In the evolution of immunotherapy, CTLA‑4 was discovered before PD‑1, yet followed a vastly different developmental path. As the first target to unlock the door to immunotherapy, CTLA‑4 monoclonal antibodies pioneered a new therapeutic paradigm through systemic immune activation, but long remained overshadowed by PD‑1 due to inherent limitations.

Safety issues have been one of the core bottlenecks restricting the development of CTLA‑4 antibodies. Early anti‑CTLA‑4 agents acted bluntly: they weakened the immunosuppressive function of Tregs through non‑selective inhibition, thereby activating systemic immunity. The drawback was an inability to distinguish Tregs in tumors from those in normal tissues, often triggering severe immune‑related adverse events (IrAEs).

Persistent cold reception in clinical practice prevented CTLA‑4 inhibitors from matching the commercial success of PD‑1 inhibitors.

To date, only two CTLA‑4 monoclonal antibodies have been approved globally: ipilimumab (BMS) and tremelimumab (AstraZeneca). Their market performance pales in comparison to the more than 20 approved PD‑(L)1 agents. Moreover, peak sales of Yervoy—the world’s first CTLA‑4 inhibitor—amounted to less than one‑tenth of Keytruda’s peak revenue.

However, a turning point arrived in 2025. When the Nobel Prize in Physiology or Medicine was awarded to three immunologists focused on regulatory T‑cell (Treg) research, the once‑marginalized CTLA‑4 target returned to the industry spotlight.

Amid this industry upswing, pharmaceutical companies worldwide have ramped up investments. In late 2025, BioNTech announced at its R&D Day that it would prioritize gotistobart, its next‑generation CTLA‑4 monoclonal antibody, in its immunotherapy pipeline, aiming to secure a cornerstone in next‑generation IO therapies.

Harbour BioMed’s HBM4003 is a key player in this CTLA‑4 renaissance. The NewCo partnership sets a new record for CTLA‑4 antibody BD deals going global and represents a major effort to revitalize this classic target.

As a fully human heavy‑chain anti‑CTLA‑4 antibody, HBM4003 directly addresses the pain points of conventional CTLA‑4 agents through its unique molecular design:

• Its small molecular weight of only 76 kDa enables more efficient tumor penetration and higher drug concentrations in the tumor microenvironment.
• Mutations in the Fc domain significantly enhance ADCC activity, allowing precise depletion of tumor‑infiltrating Tregs highly expressing CTLA‑4.

Meanwhile, Fc modification shortens the drug’s half‑life and reduces systemic exposure, effectively lowering the risk of long‑term side effects. Importantly, HBM4003 achieves strong therapeutic effects at lower doses, further improving patient safety and tolerability.

Previously released Phase II clinical data showed that in patients with previously treated MSS metastatic colorectal cancer, HBM4003 combined with tislelizumab every 21 days achieved:

• Objective Response Rate (ORR): 34.8%
• Disease Control Rate (DCR): 60.9%
• Median Progression‑Free Survival (mPFS): 4.2 months

Regarding safety, treatment‑related adverse events (TRAEs) occurred in 87.5% of patients, but the vast majority were mild Grade 1–2 events. No Grade 4 or higher serious adverse events or treatment‑related deaths were observed, fully validating the regimen’s safety and tolerability.

The successful global launch of HBM4003 further validates Harbour BioMed’s dual‑engine strategy: Technology Platform + Innovative Products.

Unlike traditional biotechs relying solely on pipeline advancement, Harbour BioMed was built around this dual‑engine model from inception. It owns the globally rare, clinically validated Harbour Mice® fully human antibody transgenic mouse platform, forming the foundational infrastructure of its core competitive barrier.

This platform breaks through bottlenecks in conventional antibody development. Its core HCAb (heavy‑chain antibody) platform has spawned multiple technologies including HBICE®, XDC (antibody‑drug conjugates), and NonaCARFx™ cell therapy, serving as a continuous source of innovation.

