CD44v9: Exploring a Novel Target and Clinical Progress in ADC-Resistant Tumors

The emergence of ADC drugs has brought new hope to many patients with solid tumors. However, it is a headache that tumor cells are simply too "smart", as they develop resistance through mechanisms such as "antigen downregulation," causing ADC drugs such as Enhertu (T-DXd) or Trodelvy (SG) to gradually lose their efficacy. 
What can be done? Scientists have turned their attention to CD44v9, a novel potential target that maintains robust expression in resistant tumors and does not cross-react with the HER2/TROP2 pathways. 
At the AACR 2026 Annual Meeting, three independent studies simultaneously pointed to CD44v9. The key data from these three studies are summarized below: 

CD44v9: Not Just a Target, But a "Ferroptosis Barrier" for Tumors

CD44v9 is an alternatively spliced isoform of the CD44 gene and a unique member of the CD44 protein family. It is a type I transmembrane glycoprotein jointly encoded by constant exons (exons 1-5, 15-17, 19) and the variant exon v9 (often accompanied by v8 and v10). Unlike standard CD44s, which is widely expressed in normal leukocytes and connective tissues, CD44v9 is almost "silent" in most normal tissues but is specifically highly expressed in solid tumors such as TNBC, gastric cancer, and pancreatic cancer. Furthermore, its extracellular domain can mediate internalization upon antibody binding. 

Figure 1. Schematic diagram of CD44v9 structure^[1]

CD44v9 serves as a "ferroptosis barrier" and a hub for drug resistance in tumors. One of its core functions is binding to the cystine/glutamate transporter xCT, preventing its endocytosis and degradation, thereby maintaining the continuous intracellular transport of cystine for the synthesis of glutathione (GSH). GSH can scavenge reactive oxygen species (ROS), helping tumor cells resist ferroptosis. In addition, the deubiquitinase OTUB1 and the mucin MUC1-C can enhance the stability of the CD44v9-xCT complex through different pathways, respectively.

Because this pathway is associated with the redox balance and stemness maintenance of tumor cells, the dependence of tumor cells on this pathway may reduce the probability of escaping targeted therapy through the loss of CD44v9. 

Figure 2. The CD44v9 resistance to ferroptosis pathway^[1]

Four Major Advantages of CD44v9 as an ADC Target

Based on existing data (as shown in Figure 3), CD44v9 exhibits the following characteristics in ADC target evaluation:

•    High tumor specificity: Expression can be detected in various solid tumors and drug-resistant tumors, while expression levels in normal tissues (including PBMCs) are extremely low, indicating high potential safety.

•    Function-driven, not easily lost: It participates in maintaining the redox balance of tumor cells, making the likelihood of antigen loss relatively low and potentially delaying drug resistance.

•    Highly efficient endocytosis: It can be rapidly internalized by cells upon antibody binding, precisely delivering "cytotoxic payloads."

•    No cross-resistance: It is independent of the HER2 and TROP2 pathways, providing a new approach to resolving existing ADC resistance. 

Figure 3. CD44v9 is highly expressed and efficiently internalized in breast cancer, while essentially absent in normal tissues (including PBMCs)^[2]

Clinical Progress: From Proof of Concept to Initial Efficacy

AMT-116 (Multitude Therapeutics): As a globally pioneering and leading CD44v9 ADC drug, its latest clinical results were disclosed at the 2025 ESMO Congress: For EGFR wild-type NSCLC subjects who had received multiple lines of therapy, the objective response rate (ORR) in the ≥3.0 mg/kg dose cohort was 40%, and the disease control rate (DCR) was 93%. For EGFR wild-type NSCLC subjects at 5.0 mg/kg, the ORR was 80% and the DCR was 100%. The safety profile of AMT-116 is consistent with other TOP1 inhibitor-based ADCs, primarily manifesting as manageable hematological toxicity with no severe skin or mucosal toxicity observed, demonstrating its good tolerability. 

SUM24.1-MMAF (CrossBridge Bio, Inc.): Acquired by Eli Lilly, CrossBridge Bio presented data at the 2026 AACR (Figure 4) showing sustained high expression of CD44v9 detected in SG-resistant TNBC cells, T-DXd-resistant HER2-positive cells, and T-DM1-resistant HER2-positive cells. Anti-CD44v9-MMAF demonstrated durable cytotoxic activity across all these models. In the SUM190-T-DXd-R xenograft model, the tumor volume in the treatment group was significantly smaller than that in the control group. 

Figure 4. Anti-CD44v9-MMAF retains anti-tumor activity in ADC-resistant breast cancer models^[2]

Accelerating R&D: High-Quality Protein Tools are the Key Cornerstone

The R&D boom for CD44v9 ADCs has already begun, and high-quality recombinant protein tools are the foundation driving all of this.

Based on its rich experience in membrane protein R&D, KACTUS has taken the lead in laying out the CD44v9 product line, launching CD44v9 recombinant proteins covering human, monkey, and mouse species with various tags. Simultaneously, it provides related variant products such as CD44s and CD44v6 to meet different target validation and comparative research needs, fully empowering the development of anti-resistant tumor drugs. 

Product Data

Loaded Anti-CD44v9 Antibody, hFc Tag on ProA-Biosensor can bind Human CD44v9, His Tag with an affinity constant of 25.90 nM as determined in BLI assay.

Immobilized Human CD44v9, His Tag at 1μg/ml (100μl/well) on the plate. Dose response curve for Anti-CD44v9 Antibody, hFc Tag with the EC50 of 1.5 ng/ml determined by ELISA.

Immobilized Biotinylated Human CD44v9, His Avi Tag at 0.5ug/ml (100ul/well) onthe streptavidin precoated plate(5ug/ml). Dose response curve for Anti-CD44v9 Antibody, hFc Tag with the EC50 of 6.2 ng/ml determined by ELISA.

Product List

References

[1] Yanova M, Stepanova E, Maltseva D, et al. CD44 variant exons induce chemoresistance by modulating cell death pathways[J]. Frontiers in Cell and Developmental Biology, 2025, 13: 1508577.
[2] Reddy D R, Flynn M K E, Anami Y, et al. CD44v9 as a therapeutic target for antibody-drug conjugate in advanced breast cancer[J]. Biomedicine & Pharmacotherapy, 2026: 119113.