ADCs: How Antibody-Drug Conjugates Target Cancer Cells

Antibody-drug conjugates, widely known as ADCs, are cancer treatments built from a monoclonal antibody chemically attached to a potent cell-killing drug through a molecular tether called a linker.¹ The idea is deceptively simple: use the antibody as a homing device to deliver toxic cargo directly to tumor cells while largely sparing healthy tissue. In practice, making that work has been one of the hardest engineering challenges in modern drug development, requiring decades of iteration on every component. The results, when the design clicks, can be striking, and the field has accelerated rapidly since the early 2020s.

How an ADC Actually Kills a Cancer Cell

An ADC circulates in the bloodstream much like a normal antibody. Once it reaches a tumor, the antibody portion locks onto a specific protein on the cancer cell’s surface. Choosing the right target protein is critical: it should be abundant on tumor cells but scarce on normal tissue, which is what gives the drug its selectivity.² After binding, the whole complex is pulled inside the cell through a process called endocytosis. The cell essentially swallows the ADC, wrapping it in a small bubble of membrane and shuttling it inward.³

That bubble fuses with compartments inside the cell called lysosomes, which are acidic environments packed with enzymes that break things down. The lysosome chews apart the antibody and the linker, freeing the toxic payload inside the cell. The released drug then goes to work, typically by damaging DNA or disrupting the structural scaffolding the cell needs to divide. The result is cell death from the inside out.

Each step in that chain has to function well, and inefficiency at any stage limits how much drug actually reaches its target. Getting the ADC inside the cell quickly and routing it to lysosomes efficiently has been a persistent bottleneck. Recent experimental work has tried to speed up this process by engineering ADCs that simultaneously recruit a cellular tagging system, promoting faster internalization and better delivery to lysosomes.⁴ These approaches are early-stage, but they reflect how much room for improvement still exists in the basic delivery mechanism.

The Three Components and Why Each One Matters

Every ADC is a three-part system, and the performance of the whole drug depends on getting all three parts right together.

The antibody determines where the drug goes. It has to bind tightly and specifically to the target on tumor cells. If the target protein also appears on healthy cells, the ADC will damage those cells too, causing side effects that have nothing to do with the drug leaking prematurely. Selectivity at the targeting level is the first line of defense against toxicity.⁵

The linker is the chemical bridge holding the payload to the antibody. An ideal linker stays intact while the ADC circulates in the blood, then breaks cleanly once the ADC is inside the target cell. In reality, linkers often release some of their payload prematurely during circulation, which is a major source of off-target toxicity.⁶ Linker design has been one of the most active areas of ADC research because even small improvements in stability translate directly to fewer side effects.

The payload is the actual cell-killing molecule. ADC payloads are far more toxic than conventional chemotherapy drugs, sometimes hundreds of times more potent. They have to be, because only a small fraction of an administered dose actually reaches the tumor. Most approved ADCs carry payloads that either disrupt the cell’s internal skeleton to prevent division or directly damage DNA. Some experimental designs are exploring dual-payload ADCs that carry two different drugs on the same antibody, attacking the cancer cell through two mechanisms simultaneously.⁷

The Drug-to-Antibody Ratio Sweet Spot

A number that comes up constantly in ADC development is the drug-to-antibody ratio, or DAR: how many payload molecules are attached to each antibody. You might assume that loading more drug onto each antibody would make the ADC more potent, but the relationship is not that simple. Preclinical studies with one class of payload found that conjugates carrying roughly two to six drug molecules per antibody had comparable clearance rates in the body and the best balance of effectiveness and tolerability. When the DAR was pushed up to about nine or ten, the ADCs were cleared from the bloodstream much faster, accumulating heavily in the liver rather than reaching the tumor.⁸

The liver accumulation numbers were dramatic: high-DAR conjugates concentrated in the liver at roughly two to three times the level of lower-DAR versions within a few hours of dosing.⁹ The heavily loaded ADCs essentially looked foreign to the body’s clearance systems, got swept up before they could do their job, and ended up being less effective despite carrying more drug. For that class of payloads, a DAR of three to four is generally preferred, though the optimal number shifts depending on the specific antibody and target.

The Bystander Effect and Tumor Heterogeneity

Tumors are rarely uniform. Within a single mass, some cancer cells might express high levels of the target protein while neighboring cells express little or none. If the ADC can only kill cells it directly binds to, those target-negative neighbors survive, and the tumor can regrow from them. This is one of the central challenges in oncology: tumor heterogeneity.

