Dual-Specific ADCs Break Through Solid Tumor Therapy: Successful Practice of Multi-Target Strategies and CDX Model Validation

With the advent of the precision medicine era, bispecific antibody–drug conjugates (bispecific ADCs) are becoming a new focal point in the oncology field, leading the third wave of anticancer therapy. Over the past few years, our team has completed preclinical in vivo efficacy evaluations of multiple bispecific ADCs across various CDX models, covering multiple target combinations such as EGFR–cMET ADCs, EGFR–PDL1 ADCs, and EGFR–B7H3 ADCs. These studies have demonstrated the significant advantages of bispecific ADCs in overcoming tumor heterogeneity and drug resistance.

01 Target Battle: Key Molecules in Solid Tumor Therapy

Epidermal growth factor receptor (EGFR) and its family member HER3, as well as hepatocyte growth factor receptor (c-Met) and B7-H3, constitute the core target network for solid tumor–targeted therapy. These molecules play critical roles in tumor growth, metastasis, and resistance mechanisms. As important members of the receptor tyrosine kinase family, EGFR and c-Met are often aberrantly activated simultaneously in solid tumors such as lung cancer. They exhibit synergistic effects in downstream signal transduction, and combined blockade can simultaneously inhibit the PI3K/AKT/mTOR and Ras/Raf/Mek pathways, effectively preventing compensatory escape of tumor cells.

B7-H3 is a transmembrane glycoprotein that plays a key role in antitumor immune responses and tumor microenvironment formation. It is overexpressed in a variety of solid tumors and is closely associated with rapid disease progression and poor prognosis. Notably, the expression patterns of these targets in tumor tissues show significant differences. EGFR mutations account for approximately 15%–40% of non-small cell lung cancer cases, while EGFR wild-type patients account for 70%–85%. This disparity provides a theoretical basis for the precision treatment enabled by bispecific ADCs.

EGFR (epidermal growth factor receptor) is a member of the EGFR family and plays an important role in cell growth, development, and differentiation. It is highly expressed in many solid tumors, including non-small cell lung cancer, head and neck squamous cell carcinoma, and glioblastoma. Over the past three decades, multiple blockbuster drugs targeting EGFR have been developed. However, small-molecule therapies often induce mutations that lead to treatment resistance. EGFR is one of the most intensively studied targets in ADC drug research, ranking among the top in terms of pipeline volume. Globally, there are currently more than 20 EGFR-ADC programs, with domestic companies leading or participating in 6 EGFR-ADC projects.

(doi.org/10.1080/19420862.2023.2229101)

02 Advantages and Frontier Progress of Bispecific ADCs

ADC (Antibody–Drug Conjugate): Like a “biological missile,” it is composed of three parts: an antibody (guidance system), a cytotoxic drug (warhead), and a linker (chain). It can precisely recognize specific targets on the surface of cancer cells and deliver highly potent cytotoxic agents for precise killing.

Bispecific ADC: Can be understood as an “upgraded dual-warhead biological missile.” Its antibody component is a bispecific antibody that can simultaneously bind two different targets (such as EGFR and HER3) or two different epitopes of the same target. This design brings multiple advantages:

Enhanced tumor targeting and reduced off-target toxicity: Dual recognition enables more precise binding to tumor cells and reduces damage to normal tissues.
Overcoming resistance: Simultaneous blockade of two tumor signaling pathways delays or reverses the development of resistance.
Promoted drug internalization: The “cross-linking effect” of bispecific antibodies accelerates internalization of the antibody–antigen complex, improving toxin delivery into tumor cells.

Bispecific ADCs include dual-target ADCs and dual-epitope ADCs, integrating the precise targeting of bispecific antibodies with the high killing efficiency of ADCs. Compared with conventional monospecific ADCs, the most notable advantage of bispecific ADCs is their ability to simultaneously bind two different antigens, expanding target coverage, further improving internalization efficiency, enhancing tumor targeting, and reducing systemic toxicity. Bispecific ADCs can significantly improve internalization efficiency through multiple mechanisms, including forced internalization, aggregation, or cross-linking to form large antigen–antibody complexes.

