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The colony-stimulating factor-1 (CSF-1) receptor pathway has been implicated in a variety of diseases, and CSF-1-dependent mechanisms are also involved in bloodborne protein clearance.Lacnotuzumab is a novel, high-affinity, humanized, anti-CSF-1 monoclonal antibody that prevents CSF-1 mediated receptor activation. This phase 1, two-part, double-blind study in healthy volunteers assessed the safety and tolerability of lacnotuzumab and its pharmacokinetics (PK) and pharmacodynamic properties. Part A (n = 36) was a single, ascending-dose assessment of eight lacnotuzumab doses (0.01-20 mg/kg); in part B (n = 16), lacnotuzumab was administered at either 5 or 10 mg/kg. In each study cohort, individuals were randomized 3:1 to lacnotuzumab or placebo. Lacnotuzumab was generally well tolerated. At higher doses (10 and 20 mg/kg), creatine kinase (CK) elevations (>5× the upper limit of normal, but asymptomatic and reversible) and mild transient periorbital swelling were reported. The majority of adverse events (AEs) were low grade, no unexpected or novel AEs were observed, and there were no discontinuations for AEs. Free/unbound lacnotuzumab serum concentration-time profiles showed nonlinear PK across doses from 0.01 to 20 mg/kg, with faster apparent elimination at lower doses or concentrations; this was consistent with apparent target-mediated drug disposition. Lacnotuzumab also showed dose-dependent, on-target effects on multiple downstream biomarkers. Preclinical investigations of the CK elevation and periorbital swelling observed after lacnotuzumab administration suggest that these are reversible, nonpathological events linked to inhibition of the CSF-1 pathway. These data support further evaluation of lacnotuzumab in clinical studies.

Background Monoclonal antibodies (mAbs) comprise a large and important class of therapeutic biologicals with the potential for treatment of a wide range of clinical indications. Secukinumab (AIN457) is a new fully human mAb targeting IL-17A for the treatment of inflammatory diseases. Administration of mAbs can be associated with immunogenicity via the induction of anti-drug antibodies (ADAs). ADAs can lead to unwanted clinical consequences, such as loss of exposure, loss of efficacy due to altered pharmacokinetics and/or functional neutralization and, in the worst case, anaphylactic reaction and immune complex diseases. The assessment of ADA formation is therefore a critical component in the assessment of biotherapeutic safety. Methods The immunogenicity assessment strategy for secukinumab follows a three-tiered approach. First, samples are analyzed for presence of ADA in a screening assay which takes a 5% false-positive rate into account. In a second step, screening assay positive samples are tested in a confirmatory assay (competition with excess drug) that identifies true positive responses. Finally, true immunogenicity-positive samples are quasi-quantified via titration. In addition, pharmacokinetics and clinical efficacy/safety data are also evaluated. A Biacore-based assay was used during the early stages of the secukinumab program (up to phase 2B), and an MSD-based bridging assay was applied during the later stages of the program (proof-of-concept, phase 2B, phase 3). The MSD assay is able to detect 4 ng/mL of a positive control anti-secukinumab antibody and can detect 500 ng/mL of this positive control in the presence of 14.7 µg/mL secukinumab, consistent with current regulatory guidelines. Samples to assess immunogenicity were obtained from individual subjects encompassing 18 clinical studies in different indications during treatment and during follow-up. So far, 1582 subjects have been tested for ADAs, of which 486 have been tested with the MSD assay. Dosing regimens included single doses such as 25 mg subcutaneously in psoriasis patients as well as multiple 7 x 10 mg/kg doses intravenously in MS patients over a six-month period. Results None of the subjects tested for immunogenicity developed sustained ADAs. In total, 4 subjects met the definition of treatment-related, transient positive immunogenicity showing low ADA titers. None of these subjects had evidence of loss of efficacy, deviating PK behavior, or reported anaphylactic reaction or immune complex disease. Conclusions Based on the available data, secukinumab appears to carry a low risk of immunogenicity. In the very few transient immunogenicity-positive patients identified so far, there has been no indication of altered pharmacokinetics or loss of efficacy, and no adverse event that could be linked to immunogenicity has been detected. More data from the ongoing phase 3 studies are required to strengthen this encouraging finding in a larger patient population. Disclosure of Interest U. Klein Employee of: Novartis, E. Liang Employee of: ...

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