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Review
. 2019 Jan 1;8(1):3.
doi: 10.3390/antib8010003.

Pharmacologic Considerations in the Disposition of Antibodies and Antibody-Drug Conjugates in Preclinical Models and in Patients

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Free PMC article
Review

Pharmacologic Considerations in the Disposition of Antibodies and Antibody-Drug Conjugates in Preclinical Models and in Patients

Andrew T Lucas et al. Antibodies (Basel). .
Free PMC article

Abstract

The rapid advancement in the development of therapeutic proteins, including monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs), has created a novel mechanism to selectively deliver highly potent cytotoxic agents in the treatment of cancer. These agents provide numerous benefits compared to traditional small molecule drugs, though their clinical use still requires optimization. The pharmacology of mAbs/ADCs is complex and because ADCs are comprised of multiple components, individual agent characteristics and patient variables can affect their disposition. To further improve the clinical use and rational development of these agents, it is imperative to comprehend the complex mechanisms employed by antibody-based agents in traversing numerous biological barriers and how agent/patient factors affect tumor delivery, toxicities, efficacy, and ultimately, biodistribution. This review provides an updated summary of factors known to affect the disposition of mAbs/ADCs in development and in clinical use, as well as how these factors should be considered in the selection and design of preclinical studies of ADC agents in development.

Keywords: Antibody-drug conjugates; Mononuclear phagocyte system; Pharmacokinetics; Pharmacology; Therapeutic proteins.

Conflict of interest statement

W.C.Z. holds equity in and licensed patent on an MPS probe. A.T.L. and W.C.Z. have filed ROI for a provisional patent on MPS FcγR technology. All other authors have no conflicts of interest to disclose.

Figures

Figure 1
Figure 1
Metabolism and elimination differences of small molecules drugs compared to antibody-based agents. (A) Therapeutic proteins (including monoclonal antibodies and antibody-drug conjugates (ADCs)) undergo metabolism and catabolism in numerous different ways compared to traditional small molecule agents. (B) Ultimately, this results in ADCs relying on two separate, but concurrent, processes to eliminate both the antibody carrier and the cytotoxic drug.
Figure 2
Figure 2
High variability in the pharmacokinetic (PK) of antibody-drug conjugates (ADCs) as represented by the relationship between ado-trastuzumab emtansine (A) and Inotuzumab ozogamicin (B) dose and PK parameters (Cmax, area under the curve (AUC)) in serum. Mean ± standard deviation (SD) of patients for each treatment group are represented by the rectangular bar. There was high inter-patient pharmacokinetic (PK) variability in studies of both solid (breast cancer; ado-trastuzumab emtansine) and hematologic (B-cell lymphoma; inotuzumab ozogamicin) malignancies. The high PK variability observed in these ADC agents may be related to the variability in the mononuclear phagocyte system (MPS). CV%, coefficient of variation; Q3W, every three weeks; Q4W, every four weeks.
Figure 3
Figure 3
Improved ADC tumor penetration by administering ADC in combination with naked antibody carrier. (A) The tumor distribution of ado-trastuzumab emtansine monotherapy administered at 3.6 mg/kg results in only perivascular tumor distribution due to rapid binding after being transported into the tissue from systemic circulation. (B,C) Improvement in the tumor penetration of ado-trastuzumab when co-administered with trastuzumab at a dose sub-saturating or saturating dose of trastuzumab. In theory, these results are due to trastuzumab competing for binding sites, requiring ado-trastuzumab emtansine to penetrate further into tumors to find available binding sites (tumor specific effect) or due to trastuzumab reducing the uptake of ado-trastuzumab emtansine by the mononuclear phagocyte system (MPS) and increasing the serum exposure, which is associated with the greater tumor delivery that has been reported for nanoparticles (NP) agents (reduced systemic clearance effect).
Figure 4
Figure 4
Serum inotuzumab ozogamicin (INO) exposures (AUCT; cycle one in orange, cycle two in blue, cycle three in green, and cycle four in yellow) in patients receiving INO monotherapy or in combination with rituximab (R-INO). R-INO combination therapy demonstrated a higher variability in INO AUCT compared to INO monotherapy. In addition, INO exposure was ~three-fold higher in patients receiving combination therapy compared to monotherapy. These findings suggest that combining two immunotherapeutic antibody agents may saturate shared mechanisms of clearance, thus increasing the likelihood of inter-patient variable exposure.

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