Why is there no biosimilar of Erbitux®?

Monoclonal antibody (mAb)-based therapies have been a major advance in oncology patient care, even though they represent a significant healthcare cost. Biosimilars, launched in Europe in 2004 are an economically attractive alternative to expensive originator biological drugs. They also increase the competitiveness of pharmaceutical development. This article focuses on the case of Erbitux® (cetuximab). This anti-EGFR (Epidermal Growth Factor Receptor) monoclonal antibody is indicated for metastatic colorectal cancer (2004) and squamous cell carcinoma of the head and neck (2006). However, despite the expiration of the patent in Europe in 2014 and estimated annual sales of 1.681 million US dollars in 2022, Erbitux® has not yet faced any approved biosimilar challenges in the United States or in Europe. Here, we outline the unique structural complexity of this antibody highlighted by advanced orthogonal analytical characterization strategies resulting in risks to demonstrate biosimilarity, which may explain the lack of Erbitux® biosimilars in the European and US markets to date. The development of Erbitux® biobetters are also discussed as alternative strategies to biosimilars. These biologics offer expected additional safety and potency benefits over the reference product but require a full pharmaceutical and clinical development as for New Molecular Entities

Influence of Renal Function and Age on the Pharmacokinetics of Levofloxacin in Patients with Bone and Joint Infections

Despite its efficacy and toxicity being exposure-related, levofloxacin pharmacokinetics in patients with bone and joint infections has been poorly described to date, so the possible need for a dose adjustment is unknown in this population. A prospective population pharmacokinetic study was conducted in 59 patients to answer this question. The final model consisted of a one-compartment model with first-order absorption and elimination. Mean parameter estimates (% interindividual variability) were 0.895 h−1 for the absorption rate constant (Ka), 6.10 L/h (40%) for the apparent clearance (CL/F), 90.6 L (25%) for the apparent distribution volume (V/F). Age and glomerular filtration rate (GFR), estimated by the modification of diet in renal disease formula, were related to CL/F by power models, and CL/F was found to increase for increasing GFR and decreasing age. For a similar GFR, the simulated area under the curve (AUC) was 55% higher in 70 years-old patients compared to 30 year-old patients. Based on this model, a 750 mg dose should provide an optimal exposure (AUC/ minimum inhibitory concentration (MIC) ≥100), with the possible exception of patients older than 60 years and with GFR <70 mL/min/m² who may necessitate a dose reduction, and patients with infections caused by bacteria with MIC close to 1 mg/L who may need an increase in the dose

Dual intra- and extracellular release of monomethyl auristatin E from a neutrophil elastase-sensitive antibody-drug conjugate

International audienceAntibody-drug conjugates (ADCs) are targeted therapies, mainly used in oncology, consisting in a three-component molecular architecture combining a highly potent drug conjugated via a linker onto a monoclonal antibody (mAb), designed for the selective delivery of the drug to the tumor site. The linker is a key component, defining the ADC stability and mechanism of action, and particularly the drug release strategy. In this study, we have developed and synthesized a cleavable linker, which possesses an Asn-Pro-Val (NPV) sequence sensitive to the human neutrophil elastase (HNE), overexpressed in the tumor microenvironment. This linker permitted the site-specific conjugation of the cell-permeable drug, monomethyl auristatin E (MMAE), onto trastuzumab, using a disulfide re-bridging technology. The resulting ADC was then evaluated in vitro. This conjugate demonstrated retained antigen (Ag) binding affinity and exhibited high subnanomolar potency against Ag-positive tumor cells after internalization, suggesting an intracellular mechanism of linker cleavage. While no internalization and cytotoxic activity of this ADC was observed on Ag-negative cells in classical conditions, the supplementation of exogenous HNE permitted to restore a nanomolar activity on these cells, suggesting an extracellular mechanism of drug release in these conditions. This in vitro proof of concept tends to prove that the NPV sequence could allow a dual intra- and extracellular mechanism of drug release. This work represents a first step in the design of original ADCs with a new dual intra- and extracellular drug delivery system and opens the way to further experimentations to evaluate their full potential in vivo

Branched pegylated linker-auristatin to control hydrophobicity for the production of homogeneous minibody-drug conjugate against HER2-positive breast cancer

International audienceTrastuzumab emtansine (Kadcyla®) was the first antibody-drug conjugate (ADC) approved by the Food and DrugAdministration in 2013 against a solid tumor, and the first ADC to treat human epidermal growth factor receptor2 positive (HER2+) breast cancer. However, this second generation ADC is burden by several limitationsincluded heterogeneity, limited activity against heterogeneous tumor (regarding antigen expression) and suboptimaltumor penetration. To address this, different development strategies are oriented towards homogeneousconjugation, new drugs, optimized linkers and/or smaller antibody formats. To reach better developed nextgeneration ADCs, a key parameter to consider is the management of the hydrophobicity associated with thelinker-drug, increasing with and limiting the drug-to-antibody ratio (DAR) of the ADC. Here, an innovativebranched pegylated linker was developed, to control the hydrophobicity of the monomethyl auristatin E (MMAE)and its cathepsin B-sensitive trigger. This branched pegylated linker-MMAE was then used for the efficientgeneration of internalizing homogeneous ADC of DAR 8 and minibody-drug conjugate of DAR 4, targeting HER2.Both immunoconjugates were then evaluated in vitro and in vivo on breast cancer models. Interestingly, this studyhighlighted that the minibody-MMAE conjugate of DAR 4 was the best immunoconjugate regarding in vitrocellular internalization and cytotoxicity, gamma imaging, ex vivo biodistribution profile in mice and efficientreduction of tumor size in vivo. These results are very promising and encourage us to explore further fragmentdrugconjugate development