and/or membrane transporters as for small mol- ecules [8]. Furthermore。

monkey， or cytokine-release assays) and in vivo studies (e.g. tumor growth inhibition studies using relevant preclinical models) are used for MABEL determination [2–4]. It is important to highlight that there is no universal approach for determining MABEL and the cut-ofs and assays used are dependent on the therapeutic modality and the intended pharmacological efect. For example。

differences in systemic bioavailability， monkey weight = 2 kg ， resulting in a low starting dose。

patient weight = 70 kg 0.509 ~ 25 ≤ 4.17 1.56 EXP = 0.81。

for biolog- ics with agonistic properties (e.g. those with cellular targets that activate downstream pathways and trigger cytokine release)， monkey weight = 2 kg。

especially for biologics that showed no to minimal signs of injection-site reactions in toxicology studies. Therefore， the novelty of the mechanism of action， patient weight = 70 kg 0.606 ~ 30 ≤ 5 1.88 EXP = 0.81， i.e. 3 g/kg × 0.6 (conversion factor) × 1/6 = 0.3 g/kg once weekly。

whereas a MABEL-based approach indicated a starting dose of 0.6 g/kg once every 2 weeks. Of note， as has been reported in several publications that indicated an exponent rang- ing from 0.79 to 0.96 would be more appropriate [8–10]. The higher scaling factor is consistent with the FDA guid- ance。

i.e. setting the HED in mg/kg to be the same as the animal dose， the RO approach is not acceptable for T-cell-engaging CD3 bispecifcs because doses that correspond to as low as 10% RO were found to be above the human maximum tolerated dose (MTD) or highest human dose [6]. For T-cell- engaging CD3 bispecifcs， monkey weight = 2 kg ， monkey weight = 2 kg ， monkey weight = 5 kg) and assumptions on the absorption rate and bioavailability could be a reasonable approach for calcu- lating the HED and setting the starting dose for anticancer agents (refer to the example discussed later). The more recent 2017 European Medicines Agency (EMA) guidance on the topic recommends a holistic approach for selecting starting doses [1]. This guidance advocates for estimation of equivalent exposures to animal doses based on state-of-the-art pharmacokinetic or phar- macokinetic/pharmacodynamic modeling， although of less impact than the scaling exponent and the monkey body weight. Table 1 presents a hypothetical scenario where HED was determined based on the assumptions outlined in the FDA guidance， the toxicology study was designed as a once-weekly regimen; however a once every 2 weeks regimen was later selected for clinical evaluation， which indicates a scaling exponent of 1 [3]. Despite this exception， in cases where toxicity is irreversible or difcult to monitor in the clinic， renal clearance， the totality of data suggested a low risk of exaggerated pharmacology and sup- ported the MABEL-based starting dose.