Schropp2019 - Target-Mediated Drug Disposition Model for Bispecific Antibodies.

October 2019, the model of the month by Johannes Meyer
Original model: BIOMD0000000788

Background

Bispecific antibodies (BsAbs) are artificial proteins that are capable of recognizing and binding to two different epitopes [1]. This dual specificity confers several advantages over conventional monoclonal antibodies: the ability to direct a specific cell-mediated immune response against tumour cells to enhance tumour cell killing, simultaneous inhibition of two different mediators or pathways that carry out distinct or common functions in pathogenesis, and increased specificity due to the recognition of an additional cell-surface antigen [2]. Various BsAbs are currently in development for treating diseases such as haemophilia [3], Alzheimer’s disease [4], and the Ebola virus [5].

A distinguishing characteristic of BsAbs is that their pharmacodynamics are governed by the activity of a ternary complex (TC). The TC is a product of a series of binding events where the BsAb first binds to one of its two specific targets, thereby forming a binary complex (BC), whereupon the BC binds the remaining target to form the TC. The binding dynamics of the BsAbs and subsequent complexes are an example of target-driven pharmacokinetics, and can be described mathematically using a target-mediated drug disposition (TMDD) model. Schropp et al. [6] have published a study presenting one such TMDD model within the context of immuno-oncology, where a BsAb molecule binds to two different targets located on the membrane of two different cells. The model was constructed with the goal of discerning optimal BsAb dosing strategies that would lead to the most rapid formation and sustained maintenance of maximal TC concentrations.

Model

Figure 1

Figure 1. Structure of the model. Reproduced from [6]

The model presented by Schropp et al. consists of six species: the BsAb molecule, two targets (here defined as receptors), two BCs, and the final TC (Fig. 1). Turnover of these species is described by four binding events, as well as synthesis, internalization and degradation reactions. The final model is a quasi-equilibrium (QE) approximation constructed on the fundamental assumption that all four binding events are characterized by effectively instantaneous rapid binding. It was also assumed that the total target concentration remains constant. These assumptions allowed a number of unknown and difficult to measure parameters from the original full bispecific TMDD model to be eliminated, thereby yielding the reduced QE approximation model capable of overcoming these practical constraints.

Results

The reduced QE model was used to reveal which properties of the model could be used to optimise potential BsAb therapy. Schropp et al. found that the optimum dosage of BsAb is one that yields a total antibody concentration lying between the minimum and maximum concentrations of both target receptors (Fig. 2). Within this dosing range, the maximum concentration of TC is produced. It was demonstrated that, in contrast to more conventional concentration-effect terms, that the maximum concentration of TC achieved can be lowered by exceedingly high BsAb doses, a finding that has been previously observed experimentally [7].

Figure 2

Figure 2. The maximum TC concentration achieved as a function of BsAb dose (left), the timecourses for total BsAb concentration (middle) and TC concentration (right) with repeated dosing. Note the maintenance of the BsAb concentration within the optimum range (left, x-axis; middle, y-axis) to sustain the highest possible TC concentration (right, y-axis). Initial concentrations for RA and RB are 101 and 102, respectively. Adapted from [6]

This behaviour is caused by cross-linking reactions: a BC requires a free, unoccupied receptor to bind with to create the TC. Higher doses of BsAb thus interfere with the formation of the TC by reducing the free, unbound receptor pool. Furthermore, the time taken to build up to and achieve the maximum TC dose was found to increase for larger BsAb dosages (demonstrated in Fig. 3 to be a delay of up to several weeks depending on the magnitude of the dose). The combination of these findings enabled a hypothetical treatment regimen to be constructed that produced a maximum TC concentration with the least delay, and maintained this concentration with optimally timed repeated dosing.

Figure 3

Figure 3. Effect of increasing BsAbs dose on time taken to reach maximum TC concentration. Dose range is regular intervals in the range 1 - 5000 mg.

Conclusion

BsAbs possess several improvements over the monoclonal antibodies that have been the mainstay of conventional antibody therapies. However, these advantages are associated with more complex kinetics that are difficult to examine accurately in the laboratory setting. The general full and reduced TMDD model shown here demonstrates how a theoretical approach can yield insights that help characterise and predict the kinetics of BsAbs. Further development of these promising immunotherapeutic modalities could thus well benefit from the use of target-driven pharmacokinetic/pharmacodynamic modelling efforts to aid the design of new molecules, optimise the treatment of existing agents, and guide the identification of novel targets.

References

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  2. Dhimolea E, Reichert JM. 2012. World Bispecific Antibody Summit, September 27–28, 2011, Boston, MA. MAbs 4:4–13.
  3. Wada H, Matsumoto T, Katayama N. 2017. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med 377:2193–4.
  4. Hultqvist G, Syvänen S, Fang XT, Lannfelt L, Sehlin D. 2017. Bivalent Brain Shuttle Increases Antibody Uptake by Monovalent Binding to the Transferrin Receptor. Theranostics 7:308–318.
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  7. Moore PA, Zhang W, Rainey GJ, Burke S, Li H, Huang L, Gorlatov S, Veri MC, Aggarwal S, Yang Y, Shah K, Jin L, Zhang S, He L, Zhang T, Ciccarone V, Koenig S, Bonvini E, Johnson S. 2011. Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma. Blood 117:4542–51.