At the 2026 AACR Annual Meeting, the rapid pace of R&D of innovative drugs in China has once again drawn industry attention.
With over 400 innovative research findings showcased and a rollout of multiple first-in-class molecules, the figures are impressive. However, unearthing the true treasures amongst such a vast array of molecules is no simple task.
Potential molecules that offer genuine incremental clinical value and solve real-world pain points are sometimes hidden away from the spotlight. Similarly, companies that prefer to let the data speak for themselves are easily underestimated.
A case in point is Lepu Biopharma Co., Ltd.
From taking the lead in pushing EGFR antibody-drug conjugates (ADCs) into the clinic, to the two newly upgraded molecules presented at this AACR — MRG008 (an EGFR×5T4 bispecific ADC) and LPD002 (a PD-1×IL-2 fusion protein) — Lepu has consistently led from the front in cutting-edge fields, yet maintains a notably low-profile operational style. If there is anything worth a second look following the conclusion of this AACR, these two molecules, MRG008 and LPD002, certainly qualify.
Pushing the EGFR Treatment Boundary: A World-First EGFR×5T4 Bispecific ADC
EGFR is a classic, well-validated target in oncology. Previously, Lepu firmly established its leadership in the single-target EGFR ADC space with the regulatory approval of MRG003.
However, a limitation of EGFR-targeted therapies is their poor efficacy in patients with low or no EGFR expression, creating an urgent need for new treatment modalities.
To overcome this bottleneck, Lepu Biopharma designed MRG008 — the world’s first EGFR×5T4 bispecific ADC — in an attempt to redefine the treatment boundaries of this field.
The core strategy behind MRG008 lies in the introduction of a second target: 5T4. As an oncofetal antigen, 5T4 is widely expressed across various solid tumours, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), and is co-expressed with EGFR in most cases. Crucially, where EGFR expression is low or even absent, 5T4 often maintains moderate-to-high expression, making it a natural backup target for EGFR.
Structurally, MRG008 utilises an Fc-silent bispecific antibody (BsAb) equipped with a cleavable linker and a topoisomerase I inhibitor payload, achieving comprehensive coverage regardless of EGFR expression status. In short, as long as there is EGFR/5T4 single-positivity or co-expression, MRG008 can precisely identify and efficiently eliminate the target cells.
MRG008 structure
Preclinical data validated this design. MRG008 demonstrated high affinity towards both antigens and potent target-mediated internalisation capabilities, exhibiting significant cytotoxicity across multiple cell lines with varying EGFR/5T4 expression profiles.
If the logic of traditional single-target ADCs is single-point detonation — where efficacy is often limited by the expression density and internalisation efficiency of a single antigen — then the dual-target synergistic strategy of MRG008 effectively expands the strike zone.
This advantage is even more apparent in in vivo models. MRG008 demonstrated significant tumour inhibition across three NSCLC patient-derived xenograft (PDX) models with differentiating EGFR/5T4 expression characteristics. Of particular note is that it remained effective in models with low or even negative EGFR expression, thereby breaking the inherent boundaries of EGFR-targeted therapy.
In vivo anti-tumour efficacy of MRG008
MRG008 also exhibited ideal drug properties. Plasma stability tests showed a payload release rate of less than 0.2% over 21 days, indicating high stability within the circulatory system and reducing the risk of off-target toxicity at the source. Combined with preliminary toxicology data from non-human primates, its overall tolerability is good, providing a solid foundation for further clinical research.
From a broader perspective, breaking through the EGFR treatment boundary first leads to an expansion of the addressable patient population. In major indications such as NSCLC and CRC, MRG008 is expected to reach patient groups that previously had difficulty benefiting from it, thus opening up a more practical clinical space.
Another trend worth exploring is that overcoming the efficacy limitations inherent in single targets — through multi-target synergy and structural design optimisation — is becoming an increasingly clear evolutionary path for ADCs.
At this year’s AACR, bispecific ADCs have become noticeably more prevalent, and at the clinical level, molecules with similar conceptual frameworks have already advanced to late-stage validation. As one of the very few candidates in this field with first-in-class attributes — led by a developer like Lepu with deep expertise in the EGFR ADC space — MRG008 undoubtedly starts from an exceptionally high vantage point.
A Differentiated Molecule Emerges in the PD-1×IL-2 Bispecific Space
If MRG008 represents an iteration in the EGFR ADC direction, then LPD002 is a highly intriguing venture into the realm of immuno-oncology (IO).