(10.1016/j.apsb.2024.01.009)

As of August 20, 2025, more than 40 bispecific ADC drugs are at the IND and clinical stages, with 3 products having entered pivotal Phase III studies. Recently, the global first-in-class EGFR×HER3 bispecific ADC Iza-bren (also known as BL-B01D1), independently developed by Biologics company, achieved its primary endpoint in an interim analysis of a Phase III clinical trial, marking a milestone breakthrough for bispecific ADCs in oncology.

03 Selection and Validation of Preclinical Models

The choice of animal models is critical in preclinical efficacy evaluation. CDX models have become an important tool for preclinical evaluation of ADC drugs. Different CDX models provide significant advantages in bispecific ADC efficacy assessment, mainly reflected in the following aspects:

Simulation of tumor heterogeneity: Different CDX models are derived from different cell lines, with variations in target expression levels, proliferation rates, and histological features. This diversity effectively simulates the heterogeneity seen in clinical tumor patients. Using multiple CDX models allows for more comprehensive prediction of drug efficacy across different patient populations and reduces bias risk.
Evaluation of target synergistic effects: The core advantage of bispecific ADCs lies in their synergistic targeting capability. For example, EGFR–cMET bispecific ADCs may be effective in tumors with high EGFR expression alone, high cMET expression alone, or dual high expression, but with varying degrees of efficacy. Testing across different CDX models, including single-target high expression and dual-target co-expression combinations, enables scientific evaluation of synergy and identification of the optimal indication population.
Enhanced data credibility and predictive value: Positive results from a single model may be incidental. Observing consistent tumor growth inhibition across multiple independently validated CDX models greatly enhances the credibility of preclinical data and its predictive value for clinical translation, providing solid, multidimensional evidence for subsequent clinical trial design such as dose selection and patient enrollment criteria.
Strong support for IND submission: Regulatory agencies such as the NMPA and FDA place great emphasis on the completeness and reliability of preclinical data during IND review. Providing consistent and effective efficacy data across multiple CDX models forms a strong evidence chain demonstrating broad-spectrum or specific antitumor potential, significantly increasing the success rate of IND submissions.

Kyinno Biotechnology’s in vivo pharmacology platform has established and validated more than 800 CDX models, covering 24 common tumor types and target-related tumor models, providing strong support for the preclinical research of bispecific ADCs.

04 Challenges and Future Directions of Bispecific ADCs

Despite their promising outlook, bispecific ADCs still face many challenges. Tumor heterogeneity and resistance remain major factors limiting ADC clinical efficacy, while safety optimization is also a key driver of ADC iteration. Future development directions for bispecific ADCs include discovering novel target combinations, optimizing linker technologies, and improving payload potency. In recent years, researchers have accelerated next-generation ADC development through multidimensional innovation strategies. Multiple types of novel ADCs are in preclinical and early clinical development, including bispecific ADCs, dual-payload ADCs, prodrug ADCs (PDCs), immune-stimulating antibody conjugates (ISACs), and antibody–drug conjugate degraders (DACs), demonstrating diverse therapeutic potential.

05 Kyinno Biotechnology Tumor Efficacy Model Service Platform: Focusing on Key Stages of Oncology Drug R&D

Antibody discovery: Proprietary platforms include light-chain bispecific antibody discovery mouse platforms and nanobody discovery mouse platforms. Traditional hybridoma immunization combined with single B-cell sequencing enables rapid and efficient screening and discovery of antibody drugs for all targets. Independently developed AI design platforms and the AB5000 platform support antibody affinity maturation, humanization, and target non-specificity validation.

In vivo and in vitro efficacy evaluation: Covers EGFR mutant, TKI-resistant, and wild-type CDX tumor models, supporting multi-cancer evaluations including non-small cell lung cancer, breast cancer, colorectal cancer, and head and neck cancer.
Dedicated bispecific ADC evaluation system: Includes analysis of key parameters such as target binding efficiency, internalization activity, and bystander effect.
Preclinical simulation of combination therapies: Evaluation of ADCs in combination with immune checkpoint inhibitors and other regimens.

To support bispecific ADC drug development, Kyinno Biotechnology leverages its strong antibody discovery, engineered cell, and in vivo and in vitro pharmacology platforms to develop a series of bispecific antibodies and bispecific ADCs. The goal is to provide more effective and better-tolerated treatment options for cancer patients carrying mutations in EGFR, c-Met, B7-H3, PDL1, VEGFR, and other targets. Contact us for more antibody discovery services, customized efficacy model solutions, and testing services to accelerate your drug development.