Immune checkpoint-targeted antibodies: a room for dose and schedule optimization?

Abstract

Anti-CTLA-4 and anti-PD-1/PD-L1 immune checkpoint inhibitors are therapeutic monoclonal antibodies that do not target cancer cells but are designed to reactivate or promote antitumor immunity. Dosing and scheduling of these biologics were established according to conventional drug development models, even though the determination of a maximum tolerated dose in the clinic could only be defined for anti-CTLA-4. Given the pharmacology of these monoclonal antibodies, their high interpatient pharmacokinetic variability, the actual clinical benefit as monotherapy that is observed only in a specific subset of patients, and the substantial cost of these treatments, a number of questions arise regarding the selected dose and the dosing interval. This review aims to outline the development of these immunotherapies and considers optimization options that could be used in clinical practice.

Modeling tumor size dynamics based on real‐world electronic health records and image data in advanced melanoma patients receiving immunotherapy

“…Our data supported an ON/OFF treatment effect, with better model performances as compared to a model with a treatment effect linearly dependent on the doses. This is in line with literature evidence indicating that, at the dose ranges used in clinical practice, the exposure‐response relationship of ICIs is at the plateau of the maximal response 4,32 …”

Use of Systemic Therapies for Treatment of Psoriasis in Patients with a History of Treated Solid Tumours: Inference-Based Guidance from a Multidisciplinary Expert Panel

“…In contrast, they are designed to stimulate immune function by blocking inhibitory checkpoints, such as CTLA4 and PD1-PDL1. The extended duration of the therapeutic effects of ICIs (and their auto-immune toxicities) often far surpasses their pharmacokinetic half-life and is highly variable [ 128 , 129 ] Radiation therapy Advances in radiation for the treatment of solid tumours have led to improved tumour targeting with reduced impact on normal tissues. Immune deficits are uncommon post-treatment [ 130 ] d Endocrine and targeted therapies (e.g.…”

Clinically relevant dosing and pharmacokinetics of DNA-encoded antibody therapeutics in a sheep model

“…by plasmid and cassette engineering, in addition to nucleotide codon and structural optimizations (25,26). Second, while reported therapeutic serum concentrations of clinical mAbs can go up to the double-digit µg/ml range, there are ample mAbs where much lower ranges suffice in oncology, auto-immune diseases and infectious diseases, be it for prophylactic, treatment induction or maintenance applications (27)(28)(29). Specific to DNA-based mAbs, in a NHP Zika challenge study, treatment with dMAb-ZK190 was associated with viral protection at serum levels below 1 µg/ml (20), albeit in a preclinical setting still.…”

“…Third, development of novel more potent mAbs and more effective combinations could result in lower therapeutic levels than currently is the case ( 30 ). Fourth, for several mAbs that originally were approved and applied at high dosing (gram level), the application of significantly lower protein dosing (milligram level) is under evaluation, as this enables significant cost reductions and improved safety, while being non-inferior compared to the higher doses ( 27 , 31 , 32 ). Overall, we believe that the attained titers in sheep are in support of the clinical translation of gene-based mAb delivery.…”