As next-generation immunotherapies, bispecific molecules represent the most promising direction for future development. Beyond the currently trending PD-1×VEGF combination, interleukin-2 (IL-2) is undoubtedly one of the directions with the greatest potential. Previously, Innovent Biologics’ heavyweight BD deal with Takeda for IBI363 completely ignited this space, proving its immense commercial and clinical value.
Amongst the myriad of immune-regulating cytokines, IL-2 has long been highly anticipated. Its advantage lies in its ability to potently activate tumour-infiltrating T-cells and induce lasting anti-tumour immune responses. However, it has safety issues — the systemic toxicity caused by broad activation of the immune system has long restricted its clinical application.
To overcome IL-2-related toxicity, LPD002 employs an alpha-biased design. This retains high affinity for IL-2Rα while significantly reducing binding capacity for IL-2Rβγ, thereby decreasing non-specific immune-related toxicities mediated by NK cells and resting T-cells.
Compared to masking peptide technology — another mainstream approach in the industry — this design pathway is simpler and more direct. Its advantage lies in that it does not rely on protease cleavage within the tumour microenvironment (TME) to become active, leading to more stable and rapid onset of action.
LPD002 structure
Simply put, the molecule simultaneously contains a PD-1-blocking domain and an engineered IL-2 mutant protein. It can precisely regulate immune signals, significantly reducing drug toxicity while enhancing anti-tumour immunity, all without compromising safety. This achieves an ideal balance between therapeutic safety and efficacy.
Preclinical data suggest that LPD002 meets expectations, with safety profiles highlighting its design advantages. At the cellular level, the drug produces almost no activation in resting T-cells, fulfilling the original intent of the alpha-biased design.
Furthermore, pharmacokinetic data show that its half-life is longer than that of the control molecule (2149), with superior safety. This means that clinical dosing can achieve more stable plasma concentrations and a broader therapeutic window, lowering treatment risks.
LPD002 pharmacokinetic data
In terms of efficacy, LPD002 has also performed exceptionally well.
Studies indicate that the drug is highly specific toward T-cells, effectively inducing STAT5 phosphorylation and promoting cell proliferation in activated CD4+ and CD8+ T-cells, with biological activity levels comparable to the control molecule. In in vivo cell line-derived xenograft (CDX) models, LPD002 similarly demonstrated potent anti-tumour activity, not only significantly inhibiting tumour growth but even achieving complete tumour clearance.
Although these are preclinical results, LPD002 has delivered satisfactory outcomes across all metrics. On the premise of comparable efficacy, it has further optimised the safety margin, already demonstrating the potential of a differentiated molecule.
As an upgraded version of IO therapy, LPD002 not only bolsters tumour-immune potency, but its tolerability and long-acting nature also provides an excellent foundation for future combinations with ADCs or other targeted drugs. With the sector heating up, the potential value of LPD002 continues to rise.
Lepu Biopharma: Constant Evolution over Chasing Trends
Having examined these two molecules, a pattern emerges when looking back at Lepu as a company: while its R&D focus has remained steadfast on ADCs and IO, the pace of its technological evolution has been remarkable.
The first stage was defined by single-target ADCs and broad-spectrum IO. Pucotenlimab (PD-1) and MRG003 (EGFR ADC) are the hallmarks of this period; both products have transitioned to the commercial stage, helping the firm establish its foundational clinical and commercial capabilities while achieving its first annual profit.
However, Lepu has not limited itself to the advantages of its current portfolio. Instead, it has maintained a long-term commitment to foundational technological innovation. Over the past few years, the company has diligently refined its R&D platforms — introducing next-generation conjugation technologies, optimising payloads, and enhancing antibody engineering capabilities. This has gradually built a more stable and reproducible R&D system, nurturing a wealth of high-quality pipelines.
These unnoticeable accumulations are the true reason the company was able to rapidly launch MRG008 and LPD002.
Lepu’s R&D strategy has become increasingly clear: identify the critical bottlenecks within known pathways for each direction, and then design targeted solutions.
MRG008 aims to solve the coverage issues for low or negative EGFR expression, while LPD002 addresses PD-1 therapeutic potency and IL-2 toxicity. These are authentic clinical pain points rather than attempts to chase trends, an approach that demands a high level of clinical insight and technical proficiency from the R&D team.
Based on the information available, the design concepts and preclinical data for both MRG008 and LPD002 provide a compelling case.
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