Model-Based Scale-up and Design Space Determination for a Batch Reactive Distillation with a Dean–Stark Trap

Batch reactive distillations are commonly used unit operations in the pharmaceutical industry to drive chemical equilibrium reactions to completion. Their scale-up and transfer to manufacturing is not straightforward due to the interplay of scale dependent and scale independent phenomena. The increased process knowledge as required by the Quality by Design (QbD) approach calls for a first-principles-based design, scale-up and transfer of such processes. This paper presents a systematic approach consisting of a combination of first principles modeling and experimentation for the scale-up from bench to pilot-plant scale. The model is then used to estimate the process performance at different scales and study the sensitivity of the process to operational parameters such as heat transfer driving force, solvent recycle, removed fraction of volatiles. This approach is capable of robustly predicting process outcomes at lab and pilot-plant scale and delivers a better understanding of the underlying physics governing the process. The model is used further to map the design space (a region in the space of operating parameters where given quality and/or performance constraints are met) taking into account both model parameter uncertainty and routine operational variability

Development of Anti-CD74 Antibody–Drug Conjugates to Target Glucocorticoids to Immune Cells

Glucocorticoids (GCs) are excellent anti-inflammatory drugs but are dose-limited by on-target toxicity. We sought to solve this problem by delivering GCs to immune cells with antibody–drug conjugates (ADCs) using antibodies containing site-specific incorporation of a non-natural amino acid, novel linker chemistry for in vitro and in vivo stability, and existing and novel glucocorticoid receptor (GR) agonists as payloads. We directed fluticasone propionate to human antigen-presenting immune cells to afford GR activation that was dependent on the targeted antigen. However, mechanism of action studies pointed to accumulation of free payload in the tissue culture supernatant as the dominant driver of activity and indeed administration of the ADC to human CD74 transgenic mice failed to activate GR target genes in splenic B cells. Suspecting dissipation of released payload, we designed an ADC bearing a novel GR agonist payload with reduced permeability which afforded cell-intrinsic activity in human B cells. Our work shows that antibody-targeting offers significant potential for rescuing existing and new dose-limited drugs outside the field of oncology

Exploration of Pyrrolobenzodiazepine (PBD)-Dimers Containing Disulfide-Based Prodrugs as Payloads for Antibody–Drug Conjugates

A number of cytotoxic pyrrolobenzodiazepine (PBD) monomers containing various disulfide-based prodrugs were evaluated for their ability to undergo activation (disulfide cleavage) <i>in vitro</i> in the presence of either glutathione (GSH) or cysteine (Cys). A good correlation was observed between <i>in vitro</i> GSH stability and <i>in vitro</i> cytotoxicity toward tumor cell lines. The prodrug-containing compounds were typically more potent against cells with relatively high intracellular GSH levels (e.g., KPL-4 cells). Several antibody–drug conjugates (ADCs) were subsequently constructed from PBD dimers that incorporated selected disulfide-based prodrugs. Such HER2 conjugates exhibited potent antiproliferation activity against KPL-4 cells <i>in vitro</i> in an antigen-dependent manner. However, the disulfide prodrugs contained in the majority of such entities were surprisingly unstable toward whole blood from various species. One HER2-targeting conjugate that contained a thiophenol-derived disulfide prodrug was an exception to this stability trend. It exhibited potent activity in a KPL-4 <i>in vivo</i> efficacy model that was approximately three-fold weaker than that displayed by the corresponding parent ADC. The same prodrug-containing conjugate demonstrated a three-fold improvement in mouse tolerability properties <i>in vivo</i> relative to the parent ADC, which did not contain the prodrug