Quantitative Clinical Pharmacology of T‐Cell Engaging Bispecifics: Current Perspectives and Opportunities

Abstract

T-cell directing/engaging bispecifics (TDBs) enable a powerful mode of action by activating T-cells through the creation of artificial immune synapses. Their pharmacological response involves the dynamic interrelationships between T-cells, tumor cells, and TDBs. This results in complex and challenging issues in understanding pharmacokinetics (PK), tissue distribution, target engagement, and exposure-response relationship. Dosing strategy plays a crucial role in determining the therapeutic window of TDBs because of the desire to maximize therapeutic efficacy in the context of known mechanism-related adverse events, such as cytokine release syndrome and neurological adverse events. Such adverse events are commonly reported as the most prominent events during the initial treatment cycles and dissipate over time. Therefore, the kinetic characterization of the interrelationships between exposure/target engagement and safety/efficacy outcomes is crucial in designing the optimal dosing regimen to maximize the benefit/risk of TDB agents. In this review, we discuss the key clinical pharmacological considerations in drug discovery and development for TDBs and provide a summary of TDBs currently in clinical development. We also propose forward-looking perspectives and opportunities to derive insights through quantitative clinical pharmacology approaches.

Quantitative systems pharmacology modeling sheds light into the dose response relationship of a trispecific T cell engager in multiple myeloma

“…In comparing simulations of the trispecific with a comparable bispecific molecule without CD28 targeting, we find that CD28 does give significant benefit at lower doses. This finding may be more relevant to the clinical active dose than the predictions for higher doses, as many T-cell engaging drugs show high potency at low doses 27 . Furthermore, CD28 engagement keeps a higher proportion of T cells activated for longer period without necessarily leading to exhaustion 34 , 35 .…”

“…When aligning model predictions with preclinical and clinical responses, trimer concentration has been found not to adequately describe dose–response and additional constructs such as active T-cell numbers, or T-cell potency, have been linked to cytotoxicity to better explain the data 26 . Furthermore, several studies and reviews discuss the complexity of dose–response found for bispecific antibodies in the clinic and the differential success of this drug in patients with different levels of disease 27 . Our model attempts to extend the understanding of dose–response to trispecific T-cell engagers, and to generate a consolidated perspective of what controls dose–response in these modalities.…”

“…When aligning model predictions with preclinical and clinical responses, trimer concentration has been found not to adequately describe dose-response and additional constructs such as active T-cell numbers, or T-cell potency, have been linked to cytotoxicity to better explain the data 26 . Furthermore, several studies and reviews discuss the complexity of dose-response found for bispecific antibodies in the clinic and the differential success of this drug in patients with different levels of disease 27 www.nature.com/scientificreports/ can lead to complex dose-response curves which vary based on E/T ratio and antigen expression, among other factors. We do see a bell-shaped curve in the number of synapses formed based on receptor occupancy as suggested in 23 , but this often is not translated into effective receptor occupancy (synapse formation) or killing due to the complex landscape of other factors contributing to the overall effect.…”

Changing the drug development and therapeutic paradigm with biologic drug combinations and bispecifics: How to choose between these two approaches?

“…Depending on the BsAb formats and MOAs, utilizing control BsAbs with null binding arms can be critical in assessing individual TE versus dual TE, and the associated functions (Sup Ref 8). More sophisticated and extensive in vivo biodistribution and functional (PK/TE/PD) studies using advanced techniques such as imaging 8 have been shown to enhance the understanding of the MOA(s) of a BsAb and to enable smarter design of a construct including the selection of binding affinities and epitopes of each arm based on experimental data 9 (Sup Ref 9) and quantitative modeling & simulation approaches (Sup Ref 10, 11) 10 . The learnings are valuable from preclinical animal models (particularly the determination of how both arms of the BsAb construct impact tissue distribution), in vivo TE and RO, and combined PD outcomes compared with a mAb combination approach for translational medicine considerations and early clinical development.…”

Anticancer effects of a single intramuscular dose of a minicircle DNA vector expressing anti-CD3/CD20 in a xenograft mouse model

“…Three BsAbs, blinatumomab (BLI; anti-CD3/CD19) and mosunetuzumab and RNGN1979 (both anti-CD3/CD20), are already approved by the US Food and Drug Administration (FDA) for treating human hematopoietic malignancies, 3 and more than 60 additional BsAbs are currently in preclinical and clinical development. 4 Another BsAb, catumaxomab, was approved for treating malignant ascites but was withdrawn from the market in 2017. BsAbs work by directing T cells to kill cancer cells via a cytolytic immune synapse formed between the two cell types.…”