Teclistamab: Mechanism of action, clinical, and translational science

Abstract

Multiple myeloma (MM) remains incurable despite improvements in treatment options. B‐cell maturation antigen (BCMA) is predominantly expressed in B‐lineage cells and represents a promising new target for MM. Teclistamab (TECVAYLI^TM) is the first T‐cell redirecting bispecific antibody approved for patients with MM. Targeting both CD3 receptor complex on T cells and BCMA on myeloma cells, teclistamab leads to T‐cell activation and subsequent lysis of BCMA+ cells. The recommended dose of teclistamab is 1.5 mg/kg subcutaneous weekly after two step‐up doses of 0.06 and 0.3 mg/kg, which was selected after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Exposure‐response analyses of efficacy and safety data were also used to confirm the teclistamab dose. Teclistamab resulted in a high rate of deep and durable responses (63% overall response, 45.5% complete response or better, with 22 months median duration of response) in patients with triple‐exposed relapsed/refractory MM. Common adverse reactions included cytokine release syndrome, hematologic abnormalities, and infections. Teclistamab is currently being investigated as monotherapy as well as combination therapy across different MM indications.

Clinical and Translational Card for Teclistamab.

Mechanism of action: BCMAxCD3 bispecific antibody.

Indication(s): Adult patients with triple‐class‐exposed relapsed/refractory multiple myeloma.

Dosage and administration: Subcutaneously administration at 1.5 mg/kg weekly, after two step‐up doses of 0.06 and 0.3 mg/kg.

Major Metabolic Pathway: Not applicable.

Key PK characteristics: C _max and AUC_tau after the first treatment dose increased proportionally over a dosage range of 0.08–3 mg/kg. Median (range) T _max after the first dose was 139 (19–168) hours. Ninety percent of steady‐state exposure was estimated to be achieved after 12 weekly doses of 1.5 mg/kg. The mean accumulation ratio between the first and 13th weekly doses of 1.5 mg/kg was 4 to 5‐fold for C _max, C _trough, and AUC_tau. Teclistamab mean (standard deviation) distribution and elimination half‐life after the 13th weekly dose of 1.5 mg/kg was 5.7 (2.4) and 27.2 (8.2) days, respectively.

INTRODUCTION

Multiple myeloma (MM) is characterized by cancerous plasma cells and is estimated to account for ~11.6% of hematologic cancers. ¹ Standard therapies for MM include immunomodulatory drugs, proteasome inhibitors, and anti‐CD38 monoclonal antibodies. Despite advances in treatment options, MM remains incurable. Patients whose disease progressed after having received standard therapies have limited options and need effective treatments that can overcome resistance and achieve a durable remission.

Teclistamab (TECVAYLI) is the first approved T‐cell redirecting bispecific antibody for adult patients with relapsed/refractory MM (RRMM). Teclistamab received conditional marketing authorization from the European Medicines Agency (EMA) and accelerated approval from the US Food and Drug Administration (FDA) in 2022 as monotherapy for the treatment of adult patients with triple‐class‐exposed RRMM. This mini‐review discusses the mechanism of action and clinical development of teclistamab with a focus on clinical pharmacology considerations.

MECHANISM OF ACTION OF TECLISTAMAB

B‐cell maturation antigen (BCMA) is a membrane protein responsible for promoting plasma cell survival. Its expression is largely restricted to plasma cells and is overexpressed on myeloma cells, making BCMA a viable target antigen. ² BCMA exists as both surface protein and a free soluble form.

Teclistamab is a humanized immunoglobulin G4‐proline, alanine, alanine (IgG‐4 PAA) bispecific antibody developed to target the CD3 receptor complex on T cells and BCMA on MM cells. With its dual binding, teclistamab draws CD3+ T cells in close proximity to BCMA+ cells, facilitating T‐cell activation and subsequent lysis of myeloma cells (Figure 1).

FIGURE 1.

Graphic illustration of mechanism of action of teclistamab. Reprinted with permission of Janssen Research & Development. Previously presented at the American Society for Hematology Annual Meeting; December 10, 2022; New Orleans, LA.

