A simple algebraic expression can determine if a drug’s clearance is non-specific or target-mediated

T-cell engagers (TCEs) and other immune engagers have seen increasing interest as oncolytic drugs in recent years, with several now approved and on the market for haematological and solid tumour indications [ 1 , 2 ]. TCEs are antibodies or other biologic molecules that are bispecific for a receptor on T-cells (such as CD3) and for a target receptor – in oncology, a tumour-associated antigen (TAA) – such as CD20. The clearance and half-lives of monoclonal antibodies are typically determined by FcRn recycling and non-specific degradation (hereafter referred to as “intrinsic clearance”), the rate of which depends on bodyweight and can be scaled allometrically between species. An example of a therapeutic use for monoclonal antibodies is to competitively block binding by another molecule to a receptor or to mark every cell that expresses that receptor for attack by the innate immune system. In this scenario, sufficiently high dosages of the antibody are given that the target is saturated and the pharmacokinetics (PK) of the free antibody is a monoexponential decay (which is a straight line on a log-scaled plot), dependent on intrinsic clearance. At low serum concentrations, target-mediated drug distribution (TMDD) becomes important, which may extend the antibody’s half-life as it is shielded from clearance, or may reduce it as the receptor turns over and destroys the bound antibody. The result of this is a characteristic interruption of the monoexponential clearance at low concentrations. TCEs are often given at low dosages, as immune-related toxic side effects such as cytokine release syndrome become more probable as dosages increase. In this scenario, it is not guaranteed that TMDD can be outdosed and so the pharmacokinetic properties of TCEs depend on their interactions with receptors on cells of the immune system. When a typical immune engager is dosed into an immunocompromised mouse, they usually exhibit antibody-like half-lives of several days, but this usually drops to an order of hours if T-cells are introduced to the animal (for example [ 3 ]), because of the turnover rates of the receptors that the engager binds to. How these interactions differ between species is essential to determine how an immune engaging drug will clear in different species, and the simple allometric (bodyweight-dependent) scaling of intrinsic clearance may not apply. The typical monoexponential PK seen for a molecule cleared intrinsically is also commonly observed for TCEs doses at low concentrations where TMDD would be expected. In order to choose the correct method to scale the PK of TCEs between species, understanding which processes are responsible for their clearance at pharmacologically active concentrations is critical.