Immune Checkpoint Bispecific Antibodies Take Center Stage at AACR 2025

Multiple Novel Bispecific Antibodies Based on Immune Checkpoints Debut at the 2025 AACR Annual Meeting, Becoming a Major Highlight of This Year's AACR Conference. Below, We Provide a Summary of the Key Highlights.

• Targeting PD-(L)1 Bispecific Antibodies: Emergence of Solutions to Overcome Resistance

Innovent Bio Discloses Two Groundbreaking Bispecific Antibody Research Achievements, Targeting the Pain Point of Immunotherapy Resistance. The CD40/PD-L1 bispecific antibody IAR037 developed by the company shows breakthrough progress. This molecule, through an innovative dual-target synergistic design, activates the CD40 co-stimulatory signal while blocking the PD-1/PD-L1 immune suppression axis, achieving significant tumor suppression in PD-1 resistant tumor models. Preclinical studies show that the combination of IAR037 with an IL-2α-biased fusion protein produces a synergistic anti-tumor effect, with minimal systemic side effects and good safety demonstrated in cynomolgus monkeys. The IND is currently in progress.

In addition, its globally first-in-class PD-1/IL-12 fusion protein IBI3026 has also attracted widespread attention. This innovative molecule achieves tumor-targeted activation by reducing IL-12 activity while enriching PD-1 positive T cells. Preclinical data show that IBI3026 demonstrates complete inhibition in multiple tumor models, and studies in cynomolgus monkeys indicate its excellent safety with a therapeutic index of 63. By combining PD-1 blockade with localized IL-12 activation, IBI3026 provides an innovative treatment strategy for tumors resistant to current immunotherapies.

• Targeting PD-1 Trispecific Antibody: Pioneering a New Path in Tumor Immunotherapy

CT111, the world’s first PD-1/CTLA-4/VEGF trispecific antibody jointly developed by Shanghai Cell Therapy Group and its U.S. subsidiary Chantibody, has become a new focus in the field of cancer immunotherapy due to its innovative triple-target synergistic mechanism and breakthrough efficacy.

As an innovative drug developed based on the fourth-generation nanobody VHHMAb® technology platform, CT111 integrates dual immune checkpoint blockade with VEGF pathway inhibition to form a triple synergistic effect of "immune activation + vascular normalization + Treg suppression," overcoming resistance to existing therapies. It has shown significant efficacy, particularly in PD-(L)1-resistant solid tumors. Its unique VHH single-domain structure reduces molecular size by 30%-40%, theoretically enhancing tumor penetration efficiency while retaining potent target inhibition activity. Preclinical data show that CT111 demonstrated superior anti-tumor efficacy in non-small cell lung cancer models with a single dose surpassing high-dose groups of control drugs. It significantly increased intratumoral CD8+ T-cell infiltration and reduced Treg proportions, while exhibiting better safety and pharmacokinetic properties than existing therapies, including longer half-life and stability, offering cancer patients a novel solution with both innovation and clinical potential.

Product Recommendation:PD-1；PD-L1；CTLA-4；VEGF；More Popular Targets and Services for Bispecific Antibodies

As a hot area of this conference, the research and development of bispecific antibody-drug conjugates (BsADC) has also made breakthroughs.

IBI3014, the world's first TROP2×PD-L1 BsADC drug developed by Innovent Bio, enhances immunogenic cell death (ICD) and T-cell infiltration by integrating TROP-2-mediated tumor killing with PD-L1 immune checkpoint blockade. It demonstrated broad-spectrum anti-tumor activity surpassing traditional ADCs in CDX models with varying TROP-2/PD-L1 expression levels. In cynomolgus monkey toxicology studies, IBI3014 maintained excellent safety even at a high dose of 50 mg/kg, offering a breakthrough strategy for solid tumor treatment.

In addition to IBI3014, Innovent Bio also announced relevant data on another BsADC drug, IBI3022, which targets TROP-2×B7-H4. Through innovative structural design, it achieves precise toxicity control by using a single-arm TROP-2 antibody and a low-toxicity NT3 linker payload to reduce off-target toxicity associated with TROP-2. In in vivo studies, IBI3022 demonstrated stronger tumor suppression effects than the benchmark ADC of monoclonal antibodies in tumor models with different expression levels of TROP-2 and B7-H4, while showing good safety.

• DuoXi Bio Differentiated Layout of PD-1/VEGF BsADC: DXA023-G017

In the context of intense competition in the PD-1/VEGF bispecific antibody field, DuoXi Biologics has differentiated its PD-1/VEGF BsADC DXA023-G017 by innovating the drug format, providing a new strategy for the treatment of advanced solid tumors. DuoXi Biologics presented the Preclinical Poster of DXA023‑G017 at the AACR 2025 conference. This drug is based on the tetravalent bispecific antibody DXA023, showing high-affinity binding to both PD-1 and VEGF. The Fc segment function was optimized through AAS mutations to reduce ADCC effects while retaining FcRn affinity to extend half-life. Additionally, it is conjugated with the small molecule compound G017 to form a dual killing mechanism of "immune checkpoint blockade + chemotherapy."

In vitro experiments showed that DXA023 has specific and high-affinity binding ability to human PD-1 and VEGF. Moreover, both DXA023 and DXA023-G017 effectively block the PD-1/PD-L1 signaling pathway and exhibit significant in vitro anti-tumor activity. In the HCC827-PBMC mouse model, DXA023-G017 demonstrated superior anti-tumor efficacy compared to DXA023 while maintaining good tolerability.