Preclinical studies demonstrated potent activity of teclistamab in MM cell lines, patient samples, and in vivo xenograft models. ³ Concentration‐dependent T‐cell mediated cytotoxicity of BCMA+ MM cell lines, T‐cell activation, and cytokine release were observed and used to define the minimum anticipated biological effect level (MABEL). Teclistamab resulted in concentration‐dependent depletion of BCMA+ cells in an ex vivo assay using bone marrow mononuclear cells from patients with MM. Teclistamab significantly inhibited tumor growth compared to vehicle and antibody controls in two in vivo BCMA+ MM murine xenograft models. In addition to establishing activity of teclistamab in preclinical models, these results were critical in setting a clinical exposure target and defining possible therapeutic dose range ⁴ and safe starting dose. ⁵

MajesTEC‐1 study

The MajesTEC‐1 study is the first‐in‐human (FIH), phase I/II study of teclistamab conducted in triple‐class‐exposed adult participants with RRMM. ⁵ , ⁶ The study was designed in two parts: the dose escalation part to identify the recommended dose (RP2D) of teclistamab, and the dose expansion part to establish the safety and tolerability of the RP2D. Teclistamab was administered intravenously (i.v.) in the early cohorts of dose escalation, and subcutaneously (s.c.) for later cohorts in dose escalation and expansion cohorts. Antitumor activity, pharmacokinetics (PKs), pharmacodynamics (PDs), and immunogenicity were assessed in both parts of the study. This section reviewed the journey of the MajesTEC‐1 study from starting dose determination to establishment of RP2D, which led to the characterization of PK, PD, immunogenicity, as well as efficacy and safety of teclistamab, and ultimately supported the approval.

PK and immunogenicity characteristics of teclistamab

The starting dose was determined based on MABEL derived from the lowest mean effective concentration that gives 20% of maximal response (EC₂₀) from the series of in vitro assays of T‐cell activation, cytotoxicity, and cytokine release. This approach is consistent with standard recommendations as described in International Conference on Harmonization (ICH) S9 guidance and has generally been used for selecting starting doses for T cell‐engaging therapies. ⁷ PK modeling and simulation estimated that the i.v. starting dose of 0.0003 mg/kg would achieve a maximal concentration (C _max) of 0.04 nM (i.e., the lowest EC₂₀), which was considered a safe starting dose. ⁵ The starting dose frequency of biweekly (q2w) was based on nonclinical half‐life of ~10 days observed in two cynomolgus monkeys. ⁸

Emerging safety and PK data were used to inform dose escalation. Seven biweekly dose levels ranging from 0.0003 to 0.0192 mg/kg i.v. followed by eight dose levels with weekly i.v. doses ranging from 0.0192 to 0.72 mg/kg were evaluated. ⁵ Following teclistamab i.v., C _max mostly occurred at the end of infusion and declined rapidly. ⁵ Dose proportional increase in exposure was observed from 0.0192 to 0.72 mg/kg weekly i.v. The regimen was changed from biweekly to weekly based on minimal accumulation observed with biweekly dosing. The occurrence and severity of cytokine release syndrome (CRS) events guided the exploration of different step‐up doses to mitigate CRS risk. An initial step‐up dose was first implemented in cohort 0.0384 mg/kg i.v. weekly and a second step‐up dose was added in cohorts 0.08 mg/kg i.v. weekly and higher.

The s.c. administration was considered the preferred administration route given the benefits of improved patient convenience, shorter injection duration, a more gradual release of drug into systemic circulation, and lower C _max to trough plasma concentration (C _trough) ratio. Selection of the initial s.c. dose was guided by preliminary modeling and simulation of the available teclistamab i.v. PK data and assumed 60% bioavailability as reported for monoclonal antibodies (mAbs) by Haraya et al. ⁴ , ⁹ The s.c. doses ranged from 0.08 mg/kg (after 1 step‐up dose) to 6 mg/kg (after 3 step‐up doses) were evaluated, with most dose levels preceded by two step‐up doses. The RP2D of teclistamab was determined as 1.5 mg/kg s.c. weekly, after two step‐up doses of 0.06 and 0.3 mg/kg s.c.. C _max and area under the concentration‐time curve (AUC_tau) increased proportionally following weekly s.c. dosing. ¹⁰ The mean s.c. bioavailability of teclistamab was 72% and the median (range) time to reach maximum concentration after the first dose was 139 (19–168) hours. Ninety percent of steady‐state exposure was estimated to be achieved after 12 weekly s.c. doses of 1.5 mg/kg. The mean accumulation ratio between the first and 13^th weekly doses of 1.5 mg/kg was four to fivefold for C _max, C _trough, and AUC_tau. Teclistamab mean (standard deviation) distribution and elimination half‐life after the 13^th weekly doses of 1.5 mg/kg was 5.7 (2.4) and 27.2 (8.2) days, respectively. ⁸

