SUMMARY

• Teclistamab is a humanized immunoglobulin G4 (IgG4) bispecific DuoBody^® antibody that recognizes B-cell maturation antigen (BCMA) on multiple myeloma (MM) cells and cluster of differentiation-3-epsilon (CD3ε) on T cells.¹
  • Teclistamab is generated via Fab-arm exchange of a BCMA and CD3 antibody using mutations and recombination at the CH3-CH3 antibody interface. Heavy and light chain homodimers combine into a single heterodimeric, bispecific antibody construct.²
  • The fragment crystallizable (Fc) region of teclistamab is silenced to eliminate Fc-dependent immune effector activity.³
  • It is hypothesized that through recruitment of CD3-expressing T cells to BCMA-expressing MM cells, teclistamab will induce T cell-mediated cytotoxicity, causing targeted cell lysis by perforins and granzymes secreted by cytotoxic T cells.¹
• Teclistamab selectively bound to and activated CD4⁺ and CD8⁺ T cells, and demonstrated dose-dependent, T cell-mediated lysis of MM cells in studies conducted in an in vitro human whole blood model and in bone marrow (BM) aspirates collected from patients with MM.^1,3
• Teclistamab specifically bound to BCMA⁺ cell lines and elicited T cell-mediated cytotoxic response in vitro. No binding, cytotoxic response, or T-cell activation was reported with BCMA×Null and Null×CD3 control antibodies, indicating that concomitant binding to CD3 on T cells and BCMA on target cells is necessary for activity.¹
• In vitro, the potency of teclistamab was not affected significantly in the presence of low to moderate concentrations of soluble BCMA (sBCMA), a proliferation-inducing ligand (APRIL) or B-cell activating factor (BAFF); however, the cytotoxic effect of teclistamab was increased by the gamma (γ)-secretase-mediated inhibition of sBCMA release.^1,3

BACKGROUND

Role of BCMA in MM Pathophysiology and Therapy

BCMA, a member of the tumor necrosis factor receptor superfamily, is expressed preferentially in mature B lymphocytes, with minimal expression in hematopoietic stem cells or nonhematopoietic tissue. Natural ligands of BCMA include BAFF and APRIL, of which APRIL has a higher affinity toward the receptor. Although BCMA is essential for the survival of long-lived bone marrow plasma cells, it is not critical for overall B-cell homeostasis.²

BCMA overexpression and activation is associated with the progression of MM both in preclinical models and humans, making it an appropriate therapeutic target. However, in MM, membrane-bound BCMA undergoes γ-secretase-mediated cleavage at the transmembrane domain, resulting in circulation of sBCMA. This may reduce therapeutic efficacy by reducing the binding of teclistamab with membrane-bound BCMA. Higher sBCMA levels have also been correlated with disease progression and shorter overall survival.^1,2

Murine xenografts with induced BCMA overexpression proliferated faster than BCMA^- controls and exhibited upregulation of both canonical and noncanonical nuclear factor kappa-B pathways, leading to enhanced expression of critical genes required for growth, adhesion, osteoclast activation, angiogenesis, metastasis, immunosuppression and survival. Similar results were observed in ex vivo human MM cells after APRIL-induced BCMA activation.²

sBCMA has been reported to inhibit BAFF activity by complex formation, leading to MM-associated immunodeficiency. Lower than normal concentrations (9 to 50-fold lower) of BCMA are expressed in plasmacytoid dendritic cells, which promote the survival of MM plasma cells (PCs) in the BM environment.²

Mechanism of Action

Teclistamab is a humanized IgG4 BCMA × CD3 bispecific DuoBody^® antibody that recognizes BCMA on MM cells and CD3ε on T cells.¹ Teclistamab is generated via Fab-arm exchange of a BCMA and CD3 antibody using mutations and recombination at the CH3-CH3 antibody interface. Heavy and light chain homodimers combine into a single heterodimeric, bispecific antibody construct.² The Fc region of teclistamab is silenced to eliminate Fc-dependent immune effector activity.³ It is hypothesized that through recruitment of CD3-expressing T cells to BCMA-expressing MM cells, teclistamab will induce T cell-mediated cytotoxicity, causing targeted cell lysis by perforins and granzymes secreted by cytotoxic T cells.¹ Data from preclinical studies that evaluated the mechanism of action of teclistamab are summarized below.

Recruitment of T Cells by Teclistamab

In an in vitro healthy human whole blood model, teclistamab selectively bound to and activated T cells (natural killer [NK], CD4⁺, and CD8⁺) but no other leukocytes. Furthermore, teclistamab demonstrated a dose-dependent, T cell-mediated lysis of H929 cells when introduced into healthy human whole blood at an H929 effector-to-target cell (E:T) ratio of 5:1 with increasing concentrations of teclistamab for 48 hours.¹

In BM aspirates collected from patients with MM (N=55), teclistamab-induced lysis of primary MM cells coincided with the enhanced expression of CD25, indicating an initial significant increase in the percentage of activated CD4⁺ and CD8⁺ T cells. Enhanced surface CD107a expression indicated teclistamab-induced degranulation of CD4⁺ and CD8⁺ T cells. A dose-dependent increase in levels of granzyme B, interferon-γ, interleukin (IL)-2, IL-6, IL-8, IL-10, and tumor necrosis factor-alfa were also reported. A significant increase in the frequency of Fas ligand (FasL)⁺ T cells after teclistamab treatment was observed, indicating potential MM cell lysis by Fas-FasL-based interactions. No activation or degranulation of NK cells was reported.³

