Background Antibody drug conjugates (ADCs) utilize a monoclonal antibody to deliver a cytotoxic payload specifically to tumor cells, limiting exposure to healthy tissues. Major clinical toxicities of ADCs include hematologic, hepatic, neurologic, and ophthalmic events, which are often dose-limiting. These events may be off-target effects caused by premature release of payload in circulation. A meta-analysis was performed to summarize key clinical safety data for ADCs by payload, and data permitting, establish a dose-response model for toxicity incidence as a function of payload, dose/regimen, and cancer type. Methods A literature search was performed to identify and extract data from clinical ADC studies. Toxicity incidence and severity were collected by treatment arm for anemia, neutropenia, thrombocytopenia, leukopenia, hepatic toxicity, peripheral neuropathy, and ocular toxicity. Exploratory plots, descriptive summaries, and logistic regression modelling were used to explore Grade ≥ 3 (G3/4) toxicities and assess the impact of covariates, including cancer type and dose/regimen. Results The dataset contained 70 publications; quantitative analysis included 43 studies with G3/4 toxicity information reported for the endpoints above. G3/4 anemia, neutropenia and peripheral neuropathy were consistently reported for MMAE ADCs, thrombocytopenia and hepatic toxicity for DM1, and ocular toxicity for MMAF. Safety profiles of MMAE, DM1, and DM4 ADCs differed between solid and hematologic cancers. Conclusions Published ADC clinical data is limited by non-uniform reporting for toxicity and lack of dosing information, limiting the ability to develop quantitative models relating toxicity to exposure. However, the current analysis suggests that key G3/4 toxicities of ADCs in the clinic are likely off-target and related to payload.

The bronchopulmonary and plasma pharmacokinetics of clarithromycin (CLA; 500 mg given twice daily for nine doses) or azithromycin (AZ; 500 mg for the first dose and then 250 mg once daily for four doses) were assessed in 41 healthy nonsmokers. Bronchoalveolar lavage was performed at 4, 8, 12, or 24 h after administration of the last dose. The concentrations (mean +/- standard deviation) of CLA, 14-hydroxyclarithromycin, and AZ were measured in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) cells by high-performance liquid chromatography assay. The concentrations of CLA achieved in ELF were 34.02 +/- 5.16 micrograms/ml at 4 h, 20.63 +/- 4.49 micrograms/ml at 8 h, 23.01 +/- 11.9 micrograms/ml at 12 h, and 4.17 +/- 0.29 microgram/ml at 24 h, whereas at the same time points AZ concentrations remained below the limit of assay sensitivity (0.01 microgram/ml) for all but two subjects. The concentrations of CLA in the AM cells were significantly higher than those of AZ at 8 h (703 +/- 235 and 388 +/- 53 micrograms/ml, respectively). However, the ratio of the concentration in AM cells/concentration in plasma was significantly higher for AZ than for CLA for all time points because of the lower concentration of AZ in plasma. These results indicate that while AZ has higher tissue concentration to plasma ratios, as shown by other investigators, the absolute concentrations of CLA in AM cells and ELF are higher for up to 8 and 12 h, respectively, after administration of the last dose.

The pharmacodynamic profile of clarithromycin (CLR) was evaluated with a murine model of pneumonia. Eight Streptococcus pneumoniae isolates, including three macrolide-sensitive and five macrolide-resistant strains, were inoculated intratracheally into immunocompromised ICR mice as 10 8 -CFU bacterial suspensions. Orally administered CLR daily doses ranging from 5 to 600 mg/kg of body weight were given over 5 days, during which animal survival was monitored. The bacterial density in lung tissues was examined after 24 h of CLR treatment and in control groups. Pharmacokinetic analysis of CLR in mice demonstrated that the regimen of 150 mg/kg twice a day was representative of human pharmacokinetics and was used to compare the efficacy of CLR against sensitive and resistant S. pneumoniae strains. Immunocompetent CBA/J mice were also infected and treated as described above and evaluated for bacterial density and survival to assess the effect of the presence of leukocytes. All three pharmacodynamic parameters, the duration (percent) of the time that serum CLR concentrations remain above the MIC (%T>MIC), the ratio of the area under the concentrationtime curve from 0 to 24 h (AUC 0-24 ) to the MIC, and the ratio of the maximum concentration of drug in serum to the MIC, were found to be closely correlated to CLR bacterial efficacy (P < 0.001). Furthermore, all parameters had close correlation to bacterial density (r 2 ‫؍‬ 0.72 to 0.82), median survival (r 2 ‫؍‬ 0.93 to 0.94), and total percent survival (r 2 ‫؍‬ 0.91 to 0.92). These in vivo data suggest that the bacterial activity of CLR is closely correlated with all three parameters over a wide range of exposures and, as a consequence of parameter interdependency, AUC 0-24 /MIC is the most reasonable predictor of antibiotic efficacy. In this neutropenic pneumonia model, CLR was less efficacious against S. pneumoniae strains for which MICs were >4 g/ml. However, the presence of leukocytes in the immunocompetent mice resulted in improved bactericidal activity, relative to that in the neutropenic animals, despite an MIC of 4 g/ml.

T‐cell–engaging bispecific antibodies (T‐BsAbs) are an important class of antibody therapeutics in immuno‐oncology. T‐BsAbs simultaneously bind to CD3 on T cells and a tumor‐associated antigen on tumor cells, activate T cells, and redirect T cells’ cytotoxicity against tumor cells. Cytokine release syndrome (CRS), a common dose‐limiting adverse event for T‐BsAbs, is associated with T‐cell activation. A “priming” dose strategy (i.e., a lower initial dose followed by a higher maintenance dose) has been implemented in the clinic to mitigate CRS and to achieve efficacious doses with T‐BsAbs. So far, the selection of the optimal priming dosing regimen is largely empirical. A “fit‐for‐purpose” semimechanistic pharmacokinetic/pharmacodynamic model was developed to characterize the cytokine release profiles upon T‐BsAb treatment, including the priming effect observed with repeated dosing. This model can be utilized to simulate cytokine profiles following various dosing regimens and may assist the design of clinical dosing strategies for T‐BsAbs programs.

A bispecific immunomodulatory biotherapeutic molecule (P-cadherin LP-DART) based on the Dual Affinity Re-Targeting (DART) scaffold has been developed as a potential antitumor treatment showing efficacy in preclinical testing. A minimal anticipated biological effect level (MABEL) approach was applied to project the first-in-human (FIH) dose, because of its immune agonistic properties following target engagement. The pharmacological activity of P-cadherin LP-DART is driven by binding to both P-cadherin on the tumor cells and CD3 on T cells. Therefore, the concentration of the tri-molecular synapse formed between drug, T cell, and tumor cell, rather than drug concentration, is responsible for efficacy. A mechanistic pharmacokinetic/pharmacodynamic (PK/PD)-driven approach was explored to understand the exposure-response relationship based on the synapse concentration to project the MABEL dose. Orthogonal approaches including PK-driven and receptor occupancy calculations were also investigated. This study showcases the application of PK/PD modeling in immune-oncology, and could potentially be implemented for other bispecific biotherapeutics.