The PK of teclistamab was adequately described by a two‐compartment model with first‐order absorption associated with s.c. administration and parallel time‐independent (representing the nonspecific clearance) and time‐dependent (representing changes in capacity of the target‐mediated clearance) elimination pathways. ¹¹ Because time‐dependent clearance decreases over time, teclistamab half‐life increased with repeated dosing. Body weight, type of myeloma, and International Staging System stage were statistically significant covariates on PKs. ¹¹ These factors did not have a clinically relevant impact on the efficacy of teclistamab based on exposure‐response analyses. The effect of body weight on teclistamab's clearance and volume of distribution is consistent with other mAbs. ¹² Because teclistamab was administered as weight‐based dose, no clinically meaningful differences (<20–25%) in PKs were observed in patients across different body weights. ¹¹

Although the highly engineered nature of bispecific antibodies can lead to increased risk of immunogenicity, the incidence of anti‐drug antibodies (ADAs) following teclistamab was low. ⁵ ADA at low titers were detected at very low frequency (<1%) in the MajesTEC‐1 study, and no ADAs were detected in patients treated at the RP2D. ⁶ Although the data were limited, ADAs did not impact the safety or PKs of teclistamab.

PD characteristics

PD markers, such as T cell number/subsets, activation/exhaustion markers, cytokine levels, BCMA surface expression, and soluble BCMA (sBCMA) levels, were measured in the MajesTEC‐1 study. Correlative analyses showed that phenotype and number of peripheral T cells were associated with clinical response. ¹³ Patients responding to teclistamab had a higher frequency of naïve CD8+ T cells and lower frequency of regulatory T cells in the peripheral blood at baseline. Baseline frequency of cells expressing receptors associated with T‐cell exhaustion or dysfunction (i.e., programmed cell death protein 1 [PD‐1], T‐cell immunoglobulin and mucin domain 3 [TIM‐3], and cluster of differentiation [CD38]) was also higher among the nonresponders. Overall, these associations suggest that baseline immune fitness is important in achieving clinical response and progression‐free survival (PFS) with teclistamab.

T‐cell activation and cytokine release following drug administration were not significantly associated with treatment response. Nonetheless, patients who responded to teclistamab had higher induction of interferon‐γ (IFN‐γ), interleukin‐6 (IL‐6), IL‐10, and IL‐2 receptor α, as well as surface levels of CD38 or TIM‐3 on CD8+ T cells after teclistamab administration. ⁶

Associations between CRS occurrence and baseline characteristics and demographics were also explored. ¹⁴ Baseline frequencies of some CD3+ and CD4+ T‐cell subpopulations expressing TIM‐3 and PD‐1 were associated with occurrence of CRS. No significant associations were observed between CRS incidence or grade and change in cytokine concentrations or T‐cell immunophenotypic expression profiles. However, a trend was observed for higher CRS grade with higher induction for IL‐10, IFN‐γ, IL‐6, and TNF‐α. In addition, a trend was observed for higher induction of CD38, TIM‐3, and lymphocyte‐activation gene 3 on CD4+ T‐cells in patients with grade greater than or equal to 1 CRS.

