Fig 1.
Overview of the bystander effect and the models.
A) ADC mechanism of action and bystander effect. B) Cell growth dynamics in models: 1) One-Cell Type Model: represents a cancer-targeting ADC directed at a tumor with homogeneous target expression among cancer cells. 2) Independent Growth Bystander Model: represents a cancer-targeting ADC aimed at a tumor with heterogeneous target expression among cancer cells. 3) Recruitment Bystander Model: represents a stroma-targeting ADC, where the target is only expressed by stromal cells and not by cancer cells. C) Overview of the Independent Growth Bystander Model. Note that the One-Cell Model does not include Ag- cells (S1 Fig). The Recruitment Bystander Model differs from the Independent Growth Bystander Model only in cell growth dynamics, where the growth of Ag+ cells depends on the Ag- cells (S2 Fig). A: ADC, E: extracellular payload, T: target antigen, AT: singly-bound ADC, AT2: doubly bound ADC, Aint: internalized ADC, I: intracellular payload in Ag+ cells, I-: intracellular payload in Ag- cells, P: permeability of the payload across the cell membrane, green circles: Ag+ stromal cells, orange circles: Ag- cancer cells, nc/nc,-: cycling Ag + /Ag- cells, nci/nci,-: damaged Ag + /Ag- cells, i = 2,3,4. Functions f(I) and f(I-) denote sigmoidal functions of the intracellular payload per cell (see Supplementary). Subscripts ce/pe denote the species in the Central/Peripheral compartments and the subscript con denotes concentration. All terms and rates are described in detail in Tables A–C in S1 Text.
Fig 2.
Comparison of cell growth and intracellular payload concentrations.
A) One-Cell Type Model. Tumor shrinks. B) Independent Growth Bystander Model. Tumor eventually grows across all tested initial Ag-:Ag+ ratios. C) Recruitment Bystander Model. Durable tumor suppression can be achieved when the initial percentage of Ag+ cells is sufficiently high. D) Intracellular payload concentrations are higher in Ag+ cells compared to Ag- cells.
Fig 3.
Effect of payload membrane permeability on ADC efficacy.
A) One-Cell Type Model. As payload membrane permeability increases, ADC efficacy decreases. B) Independent Growth Bystander Model. C) Recruitment Bystander Model. In both B) and C), payload membrane permeability is varied for both Ag+ and Ag- cells. For bystander models, as payload permeability increases, the ADC efficacy increases. Note that payload permeability may have an optimal value for a different set of parameters or time points (see S4D Fig).
Fig 4.
Effect of linker stability on ADC efficacy.
A) One-Cell Type Model. B) Independent Growth Bystander Model. C) Recruitment Bystander Model. In all models, a decrease in linker stability, i.e., an increase in deconjugation rate, initially enhances efficacy but eventually reduces it. This effect is more pronounced in the bystander models.
Fig 5.
Effect of incorporating avidity into the models.
Selected simulations from Fig 2 are repeated without including avidity in the model.