Next-Generation Antibody-Drug Conjugates
The Biological Missiles Revolutionizing Cancer Therapy
230+
ADC Drugs in Development
19
Approved ADC Therapies
$4B+
Global Sales of Leading ADC
Introduction: The Precision Medicine Revolution
Imagine a cancer treatment so precise it can distinguish between healthy and cancerous cells with exceptional accuracy, delivering its potent toxic payload directly to tumor cells while leaving healthy tissue untouched.
This isn't science fiction—it's the promise of next-generation Antibody-Drug Conjugates (ADCs), often called "biological missiles" for their ability to precisely target cancer cells. In the evolving landscape of oncology, ADCs represent a groundbreaking fusion of targeted therapy and traditional chemotherapy, offering new hope for patients with difficult-to-treat cancers.
With approximately 230 ADC drugs currently in clinical development globally and 19 already approved for various cancers, these sophisticated molecules are reshaping cancer treatment paradigms 5 .
Growth in ADC clinical development over the past decade
Precision Targeting
ADCs combine the specificity of monoclonal antibodies with the potency of cytotoxic drugs.
Reduced Side Effects
By targeting only cancer cells, ADCs minimize damage to healthy tissues compared to traditional chemotherapy.
Rapid Innovation
Next-generation ADCs demonstrate improved efficacy and innovative mechanisms of action.
The Anatomy of an ADC: Components and Mechanisms
Building the Biological Missile
The Antibody
This large protein serves as the targeting system, designed to recognize and bind specifically to antigens expressed on the surface of cancer cells.
Ideal targets are highly expressed on tumor cells but absent or minimally present on healthy cells. Modern ADCs typically use humanized or fully human antibodies to minimize immune reactions .
The Payload
This is the warhead—an extremely potent cytotoxic drug designed to kill cancer cells once released.
Payloads are typically 100-1000 times more powerful than conventional chemotherapy drugs and fall into two main categories: tubulin inhibitors and DNA-damaging agents .
Key Components of Antibody-Drug Conjugates
| Component | Function | Types | Development Considerations |
|---|---|---|---|
| Antibody | Targeting and specificity | Humanized, fully human, bispecific | Antigen specificity, binding affinity, low immunogenicity |
| Payload | Cancer cell killing | Tubulin inhibitors, DNA-damaging agents | Extreme potency, mechanism of action, bystander effect |
| Linker | Connects antibody and payload | Cleavable, non-cleavable | Plasma stability, efficient release at target site |
How ADCs Work: From Targeting to Tumor Destruction
1 Target Binding
The ADC circulates through the bloodstream until its antibody component recognizes and binds to its specific target antigen on the cancer cell surface 9 .
2 Internalization
The ADC-antigen complex is engulfed by the cancer cell through receptor-mediated endocytosis, transporting the ADC inside the cell within endosomal vesicles 9 .
3 Payload Release
These vesicles fuse with lysosomes, where the acidic environment and specific enzymes cleave the linker, releasing the active cytotoxic payload 9 .
4 Cell Death
The payload disrupts critical cellular processes—either by disrupting microtubule function during cell division or causing irreversible DNA damage—triggering programmed cell death .
Bystander Effect
Some ADCs with cleavable linkers and membrane-permeable payloads can exert bystander effects, where the released drug diffuses into neighboring tumor cells, potentially killing adjacent cancer cells regardless of their antigen expression.
This is particularly valuable in tumors with heterogeneous antigen expression 9 .
The Clinical Landscape: From Approved Drugs to Pipeline Innovations
Approved ADCs and Their Impact
The ADC field has witnessed remarkable growth since the first approval in 2000. As of June 2025, 19 ADC drugs have been approved globally for various hematological malignancies and solid tumors .
These include pioneering agents like trastuzumab deruxtecan for HER2-positive breast cancer and enfortumab vedotin for urothelial carcinoma, which have demonstrated unprecedented efficacy in patients who had exhausted other treatment options.
