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We characterized the elastase and antielastase activity of the alveolar fluid of seven patients with the adult respiratory distress syndrome (ARDS) and thirteen normal volunteers. Alpha-l-antitrypsin (AlAT) concentrations were 60-fold higher in ARDS as compared to normal lavage fluid (2,140±498 nM; 36.1±4.2 nM, respectively). ARDS fluid antineutrophil elastase activity was also considerably higher than that of normals (979±204 nM; 31.3±2.9 nM, respectively). Despite the antineutrophil elastase excess, 5 of 7 ARDS lavage samples contained elastase activity (mean, 6.1±2.4 pM) as assayed using low-molecular-mass substrate, while only 1 of 13 normal subjects had detectable elastase activity (0.2 pM) (P < 0.01, compared with ARDS). That this activity was due to alpha-2-macroglobulin (A2MG)-complexed neutrophil elastase was evidenced by (a) the Sephadex G-75 elution profile; (b) the inactivity against insoluble VHielastin; (c) the inhibitory profile with phenylmethylsulfonyl fluoride, methoxy-succinyl-alanyl-alanyl-prolyl-valyl-chloromethylketone, ethylene diamine tetraacetic acid, and AlAT; and (d) the immobilization by A2MG antibody bound to polystyrene plates. Furthermore, in agreement with the predicted affinity of AMAT and A2MG for neutrophil elastase, the ratio of A2MG to AMAT in the fluid (0.57%) coincided with the ratio of the A2MG-to AlAT-complexed elastase (0.36%). These findings suggest that the net lung protease-antiprotease balance in ARDS is shifted largely in favor of the antiproteases (chiefly AMAT), and that the antiproteases, AMAT and A2MG, have similar affinities for neutrophil elastase in vivo.

This report discusses the principles of reproductive toxicity risk assessment for biopharmaceuticals blocking the PD-1/programmed cell death ligand 1 (PD-L1) pathway, which have been developed for the treatment of patients with advanced malignancies. The PD-1/PD-L1 pathway is a T-cell co-inhibitory pathway that normally maintains immune tolerance to self. Its role in pregnancy is to maintain immune tolerance to the fetal allograft. In cancer patients, this signaling pathway is hijacked by some neoplasms to avoid immune destruction. PD-1/PD-L1-blocking agents enhance functional activity of the target lymphocytes to eventually cause immune rejection of the tumor. A therapeutic blockade of PD-1/PD-L1 pathway that occurs at full target engagement provides a unique challenge to address the risk to pregnancy because disruption of the same pathway may also reduce or abrogate maternal immune tolerance to the fetal alloantigens inherited through the father. Typically, nonclinical reproductive and developmental toxicity (DART) studies in animals (rats and rabbits) with clinical drug candidates are conducted to identify potential risk in humans and to determine exposure margin for the effects on reproduction as part of the risk assessment. However, for biopharmaceuticals for which the desired mechanism of action cannot be separated from potential deleterious effects to the fetus and when the only relevant toxicology species is nonhuman primate (NHP), the risk to reproduction can be predicted by a mechanism-based assessment using data generated from murine surrogate models as supportive information without conducting DART in NHPs. Such an approach has been used in the evaluation of pregnancy risk of anti-PD-1 agent, pembrolizumab, and has been demonstrated as an important alternative to performing DART studies in NHPs.

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