NovoCodex：Leading the Way in ADC Precision Therapy with Site-Specific Conjugation using Synthetic Amino Acids

Berlin, October 19–20, 2025 — At the highly anticipated 2025 European Society for Medical Oncology (ESMO) Congress, NovoCodex announced the Phase I clinical trial results for two innovative antibody-drug conjugates (ADCs): ARX305 and ARX788.

These two studies demonstrate the potential of the site-specific conjugation technology utilizing synthetic amino acids in ADC drug development: ARX305 shows promising anti-tumor activity and a favorable safety profile in advanced renal cell carcinoma. Its high stability in the bloodstream resulted in low off-target toxicity (such as low rates of gastrointestinal and hematological toxicity compared to other ADCs targeting CD70), indicating the high therapeutic index potential of this technology platform. ARX788 in combination with Toripalimab shows promising activity and manageable safety in patients with HER2-low advanced breast cancer. Based on its target-specific internalization mechanism and minimal bystander effect, ARX788 shows promise in the safe combination and potential synergistic enhancement of ADC with immunotherapy.

【Core technology advantage】 Site-specific conjugation with synthetic amino acids for high therapeutic index ADCs

Both results originate from the site-specific conjugation platform using synthetic amino acids. This technology may potentially revolutionize the ADC manufacturing process by precisely inserting synthetic amino acids into the antibody, achieving site-specific and controlled conjugation. This process holds promise to ensure the high homogeneity of the ADC drug, differentiating it from traditional, randomly conjugated mixtures.

The resulting possibility of high in vivo circulating stability—already validated in the Phase III pivotal study of ARX788 (study ACE-Breast-02, ASCO 2024)—means the toxic payload is less likely to be prematurely released into the bloodstream. This could greatly reduce off-target toxicity and ensure the drug is delivered to targeted tumor cells. The optimized pharmacokinetic profile suggests that ADCs developed using this platform may possess a higher therapeutic index, which could allow for the clinical exploration of relatively higher dosing to achieve good efficacy.

ØARX305 (ESMO 959P): Precision targeting of CD70, opening a new era for advanced renal cancer treatment

Background

ARX305 is a novel CD70-targeting ADC. CD70 is highly expressed in various solid tumors, particularly renal cell carcinoma, making it a promising therapeutic target. ARX305 is designed using the same technology platform as ARX788, with both ADCs employing the AS269 drug linker conjugated at a drug-to-antibody ratio (DAR) of 2. The ongoing first-in-human trial evaluated its safety, tolerability, and preliminary efficacy in patients with advanced solid tumors, with a focus on renal cell carcinoma, at doses ranging from 0.24 to 4.2 mg/kg.

Results (as of May 9, 2025)

A total of 41 patients with advanced solid tumors were enrolled, predominantly patients with renal cell carcinoma (70.7%). The median number of prior lines of therapy was 2.

Safety: No DLTs were observed up to the 4.2 mg/kg dose.Grade ≥3 treatment related adverse events (TRAEs) were reported in 39.0% of patients. No Grade 5 adverse events were reported. Common TRAEs (incidence >15%) included proteinuria, increased AST, dry eye, anemia, and blurred vision.

Efficacy: Among renal cell carcinoma patients, 6 cases achieved PR (one of which is pending confirmation). In 17 CD70-expressing renal cell carcinoma patients, the objective response rate (ORR) was 35.3%. In 14 CD70-highly expressing renal cell carcinoma patients, the ORR reached 42.9%, with a confirmed ORR of 35.7%. As of the data cutoff date, five of the six patients who achieved PR remain in response, with the longest duration of response (DOR) exceeding 365 days.

Conclusion and significance

ARX305 demonstrated a manageable safety profile and significant preliminary efficacy in patients with CD70-highly expressing advanced renal cell carcinoma.

Potent and durable activity: The ongoing and durable responses observed (longest DOR > 365 days) support ARX305’s clinical value as a CD70-targeting ADC.

Higher tolerated dose: The dose escalation reached 4.2 mg/kg in the Phase I study, demonstrating a higher therapeutic index potential. This result, in contrast to ARX788’s RP2D of 1.5 mg/kg (for breast cancer), underscores the clear difference in tolerable doses across ADCs developed on the same platform but targeting different antigens.

Unique toxicity profile: Compared to other ADCs targeting CD70, ARX305 showed significantly reduced off-target toxicities.  Notably, no interstitial lung disease (ILD) was observed in the ARX305 trial. This suggests that certain ADC toxicities (like ILD) may be more target-related (e.g., HER2), clearly demonstrating the difference in safety profiles between ADCs developed on the same technology platform but targeting different antigens. The observed toxin-related TRAEs, such as ocular toxicity and proteinuria, were all tolerable and did not lead to severe renal impairment or life-threatening consequences.

ØARX788 in combination with Toripalimab (ESMO 549P): A new potential combination therapy for HER2-low advanced breast cancer

Background

This study evaluated the tolerability and preliminary efficacy of ARX788, a HER2-targeting ADC, combined with the PD-1 inhibitor Toripalimab in patients with HER2-low advanced breast cancer (IHC 1+ or 2+/FISH-negative).

Results (as of April 11, 2025)

Patient characteristics: A total of 52 patients with HER2-low advanced breast cancer were treated with the ARX788 (1.5 mg/kg) combination therapy. These patients had typically received one or two prior lines of therapy.

Dose and safety: The combination of ARX788 at 1.5 mg/kg with Toripalimab was determined to be the RP2D. The incidence of TRAEs was 96.2%, with ≥3 grade TRAEs reported in 28.8% of patients. Common TRAEs included increased AST, dry eye, increased ALT, and ILD. The median time to ILD onset was 84 days (range 39–173 days).

Efficacy: Assessed by the IRC, the confirmed ORR reached 42.3%. The median PFS (assessed by investigators) was 5.5 months. The preliminary median OS reached 19.6 months (95% CI, 15.1–NE).

Conclusion and significance

The combination of ARX788 and Toripalimab showed promising efficacy and manageable safety in patients with HER2-low advanced breast cancer.

Efficacy: The confirmed ORR reached 42.3% and the preliminary median OS reached 19.6 months, represents a potential therapeutic advancement.

Manageable Safety: The safety profile was consistent with ARX788 monotherapy studies, with no increase in the incidence or severity of ILD. This further validates the feasibility of this therapy under manageable safety conditions.

Potential for combination therapy: The ADC developed with the synthetic amino acid site-specific conjugation technology achieves highly precise, target-mediated internalization and targeted killing. The non-cleavable linker and site-specific conjugation further determine the unique minimal bystander effect. This clinical trial suggests that this mechanism, by combining the ADC's targeted killing with the immune activation of the PD-1 inhibitor, may overcome the limitations of monotherapy in cancers with high tumor heterogeneity (such as HER2-low breast cancer).

【Company Profile】About NovoCodex

NovoCodex, a holding subsidiary of Zhejiang Medicine Co., Ltd., was established in January 2017. We consistently adhere to the mission of "Innovating Technology to Meet Clinical Needs." This study was conducted using licensed products ARX305 and ARX788, which are under exclusive licenses in China through our co-development with Ambrx Inc. (acquired by Johnson & Johnson on March 7, 2024). We firmly believe that through continuous innovation and rigorous scientific exploration, NovoCodex will persist in bringing more breakthrough therapeutic options to cancer patients globally, lighting the path of hope in the fight against cancer.

Trial Registry Numbers：CTR20222161，CTR20222247