Teclistamab-mediated lysis of MM cells was associated with a high T-cell frequency (P=0.034) and high E:T ratio (P=0.029) in BM aspirates collected from patients with MM. However, in a subgroup analysis of patients with relapsed or refractory multiple myeloma (RRMM), frequencies of activated, naïve, central memory, effector memory, or terminally differentiated effector memory T cells were not associated with response to teclistamab.³

BCMA-Dependent Activity of Teclistamab

In an in vitro cell line study, teclistamab-induced T cell-mediated cytotoxicity was reported in BCMA⁺ H929, MM.1R, and RPMI-8226 cell lines (50% effective concentration [EC₅₀], 0.15 nM in H929, 0.06 nM in MM.1R, and 0.45 nM in RPMI-8226). However, cytotoxicity was not induced in BCMA^- MV4-11 cell lines. An increase in CD25 expression (EC₅₀, 0.21 nM in H929, 0.1 nM in MM.1R, and 0.28 nM in RPMI-8226) indicated T-cell activation with BCMA⁺ cells, while no activation was reported at similar concentrations with BCMA^- cells. Cytotoxic activity did not correlate with BCMA receptor count and teclistamab did not activate the BCMA receptor as evidenced by lack of phosphorylation of downstream pathway targets.¹

Concomitant Binding of Teclistamab to BCMA and CD3

In an in vitro cell line study, teclistamab bound in a dose-dependent manner to CD138⁺ BM mononuclear cells (MNCs) collected from patients with MM (N=3). Teclistamab-induced cytotoxicity (EC₅₀ range, 1.5-4.2 nM) and teclistamab-induced T-cell activation (EC₅₀ range, 0.93-1.75 nM) against BM MNCs were similar across evaluated samples. However, no binding, cytotoxic response, or T-cell activation was reported for the BCMA×Null and Null×CD3 control antibodies, indicating that concomitant binding to CD3 on T cells and BCMA on target cells is necessary for activity.¹

In an in vitro cell line study, a dose-dependent lysis of RPMI-8226, UM9, U266, and MM1.S cell lines were reported with teclistamab regardless of the level of BCMA expression. A near-complete lysis of all 4 cell lines was reported at a dose of 0.16 µg/mL. A dose-dependent increase in cell-surface expression of CD25 and CD107a indicated teclistamab-induced activation and degranulation of both CD4⁺ and CD8⁺ T cells.³

Regulators of Teclistamab Activity

In an in vitro cytotoxicity assay, the potency of teclistamab was not significantly altered in the presence of sBCMA, APRIL, or BAFF. A significant decrease in potency was reported in response to high concentrations of sBCMA (>55.5 nM) and APRIL (>15.4 nM), however exogenous BAFF had no impact on potency. Influence of sBCMA, APRIL, and BAFF on the degree of teclistamab-induced T-cell activation correlated with cytotoxicity response.¹

In an in vitro study on RPMI-8226 cells, increasing concentrations of sBCMA significantly increased the EC₅₀ of teclistamab (EC₅₀, 0.0089 ng/mL at sBCMA 30 ng/mL and EC₅₀, 0.27 ng/mL at sBCMA 1500 ng/mL [P<0.0001, respectively]) compared with no sBCMA (EC₅₀, 0.0015 ng/mL). High concentrations of APRIL (500 ng/mL) significantly increased the EC₅₀ of teclistamab (0.034 ng/mL; P<0.0001) compared with no APRIL (EC₅₀, 0.0071 ng/mL); however, the maximum lysis capacity was not affected.³

In an ex vivo assay, teclistamab decreased sBCMA levels in a dose-dependent manner (range, 0.0064-4 µg/mL) when incubated for 48 hours with BM MNCs isolated from patients with RRMM (n=14). Although the activity of teclistamab was affected by sBCMA levels, maximal lysis of MM cells remained unchanged.³

In an in vitro study on H929 cells, inhibition of γ-secretase by LY-411575, resulting in reduced sBCMA and elevated surface BCMA expression, increased the cytotoxic effect of teclistamab (EC₅₀, 0.004 nM with 0.1 nM LY-411575; EC₅₀, 0.002 nM with 1 nM LY-411575) compared with a control (EC₅₀, 0.09 nM). Inhibition of γ-secretase also increased teclistamab-induced T-cell activation (EC₅₀, 0.001 nM and 0.0003 nM) compared with a control (EC₅₀, 0.04 nM).¹

In RPMI-8226, UM9, and U266 cell lines, the activity of teclistamab was not impacted by the presence of bone marrow stromal cells (BMSCs). A modest inhibition by BMSCs was reported in the MM1.S cell line at lower concentrations (P<0.0001), but this effect was negated by increasing the concentration of teclistamab.³

In BM aspirates collected from patients with MM, a high frequency of regulatory T cells decreased teclistamab-mediated MM-cell lysis at low doses (0.0064 µg/mL and 0.032 µg/mL) in patients with RRMM but was overcome by increasing the dose (not statistically significant). In a multivariate analysis, T-cell frequency was reported as an independent determinant of response to teclistamab (P=0.024). Overall, the efficacy of teclistamab was not associated with cytogenetic risk status or affected by the level of cell-surface expression of BCMA and programmed death-ligand 1.³

Literature search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 08 April 2024.