Baseline BCMA expression in bone marrow plasma cells was highly variable among patients with RRMM treated with teclistamab and the observed values were within the same range for responders and nonresponders. ¹³ BCMA can undergo proteolytic shedding, resulting in a truncated soluble form (i.e., sBCMA). The sBCMA, theoretically, could act as a sink and decrease the binding of some BCMA‐targeted therapies to membrane‐bound BCMA resulting in reduced efficacy. ¹⁵ It was critical to assess whether sBCMA levels would impact the efficacy, safety, and PKs of teclistamab. Population PK analysis showed that baseline sBCMA concentration did not significantly impact the PKs of teclistamab, indicating sBCMA is not a sink for teclistamab. ¹⁶ Regarding clinical activity, although patients with baseline sBCMA levels up to ~800 ng/mL responded to teclistamab, significantly lower levels of baseline sBCMA were observed in responders compared to nonresponders. ¹³ This finding is consistent with other reports that showed higher sBCMA levels were associated with poorer clinical outcomes. ¹⁷ It may also explain the observation of higher median baseline sBCMA in individuals without CRS, ¹³ because patients with poorer clinical outcomes likely have lower T cell‐mediated cell killing and therefore release less cytokines. Reductions in sBCMA levels were observed in most patients that responded to teclistamab, whereas sBCMA tended to increase in patients who did not respond. This observation was consistent with other BCMA‐targeted therapies and adds value of sBCMA as a marker for response. ¹⁶ Moreover, the magnitude of the decrease in sBCMA levels correlated with depth of response.

Dose rationale for teclistamab

The RP2D of teclistamab was selected based on totality of data, including clinical safety, PK data that achieved desired target exposure, PD data that demonstrated T‐cell activation and cytokine induction, and clinical efficacy. During dose escalation, a proactive approach was used to estimate the active dose of teclistamab. The clinical therapeutic range was established based on doses estimated to exceed target concentrations at 50% and 90% of maximum effect (EC₅₀ and EC₉₀, respectively) from the ex vivo cytotoxicity assay. Doses greater than or equal to 0.7 mg/kg i.v. and 0.72 mg/kg s.c. were predicted to achieved serum trough concentrations that reached the maximum EC₉₀. Clinical data from later cohorts confirmed that all responders treated at the RP2D of 1.5 mg/kg s.c. weekly had serum and bone marrow concentrations above the maximum EC₉₀ value on cycle three day 1, validating the target therapeutic range. ⁴

A positive exposure‐response relationship was observed for overall response rate (ORR), with the percentage of responders increasing with increasing exposure and reaching a plateau at the concentration range associated with RP2D. ¹¹ In patients receiving RP2D, no further apparent exposure‐response relationship was observed for efficacy end points, including ORR, duration of response (DOR), PFS, and overall survival (OS). In addition, optimal PD changes were observed at RP2D, including greater induction of T cell activation markers and cytokines at RP2D compared to other dose levels evaluated. ⁸

Taken together, the totality of safety, efficacy, PK and PD data supported the dose recommendation of 1.5 mg/kg s.c. weekly following two step‐up doses of 0.06 and 0.3 mg/kg s.c. implemented for CRS mitigation.

Summary of clinical efficacy and safety of teclistamab

In 165 heavily pretreated patients in the MajesTEC‐1 study treated at the RP2D with a median follow‐up of 14.1 months, rapid, deep, and durable responses were observed with an ORR of 63.0%. ⁶ First and best responses were achieved at a median (range) time of 1.2 months (0.2–5.5) and 3.8 months (1.1–16.8), respectively. As of the data cutoff of January 4, 2023, of the 104 responders, 63 patients had switched to 1.5 mg/kg q2w dosing after achieving a partial response or better (after ≥4 cycles) in phase I or a complete response (CR) or better for greater than or equal to 6 months in phase II. ¹⁸ Nine patients subsequently switched to q4w dosing. Forty‐two (42) out of 63 patients maintained a response. With a median follow‐up of ~2 years, responses to teclistamab continued to deepen (45.5% of patients had CR or better) and were durable (median DOR was 22 months in all patients), including in patients who switched to 1.5 mg/kg q2w or 1.5 mg/kg q4w dosing schedules. ¹⁹ In patients achieving CR or better, the median DOR and median PFS were 27 months and median OS has not been reached.

The most common adverse events (AEs) reported in patients treated with teclistamab at the RP2D were hematologic AEs, CRS, and infections. Hematologic AEs observed in the MajesTEC‐1 study included neutropenia (in 70.9%; grade 3 or 4: 21.2%), anemia (in 52.1%; grade 3 or 4: 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4: 21.2%).

