Figure 2. Schematic illustration of the structure and mechanism of action of E-688/HLX316. Based on the presentation by Dr. James Broaderick, this cartoon-style figure depicts a bispecific protein composed of a B7-H3-targeting arm and an engineered human sialidase, designed to remove sialic acid from the tumor surface and restore antitumor immune activity (May 2026, ChatGPT & Hanlim Moon).

A key strength of this platform lies in its expandability through the conjugation of sialidase to different tumor targets. During the presentation, HER2-, DLL3-, and PD-L1-targeted sialidase programs were also mentioned, suggesting the potential for this technology to evolve into an entirely new class of immunomodulatory biologics across multiple solid tumors. If tumor desialylation and subsequent immune activation can be successfully reproduced in clinical settings, this approach may represent not merely another anticancer drug, but the beginning of a new therapeutic field termed “glyco-immunotherapy.”

2. The Evolution of Next-Generation ADC Engineering: Dual-Payload Strategies and the Emergence of ENPP3 as a Novel Solid Tumor Target

Meanwhile, AstraZeneca’s CD30 dual-payload ADC represented one of the clearest examples of the future direction of ADC development. Conventional ADCs generally employ only a single payload, which often leads to challenges related to tumor heterogeneity and acquired drug resistance. Brentuximab vedotin (BV), a representative CD30-targeting ADC, dramatically transformed the treatment landscape of Hodgkin lymphoma; however, relapse and resistance remain major limitations.

To overcome these issues, AstraZeneca engineered an ADC incorporating two payloads with distinct mechanisms of action within a single molecule. One payload is an MMAE-based microtubule inhibitor, while the other is a TOP1 inhibitor. Notably, the MMAE drug-to-antibody ratio (DAR) was reduced to DAR2 to minimize toxicity, whereas the TOP1 inhibitor was maintained at a validated DAR of 8 to preserve antitumor efficacy. In addition, multiple conjugation-engineering technologies were employed to improve ADC stability and pharmacokinetics while ensuring a highly uniform DAR distribution. Preclinical data demonstrated that the dual-payload ADC retained activity even in resistant models where conventional MMAE-based ADCs had lost efficacy. Ultimately, this platform exemplifies how ADC development is evolving toward “therapeutic index engineering,” maximizing tumor selectivity and antitumor potency while minimizing toxicity to normal tissues.

JNJ-89862175, introduced by Johnson & Johnson Innovation, was another notable ADC platform highlighting the potential of a novel solid tumor target: ENPP3. ENPP3 is a membrane protein involved in extracellular nucleotide signaling. While its expression in normal tissues is limited, tumor cells display broad surface expression of ENPP3, making it an attractive target for tumor-selective therapy. The presentation demonstrated high ENPP3 expression across multiple solid tumors, including clear-cell RCC, papillary RCC, endometrial cancer, colorectal cancer, lung adenocarcinoma, and ovarian cancer, with particularly prominent membrane expression observed in RCC.

JNJ-89862175 is based on J&J’s Dolasynthen ADC platform, which utilizes precision conjugation technologies and branched linker structures to achieve high stability and a uniform DAR profile. The payload, AF-HPA, is an auristatin-derived cytotoxic agent characterized by a controlled bystander effect capable of impacting neighboring tumor cells. Preclinical studies demonstrated strong binding affinity, rapid cellular internalization, and potent cytotoxicity, while reduced efficacy in ENPP3-knockout cells confirmed target specificity.

Although RCC has become an increasingly competitive therapeutic field with VEGF inhibitors, immunotherapy combinations, and HIF2α inhibitors, ADCs have yet to establish a major breakthrough in this disease setting. In this context, ENPP3-targeting ADCs may represent a promising new therapeutic avenue for RCC and potentially other solid tumors.

3. The Evolution of Next-Generation T-Cell Engagers: Strategies to Reduce CRS and Achieve Selective T-Cell Activation

AZD8359 is a CD8-guided T-cell engager (TCE) under development by AstraZeneca, designed specifically to address one of the greatest limitations of TCE therapy: cytokine release syndrome (CRS). Conventional TCEs activate T cells through CD3 engagement and can induce potent antitumor responses, but they frequently cause severe CRS due to broad, nonselective T-cell activation. Prostate cancer, in particular, has been a difficult indication for TCE development because of its low T-cell infiltration and highly immunosuppressive tumor microenvironment.

