AACR 2026 Spotlight: ALPP/ALPPL2 Emerges as The New Frontier of Precision Oncology

In the field of targeted tumor therapy, searching for the ideal target that is highly expressed in tumors while almost not expressed in normal tissues has always been the basic threshold for screening targets for antibody drugs, cell therapies, and other modalities. At the 2026 American Association for Cancer Research (AACR) Annual Meeting, a previously "low-profile" target, ALPP/ALPPL2, appeared in domestic and international R&D pipelines with unprecedented density, becoming one of the most watched high-potential candidates at the conference.

ALPP/ALPPL2: Structure, Mechanism, and Development Advantages 

Strict Tumor Expression Profile and Tumor-Normal Differentiation 

ALPP (Placental Alkaline Phosphatase) and ALPPL2 (also known as ALPG, Germ Cell Alkaline Phosphatase) are highly homologous (98%) GPI-anchored proteins belonging to the alkaline phosphatase multigene family. Their expression in normal tissues is highly restricted, while sharing 57% homology with ALPL (tissue-nonspecific alkaline phosphatase) and 87% homology with ALPI (intestinal alkaline phosphatase). 

Multi-cancer analysis based on the TCGA dataset (Figure 1) shows that the expression levels of ALPP and ALPPL2 in various tumors are significantly higher than in normal tissues. This differential expression profile provides a very high therapeutic window and safety guarantee for targeted drugs, making this target an ideal candidate for multiple immunotherapy formats such as ADCs, bispecific antibodies, and CAR-T. 

Figure 1. Differential expression of ALPP and ALPPL2 across multiple cancer types based on the TCGA dataset^[1]

Dimer Structure: Functional Core and Key for Antibody Recognition 

ALPP/ALPPL2 exists on the cell membrane in the form of homodimers or heterodimers. X-ray crystal diffraction results (Figure 2) show that a large hydrophobic interface and a long N-terminal α-helix intertwine between the two subunits, forming a “crown” domain and a “metal-ion binding” domain. These unique domains are not only the core of enzyme activity regulation and allosteric effects but also serve as important epitope regions for antibody recognition and high-specificity binding. The sequences of these regions differ significantly among human APs (alkaline phosphatases) and are absent in non-mammalian enzymes. 

Notably, ALPP and ALPPL2 share high sequence homology and similar conformations, and they exhibit a "one antibody, dual target" characteristic when binding. Additionally, the two can form heterodimers, which provides a unique advantage for expanding indications and addressing target heterogeneity. 

Differentiated Advantages of Multiple Drug Formats 

ALPP/ALPPL2 can be efficiently internalized, making it suitable for ADCs to precisely deliver cytotoxic drugs. Meanwhile, due to its near-zero expression in normal tissues, high-intensity immune-activation therapies like bispecific antibodies and CAR-T can also be safely applied. Currently, drug development for this target covers mainstream immunotherapy modalities, with a batch of highly competitive candidate molecules emerging. 

Table 1: Current Global Landscape of ALPP/ALPPL2 Targeted Drugs

2026 AACR: Drug Development Accelerates Across the Board 

At the 2026 AACR Annual Meeting, the ALPP/ALPPL2 target became a high-frequency keyword in posters and oral presentations. Multiple molecules achieved phased breakthroughs, fully demonstrating that the target is accelerating from "proof of concept" to a "clinical race". 

ADC: New Generation Payloads and Structures Continue to Emerge 

Biocytogen, BCG037 is a fully human IgG1 ADC targeting ALPP/ALPG, using TOP1 as the payload with a DAR ≈ 8. As shown in Figure 3, this antibody has high nM-level affinity for both human and cynomolgus ALPP/ALPG and shows no cross-binding with other alkaline phosphatase family members such as ALPL and ALPI. In pancreatic and gastric cancer PDX models, BCG037 demonstrated tumor inhibition effects significantly superior to the control ADC (SGN-ALPV-MMAE), with no decrease in mouse body weight observed. 

Figure 3. Structure and affinity validation of BCG037^[3]

Hepius Therapeutics, HP-004 uses MMAE as the payload, with a DAR ≈ 4 after site-specific conjugation, as shown in Figure 4. In in vitro studies, the IC50 of HP-004 in ALPP/ALPPL2 high-expression tumor cell lines was approximately 248 pM. In the NCI-H1651 lung cancer CDX model, a dose of 3 mg/kg achieved complete tumor regression in 6 out of 8 mice. 

Figure 4. (a) Structure of HP-004 (b) AlphaFold-predicted HP004 scFv (VH–VL) model^[4]

Meanwhile, Hepius Therapeutics is exploring bispecific ADC formats involving HP-004 to expand coverage for heterogeneous or low-antigen tumors. 