The commercial and clinical success of these drugs, particularly trastuzumab deruxtecan which achieved global sales exceeding $4 billion in 2024 across five different cancer types, has validated the ADC approach and stimulated massive investment in further development 5 .
Target Concentration in the Pipeline
The current ADC development pipeline shows significant focus on a handful of promising targets:
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HER2: A classic tumor driver gene highly expressed in multiple solid tumors with efficient internalization characteristics 5 .
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TROP2: Widely expressed in cancers with limited treatment options such as triple-negative breast cancer 5 .
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EGFR: Overexpressed in several cancers, with recent success in bispecific ADC approaches 5 .
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Claudin18.2: Highly tissue-specific and expressed in 70-80% of gastric cancer patients, though development has faced safety challenges 5 .
Notably, these four targets account for over 50% of the current clinical ADC pipeline, demonstrating both the promise of these targets and the need for diversification to address a broader range of cancers 5 .
A Closer Look: Groundbreaking Clinical Trial of Precem-TcT
Methodology: PROCEADE-CRC-01 Phase I Study
A compelling example of next-generation ADC development comes from MSD's PROCEADE-CRC-01 trial (NCT05464030), a Phase I study evaluating precemtabart tocentecan (Precem-TcT) in heavily pre-treated colorectal cancer patients.
This study represents a significant advancement in targeting CEACAM5 (carcinoembryonic antigen-related cell adhesion molecule 5), a surface protein highly expressed in gastrointestinal cancers but with previously disappointing therapeutic results 1 .
The trial enrolled patients with advanced colorectal cancer who had exhausted standard treatment options. Participants received Precem-TcT at a dose of 2.8mg/kg. The ADC employs a topoisomerase I inhibitor payload—a strategic choice based on the observation that "the chemotherapy we want to direct to a disease such as colorectal cancer needs to be one that we know that indication will respond to" 1 .
Results and Analysis: Promising Efficacy and Manageable Safety
The results, presented at the 2025 ESMO Congress, demonstrated compelling clinical activity. The objective response rate (ORR)—the percentage of patients with significant tumor shrinkage—was 31%, a notable achievement in this heavily pre-treated population.
The ADC also showed impressive disease control, with a median progression-free survival (PFS) of 6.9 months and 64.3% of patients remaining free of disease progression at the six-month mark 1 .
The safety profile was similarly encouraging. The most common Grade 3 treatment-emergent adverse events were neutropenia (low white blood cell count) and anemia, both manageable with standard supportive care. Notably, gastrointestinal side effects—often a concern with ADCs—were consistently mild-to-moderate, with no Grade 3 GI events reported 1 .
Efficacy Results from PROCEADE-CRC-01 Phase I Trial of Precem-TcT
| Efficacy Parameter | Result | Clinical Significance |
|---|---|---|
| Objective Response Rate (ORR) | 31% | Nearly one-third of heavily pre-treated patients experienced significant tumor shrinkage |
| Median Progression-Free Survival (PFS) | 6.9 months | Meaningful disease control in advanced colorectal cancer |
| 6-Month PFS Rate | 64.3% | Majority of patients maintained disease control at 6 months |
Next Steps: Phase III Trials
Based on these promising results, MSD announced plans to advance Precem-TcT directly to Phase III trials in colorectal cancer, expected to initiate in the first half of 2026. The company will use TAS-102 plus bevacizumab (current standard of care) as the control arm to directly assess the ADC's potential to become the first widely approved ADC in colorectal cancer 1 .
Next-Generation Innovations: The Future of ADC Technology
Bispecific and Multispecific ADCs
The next wave of ADC innovation moves beyond single-target approaches. Bispecific ADCs can simultaneously engage two different antigens on tumor cells, potentially improving targeting precision and overcoming resistance mechanisms.
A standout example is Betta Pharmaceuticals' BL-B01D1, which targets both EGFR and HER3 and has demonstrated a remarkable 69% objective response rate in pretreated EGFR-mutant non-small cell lung cancer patients 5 .
