Abstract:Bispecific antibodies exhibit proven clinical benefit, and many bispecifics are currently in clinical development for oncology. Cytokine release syndrome (CRS) is a common clinical adverse effect observed following CD3‐based bispecific dosing. However, the pathophysiology of CRS is not fully understood, and no computational model mechanistically describing clinical cytokine dynamics following bispecific dosing in solid tumors exists. Here, a quantitative systems pharmacology (QSP) model describing peripheral c… Show more
“…For elranatamab, C max after the first dose was considered a significant predictor of any grade and grade 2+ CRS, and supported the switch from one step‐up dose (44 mg) to two step‐up doses (12/32 mg) to improve safety mitigation 35–37 . A complex QSP model characterizing the priming effect and linking cytokines to CRS has been available and can potentially be used in the stage of step‐up dose regimen selection 25,38 …”
Bispecific antibodies, by enabling the targeting of more than one disease‐associated antigen or engaging immune effector cells, have both advantages and challenges compared with a combination of two different biological products. As of December 2023, there are 11 U.S. Food and Drug Administration–approved BsAb products on the market. Among these, 9 have been approved for oncology indications, and 8 of these are CD3 T‐cell engagers. Clinical pharmacology strategies, including dose‐related strategies, are critical for bispecific antibody development. This analysis reviewed clinical studies of all approved bispecific antibodies in oncology and identified dose‐related perspectives to support clinical dose optimization and regulatory approvals, particularly in the context of the Food and Drug Administration's Project Optimus: (1) starting doses and dose ranges in first‐in‐human studies; (2) dose strategies including step‐up doses or full doses for recommended phase 2 doses or dose level(s) used for registrational intent; (3) restarting therapy after dose delay; (4) considerations for the introduction of subcutaneous doses; (5) body weight vs. flat dosing strategy; and (6) management of immunogenicity. The learnings arising from this review are intended to inform successful strategies for future bispecific antibody development.
“…For elranatamab, C max after the first dose was considered a significant predictor of any grade and grade 2+ CRS, and supported the switch from one step‐up dose (44 mg) to two step‐up doses (12/32 mg) to improve safety mitigation 35–37 . A complex QSP model characterizing the priming effect and linking cytokines to CRS has been available and can potentially be used in the stage of step‐up dose regimen selection 25,38 …”
Bispecific antibodies, by enabling the targeting of more than one disease‐associated antigen or engaging immune effector cells, have both advantages and challenges compared with a combination of two different biological products. As of December 2023, there are 11 U.S. Food and Drug Administration–approved BsAb products on the market. Among these, 9 have been approved for oncology indications, and 8 of these are CD3 T‐cell engagers. Clinical pharmacology strategies, including dose‐related strategies, are critical for bispecific antibody development. This analysis reviewed clinical studies of all approved bispecific antibodies in oncology and identified dose‐related perspectives to support clinical dose optimization and regulatory approvals, particularly in the context of the Food and Drug Administration's Project Optimus: (1) starting doses and dose ranges in first‐in‐human studies; (2) dose strategies including step‐up doses or full doses for recommended phase 2 doses or dose level(s) used for registrational intent; (3) restarting therapy after dose delay; (4) considerations for the introduction of subcutaneous doses; (5) body weight vs. flat dosing strategy; and (6) management of immunogenicity. The learnings arising from this review are intended to inform successful strategies for future bispecific antibody development.
“…Some HT-mediated mechanisms have an impact on key factors involved in the response to T-cell engagers; they include (1) the number of T-cells infiltrating the tumor site [215]; (2) their quality (pro-inflammatory CTLs or pro-tolerogenic Tregs) [150,215]; and (3) an environment promoting their activation, which depends on factors such as the TAA density or released cytokines [216,217].…”
Section: Potential Benefits In Combination With Hyperthermiamentioning
Despite significant advancements in the development of novel therapies, cancer continues to stand as a prominent global cause of death. In many cases, the cornerstone of standard-of-care therapy consists of chemotherapy (CT), radiotherapy (RT), or a combination of both. Notably, hyperthermia (HT), which has been in clinical use in the last four decades, has proven to enhance the effectiveness of CT and RT, owing to its recognized potency as a sensitizer. Furthermore, HT exerts effects on all steps of the cancer–immunity cycle and exerts a significant impact on key oncogenic pathways. Most recently, there has been a noticeable expansion of cancer research related to treatment options involving immunotherapy (IT) and targeted therapy (TT), a trend also visible in the research and development pipelines of pharmaceutical companies. However, the potential results arising from the combination of these innovative therapeutic approaches with HT remain largely unexplored. Therefore, this review aims to explore the oncology pipelines of major pharmaceutical companies, with the primary objective of identifying the principal targets of forthcoming therapies that have the potential to be advantageous for patients by specifically targeting molecular pathways involved in HT. The ultimate goal of this review is to pave the way for future research initiatives and clinical trials that harness the synergy between emerging IT and TT medications when used in conjunction with HT.
“…As demonstrated with a QSP model developed for tebentafusp using clinical data for model verification, simulation of different dosing scenarios could guide the selection of step-up dose regimens which provide an optimal balance between efficacy and safety, in order to improve the benefit/risk profile. 111 Figure 3. Comparison of different clinical dosing strategies for TCEs.…”
Section: Perspectives For the Next Generation Of Tcesmentioning
Innovative approaches in the design of T cell-engaging (TCE) molecules are ushering in a new wave of promising immunotherapies for the treatment of cancer. Their mechanism of action, which generates an in
trans
interaction to create a synthetic immune synapse, leads to complex and interconnected relationships between the exposure, efficacy, and toxicity of these drugs. Challenges thus arise when designing optimal clinical dose regimens for TCEs with narrow therapeutic windows, with a variety of dosing strategies being evaluated to mitigate key side effects such as cytokine release syndrome, neurotoxicity, and on-target off-tumor toxicities. This review evaluates the current approaches to dose optimization throughout the preclinical and clinical development of TCEs, along with perspectives for improvement of these strategies. Quantitative approaches used to aid the understanding of dose-exposure-response relationships are highlighted, along with opportunities to guide the rational design of next-generation TCE molecules, and optimize their dose regimens in patients.
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