Safety assessment and dose selection for first-in-human clinical trials with immunomodulatory monoclonal antibodies.

Modulating immune responses with monoclonal antibodies (mAbs) that target immune molecules has become a promising therapeutic strategy and is under investigation for the treatment of cancer and (auto)-immune diseases. A major hurdle to the development and early clinical investigation of many immunomodulatory mAbs is the inherent risk of adverse immune-mediated drug reactions in humans, such as cytokine storms, autoimmunity, and immunosuppression. Dose selection for first-in-human (FIH) clinical trials involving immunomodulatory mAbs, and mAbs in general, is based on specifically designed preclinical safety studies, primarily in nonhuman primates (NHPs), and on mechanistic ex vivo investigations. Dose selection in such trials is challenging for a number of reasons related to safety. In this context, safety-relevant differences between NHP and human immune systems, species selection/qualification and preclinical study design considerations, the receptor occupancy model and its calculation, the minimal anticipated biological effect level (MABEL) and its use in the selection of a safe starting dose in humans, microdosing and the impact of immunogenicity on safety assessment of mAbs, and safety-relevant formulation properties of therapeutic mAbs are critically reviewed. In addition, the current regulatory requirements are presented and discussed to demonstrate how the TeGenero TGN1412 case is leading to increased regulatory scrutiny regarding dose selection for FIH clinical trials.

[Recurrence or persistence of an osteoid osteoma: a case report]. / Redicive ou persistance d'un ostéome ostéoïde: une observation.

Recurrence of an osteoid osteoma treated by complete excision is thought to be very rare. Persistence of the lesion and reappearance of clinical and radiological signs have a more frequent occurrence, and are due to inadequate resection. Our case appears to be a true recurrence. It required no less than four operations first of these was probably not extensive enough. The second consisted of curettage of the osteoid osteoma after it had been exposed by abrasion of its cortical bone covering. The third and fourth resections were carried out under bone scan guidance and were controlled by postoperative radiography and computerised tomography. The uncertain aetiology of osteoid osteoma is one factor in the mysteriousness of this serial recurrence of what was apparently an ordinary osteoid osteoma. Such recurrence might be explained by an unknown persisting pathological environment.