2026 Trends in Macromolecular Drug Targets: GLP-1 Deepening, Cardiovascular Remodeling, Immune Combinations, and the "Post-PD-1" Era

2. Cardiovascular Field: Two Targets Reopening Space for Macromolecules

2.1 PCSK9: The Continuous Evolution of a Mature Target

PCSK9 is one of the few targets in the cardiovascular field that has completed the entire validation chain—from mechanistic validation and clinical validation to real-world application. From the initial successful launch of monoclonal antibodies, to the advancement of siRNA approaches, and the recent emergence of oral small molecule candidates, PCSK9 development has not stagnated but continues to evolve.

From a macromolecular R&D perspective, the core reason PCSK9 holds long-term value lies in its highly certain target biology

• It is a secreted protein with a clear site of action.
• Directly involved in the LDL receptor recycling pathway.
• Clear dose-response relationship, with efficacy monitorable in real-time via LDL-C levels clinically.

This makes PCSK9 a classic case where the risk of R&D failure stems more from molecular engineering and delivery strategies, rather than uncertainty in the target itself. In our view, PCSK9 is more like a "mature yet still optimizable" target: opportunities for product-level upgrades on this established target still exist through strategies like half-life extension, dosing frequency optimization, or combination therapies. From a longer-term perspective, the significance of PCSK9 extends beyond a single project's success; it validates that:

In the field of chronic diseases, a target with certain biology can often sustain multiple technology pathways in parallel over the long term.

CUSABIO Target Protein Recommendations:

2.2 Lp(a): An Emerging Cardiovascular Intervention Target

Lp(a) is one of the few directions in the cardiovascular field in recent years that has gradually progressed from a risk marker toward a direct intervention target. Extensive genetic and epidemiological studies have clarified its causal relationship with atherosclerosis and cardiovascular events, lending it relatively high mechanistic certainty.

From an R&D perspective, the Lp(a) target is currently still in a phase of "gradually clarifying the pathway." Although current mainstream approaches focus on nucleic acid-based drugs, its biological characteristics—emphasizing the importance of long-term, stable inhibition—leave room for future indirect regulation via protein or antibody-related strategies. The key question is not whether the target is valid, but rather the quantitative relationship between different levels of intervention and clinical benefit.

Following the readout of recent key clinical data, Lp(a) is expected to transition from a "potential target" to a "definitive R&D mainstay." For R&D teams, this represents a cardiovascular target that requires patience, but once established, will hold long-term value.

3. Oncology Field: Target Opportunities Unique to Macromolecules

3.1 Tumor Immunotherapy Beyond PD-1: Combination Strategies Driving Innovation

The PD-1/PD-L1 pathway has fulfilled its historical mission as a single target for anti-tumor immunity. However, efficacy relying solely on PD-1 inhibitors has limitations in certain solid tumors and patient populations. The current core trend in tumor immunotherapy R&D is Beyond PD-1, exploring new immune regulatory targets or combination strategies to enhance anti-tumor responses, reduce resistance risks, and improve patient coverage.

From a macromolecular R&D perspective, key target combinations worth focusing on include:

PD-1 + LAG-3

• LAG-3 is a negative regulatory receptor that suppresses T-cell activity in the tumor microenvironment.
• PD-1/LAG-3 bispecific antibodies or combination therapies have shown higher efficacy than PD-1 inhibitors alone in some solid tumors.

CUSABIO Target Protein Recommendations:

PD-1 + TIGIT

• TIGIT regulates immune responses by inhibiting NK cell and T cell activity.
• Dual-targeting strategies can enhance immune cell efficiency in killing tumors and show potential advantages in resistant patients.

CUSABIO Target Protein Recommendations:

PD-1 + TIM-3 / VISTA

• TIM-3 and VISTA belong to new negative immune checkpoints that can synergistically inhibit T cell activity with the PD-1 pathway.
• Dual-target antibodies may address the issue of non-response in some patients treated with PD-1 monotherapy.