CRS is a common AE related to T‐cell engagers and occurred in 72.1% of patients treated at the RP2D. ⁶ Most CRS events were grade 1 or 2 in severity and generally occurred after step‐up and cycle one doses, with incidence and severity decreasing over time. Most patients received supportive treatment for the management of CRS (110 of 119). Tocilizumab was administered to 36.4% of patients and did not affect the efficacy of teclistamab but decreased the risk of CRS recurrence compared to when tocilizumab was not used. ¹⁴ All CRS events fully resolved without treatment discontinuation. A single dose of tocilizumab prior to teclistamab has been evaluated in 23 patients from the MajesTEC‐1 study, which reduced the incidence of CRS to 26.1% (8.7% grade 1, 17.4% grade 2, no grade 3) without impacting response to teclistamab. ²⁰

Neurotoxicity is a unique treatment‐related AE for T‐cell engaging therapies. Investigator‐assessed neurotoxic events (14.5%) observed in the study included headache in 14 patients and grade 1 or 2 immune effector cell‐associated neurotoxicity syndrome (ICANS) in five patients, among other less frequent neurotoxic events. Seven out of nine ICANS events were concurrent with CRS, and all resolved without discontinuation or dose adjustment.

Infections and hypogammaglobulinemia were frequent, occurring in 76.4% and 74.5% of patients, respectively. Intravenous immunoglobulin was used in 52.8% of patients with hypogammaglobulinemia for management of the AE. Onset of new grade greater than or equal to 3 infections decreased over time, corresponding with the timing of switch to less frequent dosing. ¹⁸ The decrease of new onset grade greater than or equal to 3 infections and the maintenance of clinical response supported the benefit of less frequent dosing of teclistamab in patients who have achieved sustained response.

Drug–drug interaction evaluation

Cytokines (such as IL‐6) released during CRS have been shown to alter the enzymatic activity of cytochrome P450 (CYP450). Drug–drug interaction (DDI) evaluation of teclistamab as a pro‐inflammatory cytokine modulator was warranted. A physiologically‐based pharmacokinetic model estimated limited IL‐6‐related DDIs with CYP450 substrates, although close monitoring and PK assessment are recommended for CYP450 substrates with narrow therapeutic index – such as warfarin and cyclosporine – when co‐administered with teclistamab during the first 2 weeks of treatment. ²¹

OTHER KEY CLINICAL TRIALS

Teclistamab is also being evaluated in other clinical trials (Table 1), including earlier lines of therapy (RRMM with 1–3 prior lines of therapy, newly diagnosed MM, etc.) and in combination setting (including standard of care, immunomodulatory agents, bispecific antibody, etc.).

TABLE 1.

Ongoing clinical studies of teclistamab.

Study name	Phase	ClinicalTrials.gov Identifier	Key design
MajesTEC‐1 (64007957MMY1001)	Phase I/II	NCT04557098	FIH, dose escalation/expansion, RRMM
64007957MMY1002	Phase I/II	NCT04696809	Safety, tolerability, and efficacy of teclistamab monotherapy in Japanese participants, RRMM
TriMM‐2 (64407564MMY1002)	Phase Ib	NCT04108195	Daratumumab in combination with bispecific antibodies with or without pomalidomide, ≥3 prior lines of therapy
TriMM‐3 (64407564MMY1005)	Phase Ib	NCT05338775	Cetrelimab in combination with bispecific antibodies, RRMM
RedirecTT‐1 (64007957MMY1003)	Phase Ib/II	NCT04108195	Combination of teclistamab and talquetamab with or without daratumumab, RRMM
MajesTEC‐2 (64007957MMY1004)	Phase Ib	NCT04722146	Teclistamab in combination with other anticancer therapies in participants with NDMM or RRMM who meet treatment‐specific requirements
MajesTEC‐5 (64007957MMY2003)	Phase II	NCT05695508	Teclistamab in combination with daratumumab, lenalidomide, and dexamethasone with or without bortezomib as induction therapy and teclistamab in combination with daratumumab and lenalidomide as maintenance therapy in participants with NDMM who are transplant eligible
MajesTEC‐3 (64007957MMY3001)	Phase III	NCT05083169	Teclistamab in combination with daratumumab versus daratumumab, pomalidomide, and dexamethasone or daratumumab, bortezomib, and dexamethasone in participants with RRMM with 1–3 prior lines of therapy
MajesTEC‐4 (64007957MMY3003)	Phase III	NCT05243797	Teclistamab in combination with lenalidomide and teclistamab alone versus lenalidomide alone in participants with NDMM as maintenance therapy following autologous stem cell transplantation
MajesTEC‐7 (64007957MMY3005)	Phase III	NCT05552222	Teclistamab or talquetamab in combination with daratumumab and lenalidomide versus daratumumab, lenalidomide, and dexamethasone in participants with NDMM who are either ineligible or not intended for autologous stem cell transplant as initial therapy
MajesTEC‐9 (64007957MMY3006)	Phase III	NCT05572515	Teclistamab monotherapy versus pomalidomide, bortezomib, dexamethasone or carfilzomib, dexamethasone in RRMM with 1–3 prior lines of therapy, including an anti‐CD38 monoclonal antibody and lenalidomide

