Clinical translation of antibody drug conjugate dosing in solid tumors from preclinical mouse data

Abstract

Antibody drug conjugates (ADCs) have made impressive strides in the clinic in recent years with 11 Food and Drug Administration approvals, including 6 for the treatment of patients with solid tumors. Despite this success, the development of new agents remains challenging with a high failure rate in the clinic. Here, we show that current approved ADCs for the treatment of patients with solid tumors can all show substantial efficacy in some mouse models when administered at a similar weight-based [milligrams per kilogram (mg/kg)] dosing in mice that is tolerated in the clinic. Mechanistically, equivalent mg/kg dosing results in a similar drug concentration in the tumor and a similar tissue penetration into the tumor due to the unique delivery features of ADCs. Combined with computational approaches, which can account for the complex distribution within the tumor microenvironment, these scaling concepts may aid in the evaluation of new agents and help design therapeutics with maximum clinical efficacy.

Fig. 1.. Efficacy of FDA-approved ADCs for solid tumors in preclinical mouse models.

The efficacy of the six ADCs approved for treatment of solid tumor indications is shown from several published studies when the doses administered, in milligrams per kilogram (mg/kg), are close to the clinical mg/kg dose (, –104). Tumor growth curves were digitized from the indicated reference sources. The cell line and mouse strain used in each of the reported studies are shown below the ADC name. NIBIO G016 and AG-B1 PDX models were used to study the efficacy of trastuzumab deruxtecan and enfortumab vedotin, respectively. The clinical doses are 3.6 mg/kg Q3W for trastuzumab emtansine; 5.4 or 6.4 mg/kg Q3W for trastuzumab deruxtecan; 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle for enfortumab vedotin; 2 mg/kg Q3W for tisotumab vedotin; 10 mg/kg on days 1 and 8 of a 21-day cycle for sacituzumab govitecan; and 6 mg/kg Q3W for mirvetuximab soravtansine. SCID, severe combined immunodeficient.

Fig. 2.. Tissue penetration of antibodies and ADCs in mice and humans.

The high affinity anti–epidermal growth factor receptor (EGFR) antibody, panitumumab, penetrates only a few cell diameters in human patients with head and neck cancer when administered at a 1 mg/kg dose used for intraoperative imaging (A, left) (53). Likewise, the anti-EGFR antibody, cetuximab, shows a similar tissue penetration following a 1.2 mg/kg dose in a mouse xenograft model (A, right) (60). Tissue penetration can be increased by multiple mechanisms including higher antibody doses from the coadministration of unconjugated antibody, lowering the drug-to-antibody ratio (DAR) so a higher ADC dose is tolerated, or the use of lower potency payloads. In the case of trastuzumab emtansine versus trastuzumab deruxtecan, the lower potency topoisomerase inhibitor allows trastuzumab deruxtecan to be administered at 6.4 mg/kg, increasing the tissue penetration of the ADC labeled in green (B). In addition, the payload on trastuzumab emtansine does not exhibit bystander effects, meaning it cannot exit ADC targeted cells to reach untargeted cells. A pH3 marker of cells trapped in mitosis (red) only overlays with the trastuzumab emtansine labeled cells (B, left). In contrast, the DXd payload can diffuse out of targeted cells. While this does not completely overcome incomplete tissue penetration, the DXd payload released from trastuzumab deruxtecan (B, right, green) is able to cause some DNA damage in cells untargeted by the ADC as seen by the γH2AX stain (red).

Fig. 3.. Antibody and payload uptake in mouse and human tumors.

Literature reports of antibody uptake in mouse tumors are often around 30%ID/g depending on factors such as vascular density/necrosis and blood vessel permeability, with several typical values shown here (, , , –111). Because of the larger body weight of humans, the clinical uptake of antibodies, estimated from molecular imaging and biopsy samples, is ~0.01%ID/g, as seen with several typical values calculated from contemporary studies (, , , –114) (A). However, this results in a similar concentration of antibody in the tumor when administered at the same mg/kg dose (B). Clinical estimates of small-molecule drugs are also available from molecular imaging experiments, and the concentrations are typically threefold lower than the concentration of payload delivered by an ADC (–119). In addition, the concentrations drop much faster for small-molecule chemotherapeutics, providing a therapeutic advantage for ADCs (*maximum concentration shown before rapid drop). Methods used to calculate concentrations are shown in methods S3 and S4.