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

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.

Improving Intracellular Delivery of an Antibody-Drug Conjugate Targeting Carcinoembryonic Antigen Increases Efficacy at Clinically Relevant Doses In Vivo.

Solid tumor antibody-drug conjugates (ADC) have experienced more clinical success in the last 5 years than the previous 18-year span since the first ADC approval in 2000. While recent advances in protein engineering, linker design, and payload variations have played a role in this success, high expression and readily internalized targets have also been crucial to solid tumor therapy. However, these factors are also paradoxically connected to poor tissue penetration and lower efficacy. Previous work shows that potent ADCs can benefit from slower internalization under subsaturating doses to improve tissue penetration and increase tumor response. In contrast, faster internalization is predicted to increase efficacy under higher, tumor saturating doses. In this work, the intracellular delivery of SN-38 conjugated to an anti-carcinoembryonic antigen (anti-CEA) antibody (Ab) is increased by coadministering a noncompeting (cross-linking) anti-CEA Ab to improve efficacy in a colorectal carcinoma animal model. The SN-38 payload enables broad tumor saturation with clinically-tolerable doses, and under these saturating conditions, using a second CEA receptor cross-linking Ab yields faster internalization, which increases tumor killing efficacy. Our spheroid results show indirect bystander killing can also occur, but the more efficient direct cell killing from targeted intracellular payload release drives a greater tumor response. These results provide a strategy to increase therapeutic effectiveness with improved intracellular delivery under tumor saturating doses with the potential to expand the ADC target repertoire.

Generation of DAR1 Antibody-Drug Conjugates for Ultrapotent Payloads Using Tailored GlycoConnect Technology.

GlycoConnect technology can be readily adapted to provide different drug-to-antibody ratios (DARs) and is currently also evaluated in various clinical programs, including ADCT-601 (DAR2), MRG004a (DAR4), and XMT-1660 (DAR6). While antibody-drug conjugates (ADCs) typically feature a DAR2-8, it has become clear that ADCs with ultrapotent payloads (e.g., PBD dimers and calicheamicin) can only be administered to patients at low doses (<0.5 mg/kg), which may compromise effective biodistribution and may be insufficient to reach target receptor saturation in the tumor. Here, we show that GlycoConnect technology can be readily extended to DAR1 ADCs without the need of antibody re-engineering. We demonstrate that various ultrapotent, cytotoxic payloads are amenable to this methodology. In a follow-up experiment, HCC-1954 tumor spheroids were treated with either an AlexaFluor647-labeled DAR1 or DAR2 PBD-based ADC to study the effect on tumor penetration. Significant improvement of tumor spheroid penetration was observed for the DAR1 ADC compared to the DAR2 ADC at an equal payload dose, underlining the potential of a lower DAR for ADCs bearing ultrapotent payloads.

Predictive Simulations in Preclinical Oncology to Guide the Translation of Biologics.

Preclinical in vivo studies form the cornerstone of drug development and translation, bridging in vitro experiments with first-in-human trials. However, despite the utility of animal models, translation from the bench to bedside remains difficult, particularly for biologics and agents with unique mechanisms of action. The limitations of these animal models may advance agents that are ineffective in the clinic, or worse, screen out compounds that would be successful drugs. One reason for such failure is that animal models often allow clinically intolerable doses, which can undermine translation from otherwise promising efficacy studies. Other times, tolerability makes it challenging to identify the necessary dose range for clinical testing. With the ability to predict pharmacokinetic and pharmacodynamic responses, mechanistic simulations can help advance candidates from in vitro to in vivo and clinical studies. Here, we use basic insights into drug disposition to analyze the dosing of antibody drug conjugates (ADC) and checkpoint inhibitor dosing (PD-1 and PD-L1) in the clinic. The results demonstrate how simulations can identify the most promising clinical compounds rather than the most effective in vitro and preclinical in vivo agents. Likewise, the importance of quantifying absolute target expression and antibody internalization is critical to accurately scale dosing. These predictive models are capable of simulating clinical scenarios and providing results that can be validated and updated along the entire development pipeline starting in drug discovery. Combined with experimental approaches, simulations can guide the selection of compounds at early stages that are predicted to have the highest efficacy in the clinic.