD), respectively. The ORR reached 100% (21/21) at the end of the neoadjuvant therapy. Grade ≥3 treatment-related adverse events were observed in 42.9% (9/21) of patients, including decreased neutrophil count [7 (33.3%)], diarrhoea [6 (28.6%)], decreased white blood cell count [5 (23.8%)], and vomiting [2 (9.5%)]. Adverse event-related dose reduction and interruption of pyrotinib occurred in 6 (28.6%) and 11 (52.4%) patients, respectively.ConclusionsIn women with human epidermal growth factor receptor 2-positive early or locally advanced BC, neoadjuvant pyrotinib plus trastuzumab and albumin-bound paclitaxel effectively promoted total pCR rate with an acceptable safety profile (ClinicalTrials.gov, NCT04152057).

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Dataset Information

Identification of a peptide-peptide binding motif in the coating of nab-paclitaxel nanoparticles with clinical antibodies: bevacizumab, rituximab, and trastuzumab.

Publications

Identification of a peptide-peptide binding motif in the coating of nab-paclitaxel nanoparticles with clinical antibodies: bevacizumab, rituximab, and trastuzumab.

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