CUSABIO Target Protein Recommendations:

In the future, the R&D value of these combination strategies will primarily lie in the non-redundancy, amplifiability, and potential for structured design of the targets. For macromolecular R&D teams, Beyond PD-1 is not only a new direction of clinical potential but also a crucial opportunity for the application and validation of antibody, bispecific antibody, and ADC technology platforms. By precisely selecting combination targets, differentiated efficacy can be achieved, forming formidable R&D barriers against competition.

4. Autoimmune Diseases: Core Pathways and Target Combinations

Autoimmune diseases have long been a key area for macromolecular drug (antibodies, fusion proteins, bispecific antibodies) R&D, including rheumatoid arthritis, psoriasis, inflammatory bowel disease, etc. With deepening understanding of immune regulatory pathways, several targets have shown high biological certainty and druggable potential.

4.1 IL-23 / IL-12p40: Key Nodes in Inflammatory Diseases

• IL-23 is a core factor for Th17 cell differentiation, driving multiple inflammatory diseases.
• IL-12p40, as a shared subunit of IL-12 and IL-23, is the target of existing antibodies (e.g., ustekinumab).
• Dual-targeting or specific subtype antibody strategies can enhance efficacy while reducing side effects, providing continuous iteration space for macromolecular R&D.

CUSABIO Target Protein Recommendations:

4.2 IL-17A / IL-17RA: Targets for Psoriasis and Arthritis

• IL-17A plays a central role in inflammation amplification and tissue damage.
• Antibody blockade of IL-17A or its receptor IL-17RA has proven effective in psoriasis and ankylosing spondylitis.
• Macromolecular development can further optimize selectivity, half-life, and dosing regimens, improving patient adherence and long-term efficacy.

CUSABIO Target Protein Recommendations:

4.3 TNF-α: A Classic Yet Optimizable Immune Regulatory Target

• TNF-α was among the first inflammatory mediators successfully targeted by antibodies.
• Despite multiple TNF-α inhibitors being on the market, opportunities to improve efficacy and safety remain through Fc engineering optimization, bispecific designs, or local delivery.
• For macromolecular R&D teams, the TNF-α target remains a typical case of low scientific risk and an opportunity to validate platform capabilities.

CUSABIO Target Protein Recommendations:

4.4 JAK / STAT Pathway Auxiliary Targets

• Although small molecule JAK inhibitors are already used, blocking the cytokine–JAK–STAT pathway via macromolecules still holds potential in specific autoimmune disease subtypes.
• Antibodies or fusion proteins can be designed to block key upstream cytokines (e.g., IL-6), achieving precise immune modulation.

CUSABIO Target Protein Recommendations:

In the future, target selection for autoimmune diseases should focus on core pathway nodes, non-redundant actions, and druggable potential. IL-23/IL-12p40, IL-17A/IL-17RA, TNF-α, and specific cytokine–JAK-STAT combinations all belong to the category of targets with clear mechanisms, suitable for in-depth macromolecular optimization. They not only provide solid scientific rationale but also support long-term pipeline planning and structural iteration.

5. CUSABIO: Providing Reliable Tools for Target Validation, Supporting Next-Generation Macromolecular R&D

In today's drug development landscape, shifting from "platform competition" back to "target competition," selecting a scientifically sound and developable target has become the primary prerequisite for project success. CUSABIO continuously monitors global R&D trends, focusing on core areas such as metabolism, cardiovascular, oncology, and autoimmunity, providing high-activity, high-purity, rigorously validated target proteins and related reagents.

We are committed to providing you with:

• Recombinant proteins covering cutting-edge targets, supporting mechanism research and antibody screening.
• Multiple active forms and tag options, adaptable to various experimental and development scenarios.
• A continuously updated target pipeline, keeping pace with global drug R&D trends.

Whether you are engaged in antibody engineering, bispecific antibody construction, ADC development, or exploring new immune combination strategies, we aim to be your reliable partner during the target validation and molecular discovery stages. Let science return to the target, and let tools empower innovation.