Dados do Trabalho

Título

DOUBLE-BINDING AND EFFECTOR ACTIVITY OF TRASTUZUMAB-DKST BIOSIMILAR COMPARED TO ORIGINATOR TRASTUZUMAB IN COMBINATION WITH PERTUZUMAB IN HER2-POSITIVE BREAST CANCER CELL LINES

Introdução

Trastuzumab and pertuzumab bind to HER2 synergistically, in different subdomains (IV and II, respectively), improving the clinical benefit of breast cancer treatment. Recently, biosimilars of trastuzumab have been approved worldwide after comparison with the originator, proving high similarity in structure and activity, and equivalent efficacy, safety and immunogenicity.

Objetivo

This study aimed to evaluate mechanisms of synergistic action of trastuzumab and pertuzumab related to biological potency: binding assay and antibody-dependent cell-mediated cytotoxicity (ADCC) elicited by biosimilar trastuzumab compared to originator trastuzumab, alone or in combination with pertuzumab.

Método

Human breast cancer cell lines BT474 (HER2+/estrogen (ER) and progesterone receptor (PR)-positive) and HCC1954 (HER2+/ER and PR-negative) were used. Anti-HER2 antibodies: TZB (trastuzumab 440mg, Roche, batch:N7194B11-B3064); BS-TZB (biosimilar of trastuzumab 440mg, Libbs/Biocon (trastuzumab-dkst), b:18F0072) and PTZ (pertuzumab 420mg, Roche, b:H0260B01) were commercially acquired. Fluorescent labeling of TZB and BS-TZB with Alexa 488 and PTZ with Alexa 647; FACS-based antigen binding evaluations and live cell imaging were performed (TZB or BS-TZB, and PTZ at concentrations of: 0; 10; 100; 1,000 ng/mL in every combinations). Predefined acceptance criteria for ligand-binding assay (LBA) was ±20% (25% at lower limit of quantification - LLOQ).
ADCC assay: cells were incubated with TZB or BS-TZB, with/without PTZ. To determine the cytotoxicity percentage it was measured the LDH activity using the CytoTox-ONE.

Resultado

Mean percentage of BT474 cells with double bind to BS-TZB or TZB at 1,000 ng/mL, and PTZ at 100 ng/mL were 70%±0.3 and 73%±0.3, respectively, 90% CI DBM (difference between means, TZB-BS – TZB) was -4.5% to -3.4%. Double bind to BS-TZB or TZB, and PTZ in HCC1954 cells were 94%±0.3 and 88%±0.1, 90% CI DBM: 5.8% to 6.4%.
ADCC activity of BS-TZB was non-inferior than that of TZB in both cell lines. Combined with PTZ, BS-TZB showed slightly higher ADCC activity than TZB (EC50(ug/mL): 0.90 and 1.15, for BT474; 0.13 and 0.19, for HCC1954).

Conclusão

In association with pertuzumab, trastuzumab biosimilar compared to originator trastuzumab showed equivalent binding potency and non-inferior effector activity (ADCC assay). This study explored mechanisms elicited by dual HER2 blockade, showing the same pattern of response for BS-TZB as well as TZB, combined with PTZ, in two HER2-positive breast cancer cell lines.

Palavras-chave

biodrugs, targeted therapy, biological drug