Abbreviations: FIH, first‐in‐human; NDMM, newly diagnosed multiple myeloma; RRMM, relapsed or refractory multiple myeloma.

OTHER BCMA‐TARGETED THERAPIES

There are several other BCMA‐targeted T‐cell engagers under clinical development, such as elranatamab (approved), alnuctamab, linvoseltamab, and more. Other BCMA‐targeted modalities are antibody‐drug conjugates (ADCs) and chimeric antigen receptor (CAR) T‐cell therapy. Despite the convenient administration of ADC without CRS, its effectiveness remains relatively low, and it can result in corneal toxicities. ²² T‐cell engagers and CAR‐T therapy have demonstrated exceptional efficacy and tolerable safety profiles. Bispecific antibodies are off‐the‐shelf treatments, distinguishing them from CAR‐T therapies. Despite logistical challenges, CAR‐T therapies provide an attractive therapy option, with much shorter treatment time, and deep and durable responses.

SUMMARY AND PERSPECTIVES

In this review, we summarized the journey of teclistamab from discovery to approval, with a focus on clinical pharmacology considerations. As a novel modality, a conservative approach based on the lowest EC₂₀ was used for starting dose determination. With evolving clinical experience, different effector‐to‐tumor cell ratio, more relevant T‐cell assay using whole blood, and higher percentage of maximal effect (such as EC₅₀) could be used for an improved starting dose selection that is both safe and closer to the efficacious dose range. ²³ Although the MajesTEC‐1 study began at a conservative starting dose that was thousands‐fold lower than the active doses, several approaches were used to shorten the time to escalate to active doses and maximize patients' clinical benefit. Two‐fold dose escalation increment and single patient dose escalation in early cohorts minimized the number of patients exposed to subtherapeutic levels of teclistamab. In addition, a novel translational modeling approach was utilized to estimate the active dose of teclistamab during early clinical development to inform dose escalation decisions. This approach has limitations, for example, intrapatient variability of effector‐to‐tumor cell ratio was not accounted for, and assay conditions may impact EC₉₀ evaluation. The s.c. administration was implemented relatively early in the MajesTEC‐1 study and registrational data were generated using s.c. administration. This strategy prevented the need for a separate s.c. development program and i.v.‐to‐s.c. bridging. Following accumulated clinical experience with T‐cell redirecting bispecifics, latter molecules can start FIH study with s.c. administration, which reduces the complexity of clinical study, drug supply, and formulation development, and accelerates the development.

Continued optimization is important for the management of CRS and other treatment emergent AEs. Combination with other anti‐myeloma agents may enable the ability to overcome resistance and achieve better outcomes. Dose optimization of combination therapies is needed to achieve maximal efficacy while maintaining safety. Mechanistic modeling, including quantitative system pharmacology modeling, that integrates disease and immune dynamics, is an exciting research area that could be used to support optimization of CRS management ²⁴ and combination strategy ²⁵ for bispecific antibodies.

FUNDING INFORMATION

No funding was received for this work.

CONFLICT OF INTEREST STATEMENT

Y.G., N.A.Q.C., L.K., A.B., R.K., K.C., C.U., K.P., M.D., J.S., N.H.‐B., and D.O. are employees of Johnson & Johnson and may hold stock in Johnson & Johnson. R.V. was an employee of Johnson & Johnson at the time the work was performed and is currently an employee of AbbVie, Inc., North Chicago, IL.

Guo Y, Quijano Cardé NA, Kang L, et al. Teclistamab: Mechanism of action, clinical, and translational science. Clin Transl Sci. 2024;17:e13717. doi: 10.1111/cts.13717