Engineering the Therapeutic Window for Solid Tumor T-Cell Engagers

T-cell engagers have established their clinical value in hematologic malignancies, but translation into solid tumors remains more difficult. Solid-tumor targets are often heterogeneous, expressed to some degree in normal tissue, and embedded in immunosuppressive microenvironments—making efficacy and safety harder to balance (Baeuerle, et al. 2026).

Tarlatamab provides an important proof of concept. In previously treated SCLC, it achieved a 40% ORR with a median duration of response of 9.7 months, demonstrating that systemic T-cell engagement can deliver meaningful activity in solid tumors (Ahn, et al. 2023). At the same time, CRS and neurologic toxicity (U.S. Food and Drug Administration, 2024, Amgen Inc, 2025) highlight the central development challenge and opportunity for improvement: creating durable antitumor activity within a controllable therapeutic window.

♦ Representative Solid Tumor TCE Landscape:

Together, these programs demonstrate that T-cell redirection is clinically feasible in solid tumors, but successful development remains highly dependent on target biology and control of T-cell activation. 

The Solid Tumor TCE Bottleneck

1. T-Cell Activation & Persistence: The safety-efficacy trade-off

• Excessive systemic activation → CRS: Unlike payload-driven ADCs, TCEs activate living T cells and can amplify immune responses through repeated killing and cytokine release. Excessive CD3 activation therefore creates a systemic safety liability.
• Excessive CD3 attenuation → insufficient tumor killing: Simply reducing CD3 activity may improve safety, but solid tumors already face limited T-cell infiltration and an immunosuppressive TME, making adequate antitumor activation difficult to sustain. AMG 340, a PSMA x CD3 TCE, illustrates this trade-off: low-affinity CD3 engagement reduced severe CRS, but clinical antitumor activity remained insufficient for further development (Falchook, et al. 2024).
• Repeated stimulation → T-cell exhaustion: Continuous TCE exposure can progressively impair T-cell function and lead to exhaustion; T-cell persistence becomes as important as initial activation (Philipp, et al. 2022).

2. Tumor Selectivity & Accessibility: The antigen ceiling

• Limited tumor selectivity and therapeutic window: Unlike lineage-associated targets such as CD19 and BCMA, most solid-tumor antigens are TAAs with some degree of normal-tissue expression (Baeuerle, et al. 2026). This increases on-target/off-tumor risk and can limit dose escalation before achieving optimal tumor exposure.
• Heterogeneity and accessibility: Variable antigen density and restricted epitope accessibility can further reduce effective TCE engagement and create uneven responses across tumors.

Design Principles for Next-Generation Solid Tumor TCEs

Expanding the therapeutic window of solid-tumor TCEs requires coordinated engineering of target engagement, T-cell activation, costimulation, and molecular architecture. Rather than optimizing potency alone, these variables need to be balanced according to the biology of each tumor target. 

• Select the right tumor target. Prioritize antigens with sufficient tumor density, limited accessible expression in normal tissues, and favorable epitope accessibility to support productive tumor engagement while reducing on-target/off-tumor risk (Garcia-Lorenzo, et al. 2026).
• Tune T-cell activation. CD3 signaling can be modulated through affinity, valency, and steric configuration to balance tumor-cell killing with systemic cytokine activation. Conditional strategies, such as protease-cleavable masking, can further restrict activation to the tumor microenvironment. 
• Integrate tumor-directed costimulation. Incorporating costimulatory signals such as 4-1BB or CD28 can provide Signal 2 to support T-cell expansion, survival, and functional persistence alongside CD3-mediated activation (Sun, et al. 2025). 
• Optimize avidity and molecular architecture. Valency, geometry, and multispecific format can be used to strengthen tumor-antigen engagement while maintaining controlled T-cell redirection. Format choices can also incorporate established heterodimerization and antibody-engineering approaches to enable increasingly complex TCE architectures. 

Together, these principles support a target-specific approach to TCE design, in which target biology and molecular architecture are engineered as an integrated system to improve the balance between efficacy and safety.

Biocytogen’s Solid Tumor TCE Solutions

Different solid-tumor targets may require different solutions to the therapeutic-window problem. Biocytogen's portfolio illustrates three complementary design strategies: costimulation, tumor avidity, and controlled CD3 engagement.

► BCG024: DLL3 × CD3 × 4-1BB Trispecific TCE

Design Strategy: Sustain T-cell function through localized 4-1BB costimulation

Asset Highlights:

• Validated DLL3 Tumor Targeting: The fully human anti-DLL3 antibody generated from RenMice® provides high-affinity DLL3 binding to support efficient tumor localization.
• CD3-Mediated T-Cell Redirection: BCG024 incorporates a SP34-derived anti-CD3 scFv, with a head-to-tail fusion designed to facilitate immunological synapse formation. Steric hindrance reduces CD3 binding, which helps further widen the therapeutic window.
• RenNano®-Derived 4-1BB Costimulation: The fully human anti-4-1BB VHH derived from RenNano® mice provides an additional costimulatory signal to enhance T-cell function, while its compact VHH format facilitates efficient trispecific antibody assembly.
• Balanced Preclinical Efficacy and Safety: BCG024 combines potent in vitro and in vivo activity with favorable preliminary safety, acceptable PK, and repeat-dose tolerability in non-human primates.

• BCG024 sustains T-cell function under repeated antigen challenge:

• BCG024 shows acceptable PK and favorable NHP tolerability:

► CDH17 × CD3 × CD28 Trispecific TCE

Asset Highlights:

• Tumor-Selective CDH17 Targeting: CDH17 is highly expressed in colorectal cancer (CRC) with limited expression in normal tissues, supporting its potential as a differentiated tumor-associated antigen for TCE development.
• CD28 Costimulation for Enhanced T-Cell Activation: Integrated CD28 costimulation reinforces CD3-mediated T-cell activation, driving TAA-dependent cytotoxicity without significant T-cell exhaustion.
• Potent Preclinical Activity with Favorable Safety: The CDH17-directed TCE demonstrates potent in vitro cytotoxicity and robust in vivo antitumor activity, with favorable safety profile in mouse models.

Preclinical Data Highlights:

• CD3 × CD28 × dual-CDH17 TCE shows enhanced in vivo antitumor efficacy:

 

 

Dual-CDH17-targeting tsAbs (2CDH17, tsAb=trispecific Ab) exhibited enhanced antitumor efficacy compared to single-CDH17 tsAbs.

• CD3 × CD28 × dual-CDH17 TCE demonstrated favorable safety in humanized mice:

► CRB2104: AMHR2 × CD3 TCE

• Emerging AMHR2 Tumor Target: AMHR2, a member of the TGF-β receptor superfamily, is expressed in 69% of primary epithelial ovarian cancer and 53% of colorectal cancer, supporting its potential as a solid-tumor TCE target (Barret, et al. 2021, Bakkum-Gamez, et al. 2008).
• 2:1 Avidity-Driven Design: Two high-affinity AMHR2-binding arms (KD = 133 pM) are designed to enhance tumor-antigen engagement, while a single CD3 arm enables monovalent T-cell redirection.
• Preclinical validation data available to download: A Novel 2:1 AMHR2/CD3 T Cell Engager with Potent Antitumor Activity and Mitigated CRS Risk in AMHR2+ Solid Tumors

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