Global Innovations in T Cell Engager (TCE) Pipelines Highlighted at AACR 2025: AstraZeneca, Qilu Pharmaceutical, Leads Biolabs and More

InThe emergence of immune checkpoint inhibitor antibody drugs targeting PD-1/PD-L1, CTLA-4, etc., has completely changed the landscape of cancer treatment. However, as the clinical research on these immune inhibitory molecules continues to deepen, the efficacy of some indications is gradually showing a bottleneck.Novel tumor immunotherapy antibody drugs based on immune-stimulating pathways have emerged.。

T Cell Engager（TCE)As an emerging cancer immunotherapy antibody, it works by spatially bringing T cells closer to target cells.Trigger T cell activation, implementEfficient Tumor Killing。Its unique advantage lies in mediating tumor cell recognition without relying on the major histocompatibility complex.（MHC）, effectively circumventing the challenge of tumor cells evading immune surveillance by downregulating the expression of MHC class I molecules. With high efficiency and flexibility, TCE has become a key research and development focus for global companies and scientific institutions.

American Association for Cancer Research（AACR）The annual meeting is a top academic event in the field of cancer research, known for its authority and influence. The cutting-edge achievements released each year are regarded as the global benchmark and innovation engine for the development of the oncology industry. The 2025 AACR Annual Meeting will be held grandly in Chicago, USA, from April 25 to 30. This article reviews representative TCE pipelines selected for the conference abstracts, providing references for industry practitioners.

Swipe up to view

▲ Representative TCE pipelines of enterprises selected for this year's AACR (the above ranking is not in any particular order)

According to incomplete statistics, the TCE track of this conference has attracted multinational pharmaceutical giants such as Amgen and AstraZeneca.（MNC）, about 20 biopharmaceutical companies in China have become standout players, including Innovent Biologics, Hengrui Medicine, and Qilu Pharmaceutical.

In terms of antibody types, from bispecific engagers, trispecific engagers to the MET/EGFR/CD2/CD3 tetraspecific engager innovatively developed by Qilu Pharmaceutical（QL615）, Technological iteration is accelerating.

In terms of indications, solid tumors and hematological tumors remain the focus of research, while some companies are also actively exploring the field of autoimmune diseases.

Target selection is the core key in TCE development. While most companies use CD3 as the T-cell target, AstraZeneca has taken a different approach by adopting a CD8-guided TCE design. In addition to the common targets such as CD19, CD20, BCMA, GPC3, and DLL.Novel targets such as CDH17, LY6G6D, LILRB4, and p53 R175H continue to emerge, and the targeted strategy combining tumors with immune checkpoints has also become a new trend.

The following is a detailed description of some representative company pipelines:

CC312 is based on Huihe Bio's new generation of costimulatory signal TCE platform TriTE.^TMIndependently developed, mainly targeting tumors and autoimmune diseases, it is also the world's first approved clinical trial application for a new drug for systemic lupus erythematosus.（IND）TheCD19/CD28/CD3 Targeted Tri-Antibody.

CC312 bridges T cells and target cells, enabling T cells to strongly, precisely, and persistently kill tumors under the dual action of the primary activation signal CD3 and the co-stimulatory signal CD28, while also treating autoimmune diseases by effectively depleting B cells.

An investigator-initiated clinical trial is evaluating the safety, tolerability, and efficacy of CC312 for the treatment of B cell-related autoimmune diseases, including refractory systemic lupus erythematosus, idiopathic inflammatory myopathy, and systemic sclerosis.

Current data shows that CC312 is well-tolerated, with no occurrence of grade 3 or higher cytokine release syndrome.（CRS）Immune Effector Cell-Associated Neurotoxicity Syndrome（ICANS）. Even at the lowest dose(5 micrograms/dose)Below, CC312 can also achieve comprehensive depletion of peripheral B cells and their subsets, accompanied by improvement or remission of patients' disease symptoms, demonstrating great clinical application potential.

In the Phase Ia clinical trial conducted among patients with relapsed/refractory B-cell non-Hodgkin lymphoma and relapsed/refractory lymphocytic leukemia, CC312 demonstrated favorable clinical safety. Different doses of CC312 effectively achieved multiple depletions of B cells in peripheral blood and significantly promoted the expansion and activation of CD4 and CD8 T cells in patients with B-cell lymphoma.

EVOLVE205 is a dual-target agent with integrated CD2 agonist activity developed by EvolveImmune.（2:1）CD20-targeted TCE. This TCE optimizes T-cell redirection through a CD2 co-stimulatory mechanism while enhancing affinity for CD20, potentially achieving superior performance compared to clinical benchmarks.

At the cellular level, EVOLVE205 demonstrated potent cytotoxicity in both diffuse large B-cell lymphoma cell line models and primary tissue B cells.

Particularly noteworthy is that in the co-culture experiment of B-cell depleted peripheral blood mononuclear cells with HT tumor cells, compared with the marketed CD20/CD3 TCE drug gefutumab（Glofitamab）, the tumor-killing efficacy of EVOLVE205 has increased up to 70 times; compared with traditional anti-CD20 monoclonal antibodies(such as Rituximab)By comparison, its killing ability is more than 1000 times stronger.

Animal studies have shown that at the dose level allowing tumor growth for gefitumab, EVOLVE205 demonstrated significantly enhanced tumor growth inhibition.

