Over the past decade, bispecific antibodies (agents designed to target 2 antigens simultaneously) have emerged as treatments for various cancer and noncancer conditions.1 These agents can be categorized into 2 classes: T-cell engaging, which activate T cells to induce the destruction of cancer cells; and non–T-cell engaging, which employ mechanisms such as ligand blocking, receptor degradation, and antibody-dependent cellular cytotoxicity.2 Unlike non–T-cell-engaging therapies, T-cell–engaging therapies may cause cytokine release syndrome (CRS) and neurotoxicity, necessitating gradual dose increases and, in some cases, extended monitoring in a health care setting.3
Despite growing use and clinical relevance, bispecific antibodies remains a broad, imprecise term that does not address diverse mechanisms, structures, targets, adverse events (AEs), and operational considerations. This ambiguity can confuse health care professionals and hinder patient communication, requiring more standardized, descriptive terminology. This article aims to clarify the key differences between bispecific T-cell engagers and non–T-cell engagers while also laying the groundwork for a broader discussion on the evolution of terminology in multitargeted engager therapies.
Current Drug Approvals
As of December 2024, a total of 17 bispecific therapies are available across the global market, 13 of which have been approved by the FDA in the US for various conditions.4
The Table presents a list of FDA-approved bispecific therapies (through March 2025), detailing their targets, indications, and requirements for step-up dosing and observation.5-17
Implications of AEs Unique to Bispecific T-Cell Engagers
Bispecific therapies offer a novel approach in treating invasive cancers through a variety of mechanisms involving targeted antigens. The presence or absence of T-cell engagement can influence the toxicity profiles of bispecific therapies, leading to variability among agents within this class.
Bispecific T-cell engagers are associated with an inflammatory process that involves the excessive immune system release of cytokines into the bloodstream by means of direct T-cell activation, known as CRS.18,19 Under normal physiological conditions, cytokines act as immune system fighters, protecting against infections, controlling inflammation, and regulating cellular processes. When released uncontrollably (a result of T cells and innate immune cells overactivation), CRS can lead to widespread systemic inflammation and organ damage.20 In most patients, symptoms of CRS mimic mild flu-like manifestations, including fevers and myalgia; however, CRS has the capability of causing widespread systemic inflammation, which can present as hypotension, coagulopathy, vascular leaks, and even pulmonary edema.21
Neurologic AEs, including immune effector cell–associated neurotoxicity syndrome (ICANS), have been reported in patients receiving bispecific T-cell engagers and are often preceded by CRS.22,23 ICANS is a condition of the central nervous system following immunotherapy, which triggers the activation or engagement of endogenous or infused T cells and/or other immune effector cells.23 Common clinical presentations of ICANS following administration of bispecific T-cell engagers include tremors, impaired attention, apraxia, dysgraphia, and mild expressive aphasia.23
Because of these significant AEs, enhanced monitoring may be warranted, and individual patient tolerability should be graded using the 2019 American Society for Transplantation and Cellular Therapy (ASTCT) criteria.23 The ASTCT grading criteria directly informs supportive care measures such as the administration of antipyretics, tocilizumab, and/or steroid initiation.23 Effective implementation of the ASTCT grading system relies on close collaboration among physicians, advanced practice providers, nurses, and pharmacists, whose collective expertise ensures timely recognition and management of toxicities.
Step-Up Dosing
Given the potential for serious immune-related AEs such as CRS and neurotoxicity with bispecific T-cell engagers, step-up dosing is commonly used to mitigate their incidence and severity. Ten FDA-approved therapies have used this unique approach in clinical trials (Table).5-17,24 Step-up dosing involves gradually increasing the bispecific T-cell engager dose to the target level, priming the immune system through repeated exposure and reducing CRS and ICANS risk via immune desensitization.19,24
Step-up dosing is often implemented during the first cycle of therapy, as seen with tarlatamab-dlle (Imdelltra; Amgen), the latest FDA-approved bispecific T-cell engager for extensive-stage small cell lung cancer.5 Tarlatamab employs a 1-mg step-up dose on cycle 1 day 1, followed by full treatment doses (10 mg) on days 8 and 15 if tolerated.5 In addition to the initial dose escalation during the first treatment cycle, step-up dosing is commonly employed following dose delays in subsequent cycles to support gradual immune reactivation.
A key consideration with step-up dosing is determining the timing of CRS onset, as variability may exist among agents. An analysis of CRS among the currently approved dosing regimens revealed that CRS rates in step-up dosing regimens typically increase gradually until the full treatment dose is reached or peak after the first dose increase before decreasing over time.3,19
It’s important for health care professionals to recognize that terminology surrounding dose escalation may vary across therapies. Although step-up dosing is commonly used to describe the graduated approach to mitigate CRS and ICANS, not all manufacturers use this exact phrasing. Alternative terminology includes ramp-up dosing or unlabeled visual escalation in dosing within the package insert. For example, blinatumomab (Blincyto; Amgen) does not explicitly mention step-up or ramp-up dosing in its package insert; however, dose escalation is required for one of its indications: relapsed or refractory B-cell precursor acute lymphoblastic leukemia.13 Awareness of these nuances ensures appropriate monitoring protocols are applied, even in the absence of standardized language.
Operational Considerations
Bispecific therapies present unique operational challenges for health care institutions, requiring a multidisciplinary approach to ensure safe and efficient administration. Thorough monitoring protocols must be established for AEs, with intervention strategies ideally integrated into the electronic medical record (EMR) system for prompt recognition and management.23 Staff education is also critical, necessitating specialized training to enhance competency in administration, toxicity management, and adherence to Risk Evaluation and Mitigation Strategies requirements if applicable.25
Financial challenges, including billing and coding complexities, high drug costs, and reimbursement, pose additional obstacles that institutions must navigate.26 Smaller community centers may experience financial strain and lack of resources and staffing, necessitating efficient integration to ensure the sustainability of administering these therapies. Institutions should also assess on-call staffing needs to ensure continuous coverage for emergent AEs and situations, particularly in the outpatient infusion setting. Transportation and caregiver needs should be considered, as some bispecific therapies require patients to stay within a certain radius of a hospital or clinic for monitoring.25
Lastly, optimizing EMR utilization through automated order sets, AE tracking, and clinical decision support can streamline workflow and improve patient safety. These operational considerations highlight the need for a proactive approach to integrating bispecific therapies into clinical practice to ensure safety and optimal patient outcomes.