AZD8359 targets STEAP2, which is highly and relatively uniformly expressed in prostate cancer. The presentation suggested that STEAP2 exhibits greater tumor specificity and more homogeneous expression than PSMA, highlighting its promise as a prostate cancer–specific target. The most distinctive feature of AZD8359 is its “CD8-guided activation” mechanism. Whereas conventional TCEs broadly activate CD3-positive T cells, AZD8359 employs an anti-CD8 guiding arm to preferentially activate CD8-positive cytotoxic T cells. In essence, the strategy aims to preserve antitumor efficacy while reducing CD4-mediated cytokine release.

Preclinical data demonstrated STEAP2-dependent cytotoxicity, selective CD8 activation, reduced cytokine release, and complete remission in bone metastasis models. These findings suggest the potential for a substantially improved therapeutic index compared with existing TCEs. Current treatment strategies for metastatic castration-resistant prostate cancer primarily rely on AR pathway inhibitors, chemotherapy, PARP inhibitors, and radiopharmaceuticals, while the role of immunotherapy remains limited. If AZD8359 can demonstrate both strong efficacy and reduced CRS risk in clinical studies, it may reshape not only prostate cancer treatment but also the broader development paradigm for solid tumor TCEs.

IPN01203, presented by IPSEN Bioscience, represented a highly unique immuno-oncology platform centered on the concept of a “specific T-cell activator,” selectively expanding only particular T-cell clones. Unlike CAR-T therapies, which generate entirely new immune responses, or conventional T-cell engagers, which broadly activate the T-cell population, IPN01203 selectively activates endogenous T-cell subsets carrying the Vβ6/Vβ10 TCR repertoire. According to the presentation, Vβ6/Vβ10 T cells constitute approximately 11% of tumor-infiltrating lymphocytes (TILs). IPN01203 combines an anti-TCR Vβ6/Vβ10 arm with IL15 receptor co-activation to selectively expand these clones.

Structurally, the molecule integrates an anti-TCR arm, an IL15/IL15Rα sushi domain, and Fc engineering into a multi-domain biologic capable of simultaneously inducing TCR and IL15R signaling. This design resulted in selective expansion of Vβ6/Vβ10 clones, preferential CD8-oriented proliferation, expansion of memory T-cell phenotypes (Tcm), and remodeling of the tumor microenvironment. Importantly, compared with pan-CD3 engagers, IPN01203 exhibited relatively limited cytokine release and NK-cell activation. In other words, this platform seeks to achieve both efficacy and safety through highly selective amplification of specific T-cell clones.

Naturally, limitations remain. Because this strategy depends on pre-existing T-cell infiltration and endogenous antigen recognition, its efficacy may be limited in immune-desert tumors. Accordingly, combination approaches involving PD-1 inhibitors, cancer vaccines, radiotherapy, or ADCs will likely be important. Nevertheless, IPN01203 is significant in that it introduces a new immuno-oncology paradigm: “programmable endogenous T-cell amplification,” rather than simply another cytokine therapy or T-cell engager.

AACR “New Drugs on the Horizon” Highlighted the Era of Selective Immunomodulation and Precision Biologic Engineering

The non-TPD platforms introduced during the AACR 2026 “New Drugs on the Horizon” session were meaningful not merely because they presented new targets or more potent therapeutics, but because they demonstrated a broader shift toward simultaneously optimizing tumor selectivity, immune modulation, drug delivery, and safety. Although approaches such as glyco-immunotherapy, dual-payload ADCs, next-generation T-cell engagers, and selective T-cell activators may appear technologically distinct, they collectively reflected a common direction: the increasingly sophisticated re-engineering of the tumor microenvironment and immune response itself.

Of course, major challenges remain, including toxicity to normal tissues, resistance mechanisms, biomarker development, and reproducibility in clinical settings. Nevertheless, this session clearly illustrated that the future competition in anticancer drug development is moving beyond simply increasing cytotoxic potency and toward how selectively and precisely cancer biology and immune systems can be modulated.