Overall, EVOLVE205 demonstrated potent tumor-killing ability in vitro without inducing excessive cytokine production, and also showed significant in vivo efficacy along with favorable developability characteristics.

Compared with clinically existing TCE targeting CD20 and anti-CD20 monoclonal antibodies used for the treatment of B-cell lymphoma and B-cell mediated autoimmune diseases, EVOLVE205, which integrates CD2 co-stimulatory function, offers superior efficacy and safety advantages.

AZD9793 is an innovative CD8-guided trispecific TCE developed by AstraZeneca, currently under development for the treatment of GPC3-positive solid tumors, including hepatocellular carcinoma.（HCC）。

It consists of two antigen-binding fragments that bind to GPC3 on the surface of cancer cells.（Fab）Domain, one with the human T-cell receptor（TCR）Composed of a nanobody domain binding to the surface human CD8 co-receptor on T cells.

In vitro studies have shown that AZD9793 effectively kills hepatocellular carcinoma cells by preferentially recruiting CD8+ T cells through binding with CD8/TCR, while reducing the activation of CD4+ T cells. This bias significantly limits the production of CRS-related cytokines compared to traditional GPC3/CD3 TCEs.

In humanized mouse models, AZD9793 demonstrates potent and dose-dependent anti-tumor efficacy against hepatocellular carcinoma and non-small cell lung cancer xenografts by enhancing T-cell infiltration and increasing the CD8/CD4 T-cell ratio within tumors. Additionally, AZD9793 acts in a manner dependent on interferon-γ.（IFN-γ）The mechanism mediates the bystander killing effect on antigen-negative cells in the tumor microenvironment and effectively controls tumors with heterogeneous GPC3 expression.

HY05350 is a trispecific TCE targeting PD-L1/MSLN/CD3 independently developed by Huiyu Pharmaceutical. It can recognize and recruit T cells through the CD3 antibody, identify and target tumor cells via the MSLN antibody and/or PD-L1 antibody, while also reactivating immune cells by blocking the immunosuppressive effect of tumor cells on T cells through the PD-L1 antibody.

In vitro and in vivo studies have shown that, compared with traditional bispecific antibodies（MSLN/CD3）HY05350 can induce a stronger second signal for T-cell activation. The key lies in the CD3/PD-L1 domain, which targets PD-L1 on the surface of antigen-presenting cells, indirectly enhancing T-cell function by activating APC, thereby triggering a more efficient anti-tumor immune response than directly bridging T cells and cancer cells, significantly improving therapeutic efficacy.

In multiple human tumor cell line xenograft mouse models, HY05350 demonstrated potent anti-tumor activity. GLP toxicity studies in cynomolgus monkeys showed that HY05350 was well-tolerated, with a toxicity profile comparable to typical CD3-based bispecific antibodies and acceptable pharmacokinetics/pharmacodynamics.（PK/TK）Characteristics, with a half-life of 12 to 35 hours.

QL615 is a quad-specific TCE developed based on Qilu Pharmaceutical's TECAD platform, which effectively addresses the issues of insufficient tumor selectivity and limited efficacy through a unique quad-specific molecular design and CD2-conditioned activation-mediated CD3 co-stimulation mechanism.

Cell binding experiments confirmed that QL615 exhibits nanomolar half-maximal effective concentration (EC50) on tumor cells co-expressing MET and EGFR.（EC50）; whereas in the low-level expression of a single target(MET or EGFR)On the cells, its binding affinity is nearly negligible, significantly reducing the off-target risk.

QL615 exhibits over 1,000-fold selectivity for the lysis of double-positive tumor cells; compared with traditional constructs that only possess CD3 redirection functionality, the TECAD platform enhances tumor cell killing ability by approximately 30 times through CD2 co-stimulation. In in vivo experiments, QL615 demonstrated superior tumor growth control effects compared to similar products under development.

LILRB4 belongs to the LILRB family and is a type I transmembrane protein, with a structure that includes two extracellular Ig domains, a transmembrane domain, and three cytoplasmic immunoreceptor tyrosine-based inhibitory motifs.（ITIM）, mainly involved in the negative regulation of immune response. Studies have found that LILRB4 is associated with multiple myeloma.（MM）It exhibits high-specificity expression in China, making it a highly promising targeted therapeutic target for MM.

LBL-043, developed by Leads Biolab based on its self-developed LeadsBody CD3 bispecific antibody technology platform, is a bispecific TCE targeting LILRB4. This TCE features a unique molecular design and mechanism of action. LBL-043 can only perform specific targeted killing when the target cells express LILRB4, and it demonstrates potent killing effects on tumor cells with both high and low expression of LILRB4.

In the NCI-H929 human tumor cell line xenograft mouse model, LBL-043 demonstrated significant anti-tumor activity. Dose exploration studies in drug toxicology evaluations have shown that LBL-043 has good safety in cynomolgus monkeys.

Exciting Live Broadcast Preview

Press and hold to scan the QR code to participate immediately ↓

Swipe up to view

Recommendation 1

April 28, 19:00-20:00

Industry-Research Dialogue: Innovation and Translation of CAR-NK Therapy for Solid Tumors

Recommendation 2

April 29, 15:00-16:00

Development and Safety Testing of "Universal" Technology in Cell Therapy

In Collaboration with 医麦客 IBI EXPO 2026

DianDian "Share”、“Like" and "In View", give me a little recharge~"