Immunomodulatory ADCs (iADCs)
Another frontier combines ADC technology with immunotherapy. Henlius' HLX43 pioneers this approach by leveraging a dual anti-tumor mechanism: traditional ADC-mediated cytotoxicity combined with PD-L1 blockade-induced immune activation.
Phase I data presented at ASCO 2025 showed efficacy across NSCLC patients with varying PD-L1 expression, including difficult-to-treat populations 5 .
Advanced Linker Technologies
Innovations in linker design are addressing long-standing challenges with stability and payload release. The Sac-TMT linker from Sichuan Kelun-Biotech combines pH sensitivity and enzymatic cleavage to optimize bystander effects while reducing off-target toxicity 5 .
Similarly, novel conjugation methods are enabling more precise control over the drug-to-antibody ratio (DAR), optimizing both efficacy and safety profiles.
Computational and AI-Driven Design
The integration of computational methods and AI-driven structure prediction has become essential for accelerating ADC development. These approaches enable researchers to model antibody-antigen interactions, predict linker stability, and optimize payload performance in silico, reducing experimental labor and accelerating candidate selection 2 9 .
The Scientist's Toolkit: Essential Reagents for ADC Research
The development of advanced ADCs relies on specialized research tools and reagents that enable precise design, testing, and optimization.
Essential Research Reagent Solutions for ADC Development
| Research Tool | Function | Application Examples |
|---|---|---|
| Cytotoxic Payloads | Provide the cell-killing component | DNA damaging agents, tubulin inhibitors for warhead selection 3 |
| Specialized Linkers | Connect antibodies to payloads | Cleavable and noncleavable linkers for optimizing stability/release balance 3 |
| Conjugation Kits | Enable antibody-payload conjugation | Perkit™ kits for biomolecule-payload coupling 3 |
| Anti-Payload Antibodies | Detect and analyze ADC distribution | Antibodies against MMAE, Dxd, DM1 for pharmacokinetic studies 7 |
| Target Antigen Proteins | Validate antibody binding | Recombinant proteins for popular ADC targets (HER2, TROP2, CEACAM5, etc.) 7 |
| Drug-Linker Conjugates | Simplify ADC assembly | Pre-conjugated payload-linker combinations 3 |
| ADC Functional Assays | Assess efficacy and mechanisms | Binding (ELISA), potency (cell kill), internalization assays 6 |
These tools collectively enable researchers to address the dual challenge of safety and efficacy that has long complicated ADC development. Particularly valuable are anti-payload antibodies, which allow precise tracking of ADC distribution and metabolism—critical for understanding both efficacy and toxicity profiles 7 .
Conclusion: The Future of Targeted Cancer Therapy
Next-generation Antibody-Drug Conjugates represent a remarkable convergence of oncology, immunology, and chemical engineering—a testament to the power of interdisciplinary science.
As the field advances, we're witnessing a paradigm shift from broadly cytotoxic chemotherapy to precisely targeted molecular interventions that respect the patient's healthy tissues while delivering unprecedented anti-cancer efficacy.
The future of ADCs lies in addressing remaining challenges: expanding their applicability to more cancer types, overcoming resistance mechanisms, further improving therapeutic indices, and making these sophisticated treatments more accessible.
Expanded Target Range
Development of ADCs for currently untreatable cancers with novel targets.
Combination Therapies
Strategic pairing of ADCs with immunotherapies and targeted agents.
Personalized ADCs
Patient-specific ADCs based on individual tumor antigen profiles.
Enhanced Delivery Systems
Novel technologies to improve tumor penetration and payload release.
The industry is on the brink of a breakthrough, though it is yet to be seen who makes it to market first.
— Dr. Victoria Zazulina of MSD 1
With innovations in bispecific targeting, immunomodulatory approaches, linker technology, and computational design, the next generation of "biological missiles" will become increasingly precise, powerful, and versatile.
What remains certain is that this breakthrough will fundamentally transform cancer therapy, offering new hope to patients worldwide through the continuing evolution of Antibody-Drug Conjugates.