Broadly, Harbour BioMed’s development can be divided into three strategic phases:

1. Technology Integration (2016–2018)
2. Pipeline Validation (2019–2022)
3. Ecosystem Construction & Commercial Explosion (2023–present)

The company has steadily strengthened its foundational technology while expanding globally.

2024–2025 marked a watershed for Harbour BioMed. The company successfully transitioned its business model from “traditional independent R&D” to “sustainable BD licensing for self‑sustainability.” Through technology licensing and collaborative development via its subsidiary NonaBiosciences, it achieved a flywheel effect in growth.

Since its founding, Harbour BioMed has accumulated total collaboration value exceeding US$12 billion. Its BD deals are numerous, span preclinical to late‑stage assets, and involve top global MNCs, clearly embodying a “Global for Global” approach.

2025 in particular was a breakout year for Harbour BioMed’s BD collaborations:

• Windward Bio (January): Partnered with Kelun‑Biotech to license HBM9378 to a newly formed overseas NewCo. The companies received US$45 million upfront, up to US$925 million in milestones, and equity, enabling flexible asset monetization and incubation.
• AstraZeneca (March): Multi‑year, multi‑asset global strategic collaboration with US$175 million in upfront and near‑term milestones, US$4.4 billion in future R&D and commercial milestones, plus a US$105 million equity investment—one of the deepest platform integrations between an MNC and a Chinese biotech.
• Otsuka Pharmaceutical (June): Licensed overseas rights to HBM7020, receiving US$47 million upfront and up to US$623 million in milestones, validating the value of its TCE pipeline.
• BMS (December): US$90 million upfront payment in another multi‑asset BD deal, with deep clinical development collaboration.

Harbour BioMed’s BD partnerships cover a wide spectrum: from bispecific/multispecific antibodies to next‑generation CTLA‑4 antibodies with novel mechanisms, reflecting deep expertise in both antibody engineering and biology.

Notably, beyond single‑asset licensing, Harbour BioMed completed multiple multi‑program collaborations with MNCs in 2025, accelerating deep strategic integration.

The AstraZeneca partnership, for example, is a decade‑long, multi‑asset alliance built around a large‑scale “2+X” framework, with a potential total value of **US$4.6 billion**. AstraZeneca also invested US$105 million to subscribe to new Harbour BioMed shares at HK$10.74 per share, acquiring approximately 9.15% ownership.

This equity investment is rare in MNC–Chinese biotech partnerships. It goes beyond traditional pipeline licensing, signaling AstraZeneca’s strong confidence in Harbour BioMed’s technology platform and long‑term value, and deeply aligning both parties’ interests through capital.

On October 25, 2025, the Harbour BioMed‑AstraZeneca Innovation Lab was officially inaugurated in Beijing, greatly improving communication efficiency and project execution, marking a shift from “simple licensing” to “joint R&D.”

Overall, Harbour BioMed’s dual‑engine business model was fully validated in its 2025 financial results. On February 4, the company released a positive profit alert, forecasting full‑year 2025 net profit of **US$88–95 million** (approximately HK$700 million).

Profit growth was mainly driven by rising technology licensing fees and milestone payments. This model’s strength lies in not relying on the clinical success of a single drug—upfront payments are recognized as revenue even if a drug fails—enabling genuine self‑sufficiency.

From quiet accumulation during technology integration, to clinical breakthroughs in pipeline validation, to sustainable revenue generation in ecosystem building, Harbour BioMed has solidified its foundational technology and proven its business model.

As classic targets like CTLA‑4 return to center stage under the Nobel Prize spotlight, as MNCs deepen ties with Chinese biotechs via equity investments, and as BD transactions evolve from occasional blockbuster news to a steady “self‑sustaining engine”—Harbour BioMed’s journey may well epitomize China’s innovative drugs moving to the center of the global competitive stage.

The Year of the Horse kickoff is only the beginning.