Chipscreen Biosciences, NW024-1 utilizes a Top1 inhibitor payload combined with a hydrophilic linker (DAR 8). In the ALPP/ALPPL2-positive gastric cancer NCI-N87 CDX model, it achieved nearly complete tumor regression (TGI 116.33%) and was well-tolerated in mice. 

Axcynsis, AT-2604 is another ADC candidate frequently appearing since 2025. In gastric and pancreatic cancer mouse xenograft models, a dose of only 1 mg/kg (QW3×2) achieved over 90% tumor growth inhibition. 

Bispecifics and Immune Cell Engagers: Moving from CD3 to More Immune Cells 

Beyond the ADC field, bispecific antibodies and immune cell engagers have also gained diverse layouts for the ALPP/ALPPL2 target: 

• Eli Lilly, LY4336619: An ALPPL2×CD3 bispecific antibody using a common light chain and an Fc-silenced IgG1 backbone. Its in vitro specificity, potency, and in vivo anti-tumor activity have been fully validated in ALPPL2-positive tumor models, where synergistic effects with FRα-ADCs were also observed.

• Antengene, ATG-112: Utilizes a 2+1 IgG-based bispecific antibody design, bivalent binding to ALPP/ALPPL2 and monovalent binding to CD3. It also employs masking technology to restrict CD3 arm activity in normal tissues, thereby reducing the risk of systemic cytokine release syndrome (CRS).

Structure of ATG-112^[5]

CAR-T Therapy: From Preclinical to Phase I 

In the CAR-T direction, TC-A101, developed by TCR Cure Biopharma, has entered Phase I/II clinical trials for the treatment of recurrent/metastatic ovarian, endometrial, and cervical cancers. 

High-Quality Recombinant Proteins: The Foundation of Target R&D

The dense disclosures at AACR 2026 show that ALPP/ALPPL2 is rapidly growing into a hot target with multi-modal layouts and clear clinical translation prospects. Companies like Eli Lilly, Antengene, Biocytogen, Henlius, Chipscreen, and Hepius have already established footprints. 

However, regardless of the drug format, the starting point of R&D is inseparable from high-purity, high-activity, and conformationally correct recombinant proteins. Every step from antibody screening and affinity measurement to specificity evaluation and internalization analysis, places strict requirements on protein quality. 

KACTUS has created a complete matrix of high-activity recombinant dimeric protein products for the ALPP/ALPPL2 target. This matrix covers ALPP/ALPPL2 from multiple species and provides proteins with various tags and ultra-low endotoxin formats, fully supporting antibody discovery, affinity measurement, immunization, and screening stages. 

Data Examples:

Immobilized Human Alkaline Phosphatase (Placental type), His Tag at 1μg/ml (100 μl/Well) on the plate. Dose response curve for Anti-Alkaline Phosphatase Antibody, hFc Tag with the EC50 of 2.8ng/ml determined by ELISA. (QC Test)

Immobilized Human Alkaline Phosphatase (Germ type), mFc Tag at 1μg/ml (100μl/well) on the plate. Dose response curve for Anti-Alkaline Phosphatase Antibody, hFc Tag with the EC50 of 13.0ng/ml determined by ELISA. (QC Test)

Anti-Alkaline Phosphatase Antibody captured on CM5 Chip via Protein A can bind Cynomolgus Alkaline Phosphatase (Placental type), His Tag with an affinity constant of 0.11 μM as determined in SPR assay (Biacore T200).

Measured by its ability to cleave a fluorogenic substrate, 4-Methylumbelliferyl phosphate (4-MUP). The specific activity is > 12000 pmol/min/µg. (QC Test)

Product List

Reference

1.  Huang Y, Liang X, Xue Y. A novel antibody-drug conjugate targeting alkaline phosphatases ALPP and ALPPL2 in solid tumors[J]. Cancer Research, 2026, 86(7_Supplement): 4401-4401.

2.  Hélene Le Du M, Stigbrand T, Taussig M J, et al. Crystal Structure of Alkaline Phosphatase from Human Placenta at 1.8 A Resolution[J]. 2001.

3.  Xie Y, Li P, Zhu Y, et al. BCG037, a first-in-class anti-human ALPP/ALPG therapeutic ADC that inhibits tumor growth in pancreatic cancer and gastric cancer PDX models[J]. Cancer Research, 2026, 86(7_Supplement): 5641-5641.

4.  Huang Y, Liang X, Xue Y. A novel antibody-drug conjugate targeting alkaline phosphatases ALPP and ALPPL2 in solid tumors[J]. Cancer Research, 2026, 86(7_Supplement): 4401-4401.

5.  Chen J, Bai Y, Bai S, et al. ATG-112, a novel ALPP/G x CD3 bispecific T cell engager, for the treatment of ALPP/G+ solid tumors[J]. Cancer Research, 2026, 86(7_Supplement): 1620-1620.