• Alphamab Oncology FIC BsADC: JSKN022(PD-L1/ITGB6)

Alphatean

Product Recommendation:TROP-2；ITGB6；B7-H4; ADC Drug Development Solutions

T-cell engagers (TCE) have become a new favorite in the field of immunotherapy by bridging T cells and tumor cells to directly activate T-cell mediated tumor killing. At this year’s AACR annual meeting, significant progress has been made in target selection and structural design of TCE technology, opening new dimensions for TCE development.

• Huihe Bio: CD19/CD28/CD3 Trispecific TCE, Pioneering in Oncology and Autoimmune Diseases

Huihe Biopharmaceuticals announced at the AACR conference groundbreaking progress on CC312 (CD19/CD28/CD3), the world’s first co-stimulatory tri-specific antibody to receive IND approval for systemic lupus erythematosus (SLE). The team clearly stated that CC312 synergistically activates the T-cell receptor and CD28 co-stimulation signaling pathways, effectively avoiding T-cell exhaustion while enhancing TCE killing efficacy under low B-cell burden. This demonstrates dual therapeutic potential in both B-cell malignancies and autoimmune diseases. Phase Ia clinical trials showed that a very low dose of 5μg/kg led to complete depletion of peripheral B cells, with no occurrence of Grade 3 or higher cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS), setting a new benchmark for efficacy and safety in the treatment of B-cell-related diseases.

• EvolveImmune EVOLVE205: A More Efficacious CD20/CD2/CD3 Tri-Specific Antibody

EVOLVE205, developed by EvolveImmune, revolutionizes TCE design through the CD2 co-stimulation mechanism. The drug adopts a 2:1 structural design, enhancing T-cell activity via CD2 co-stimulatory signals. In vitro experiments demonstrate that its killing efficacy in a B-cell depletion PBMC and HT tumor cell co-culture model is 70 times higher than the marketed CD20/CD3 bispecific antibody Glofitamab and over 1000 times more potent than Rituximab. Animal studies show significantly superior tumor suppression at equivalent doses, with lower cytokine release levels, showcasing dual breakthroughs in efficacy and safety.

• Zymeworks: CD28 Co-stimulatory Tri-specific Antibody

Notably, Zymeworks' ZW209 trispecific antibody, unveiled at AACR, employs an innovative enforced cis-binding mechanism to achieve sustained T-cell activation by integrating CD28 co-stimulatory signals. Preclinical studies demonstrate that this molecule exhibits prolonged anti-tumor activity surpassing traditional TCEs both in vivo and in vitro. Toxicology studies in monkeys confirm a half-life exceeding 7 days with good tolerability and no occurrence of T-cell fratricide. As the first CD28 co-stimulatory trispecific antibody to enter clinical trials, ZW209 is expected to initiate IND in 2026, potentially redefining the TCE treatment paradigm.

Product Recommendation:CD19；CD28；CD3；CD2；Excitatory Target Protein

ZW209Structural Diagram

• CTLA-4 Protein Dimer Structure Validated by SEC-MALS

The purity of Human CTLA-4, His Tag (Cat. No. CT4-H52H9) is more than 90% and the molecular weight of this protein is around 45-60 kDa verified by SEC-MALS.

• PD-1 Binding Activity with Antibody Validated by ELISA

Immobilized Human PD-1, His Tag (Cat. No. PD1-H5221) at 2 μg/mL (100 μL/well) can bind Nivolumab with a linear range of 0.1-3 ng/mL (Routinely tested).

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• CD2 binding activity with ligand validated by ELISA

Immobilized Human CD58, Fc Tag (Cat. No. LF3-H5256) at 5 μg/mL (100 μL/well) can bind Human CD2, His Tag (Cat. No. CD2-H5226) with a linear range of 39-312 ng/mL (QC tested).

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• The binding activity of PD-1 and PD-L1 was verified by SPR.

Human PD-1 Protein, Fc Tag (Cat. No. PD1-H5257) captured on CM5 chip via anti-human IgG Fc antibody, can bind Human PD-L1, His Tag (Cat. No. PD1-H5229) with an affinity constant of 3.6 μM as determined in a SPR assay (Biacore T200) (Routinely tested).

• B7-H4 Binding Activity with Antibody Validated by SPR

Anti-B7-H4 antibody, Human IgG1 captured on CM5 chip via Anti-human IgG Fc antibodies surface can bind Canine B7-H4, His Tag (Cat. No. B74-C52H8) with an affinity constant of 8.59 nM as determined in a SPR assay (Biacore 8K) (Routinely tested).

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• Pharmacokinetic Analysis - PK Analysis

Quantitative Analysis of CTLA-4 x OX40 Bispecific Antibody in Human Serum by Intact Assay.
Immobilized Human OX40 Protein, His Tag (MALS verified) (Cat. No. OX0-H5224) at 2 μg/mL, add increasing concentrations of CTLA-4 x OX40 bispecific antibody in 50% Human serum and then add Biotinylated Human CTLA-4, His, Avitag (Cat. No. CT4-H82E3) at 0.2 μg/mL. Detection was performed using HRP-conjugated streptavidin with sensitivity of 4 ng/mL (Intact assay, Routinely tested).

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