Some ADCs get around this through what is called the bystander effect. After the ADC is internalized and its payload is released inside a target-positive cell, the freed drug can diffuse out through the cell membrane and enter nearby cells, killing them regardless of whether they express the target protein.¹⁰ Whether this happens depends heavily on the properties of the payload and the linker. Hydrophobic, membrane-permeable payloads diffuse out more readily. Cleavable linkers that release the drug in a form that can cross membranes also contribute.¹¹

A concrete example: trastuzumab deruxtecan (T-DXd) carries a payload called DXd that is highly membrane-permeable, giving it a strong bystander effect. In lab experiments, T-DXd killed both HER2-positive and neighboring HER2-negative breast cancer cells. An older ADC called T-DM1 carries a payload with low membrane permeability and did not kill the HER2-negative bystander cells under the same conditions.¹² The bystander effect is a double-edged sword, though. The same property that lets the drug spread through a heterogeneous tumor can also cause it to leak into surrounding healthy tissue, which is part of why managing the range of killing is an active design challenge.

A Landmark Clinical Result

The DESTINY-Breast03 trial, which compared trastuzumab deruxtecan head-to-head against the older trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, produced results that reshaped clinical practice. Among over 500 patients, roughly three in four on trastuzumab deruxtecan were alive without disease progression at 12 months, compared with about one in three on the older drug. The overall response rate was about 80% versus 34%.¹³ Those are not incremental improvements. Moving from a 34% to an 80% response rate with a newer version of essentially the same concept, a HER2-targeting ADC, demonstrated how much engineering improvements in the linker, payload, and DAR actually matter in the clinic.

The results led to regulatory approval of trastuzumab deruxtecan for patients with HER2-positive metastatic breast cancer who had received prior treatment.¹⁴ Beyond breast cancer, ADCs are now approved or in advanced trials across a range of solid tumors and blood cancers, with new targets and payloads entering the clinic every year.

Interstitial Lung Disease and Other Safety Concerns

The most worrying safety issue across the ADC class is interstitial lung disease (ILD), a form of lung inflammation and scarring that can become severe or fatal. A large pharmacovigilance study covering 2014 to 2023 identified over 1,200 reported cases of ADC-associated ILD. Trastuzumab deruxtecan accounted for the highest proportion, about 38% of cases. More than a quarter of all ADC-related ILD cases resulted in death, and when the lung disease progressed to acute respiratory distress syndrome, the fatality rate reached 65%.¹⁵

Why ADCs cause lung problems is not fully understood. The leading hypotheses involve the payload reaching lung tissue, either through premature release in the bloodstream or through uptake of the ADC by healthy lung cells that happen to express low levels of the target protein. Research into the distribution patterns of ADCs in the body suggests that payload accumulation in the lungs plays a role, but the exact mechanism likely varies by drug.¹⁶ In practice, patients receiving ADCs with known ILD risk are monitored with imaging and lung function tests, and treatment is interrupted or stopped at the first signs of lung inflammation. Early detection and dose management have improved outcomes, but ILD remains a serious risk that shapes how aggressively these drugs are used.

How Tumors Develop Resistance

Like nearly all cancer therapies, ADCs eventually face resistance. Tumors can evade them at multiple points along the delivery chain. The most straightforward route is downregulating the target protein on the cell surface: if the lock disappears, the key cannot get in. Tumors can also reduce how efficiently they internalize the ADC after binding, or disrupt the intracellular trafficking that routes the ADC to lysosomes for payload release.¹⁷

Even when the payload is successfully released inside the cell, resistance can still develop. Cancer cells may upregulate drug efflux pumps, molecular transporters that actively pump the payload back out of the cell before it can do damage. Others develop ways to chemically neutralize the payload through detoxification pathways.¹⁸ The fact that resistance can arise at so many different points in the ADC’s mechanism explains why researchers are pursuing combination approaches and next-generation designs rather than relying on any single ADC strategy.

Pairing ADCs with Immunotherapy

One of the most promising directions in ADC development is combining them with immune checkpoint inhibitors, the class of immunotherapy drugs that help the immune system recognize and attack cancer. There is growing evidence that ADCs do more than just poison tumor cells directly. When an ADC kills a cancer cell, the dying cell can release signals and fragments that alert the immune system, a process called immunogenic cell death. Dendritic cells, which serve as the immune system’s scouts, pick up these tumor fragments and present them to T cells, potentially broadening the immune response to recognize cancer cells the ADC itself never touched.¹⁹

When checkpoint inhibitors are added on top of this, the idea is that the ADC primes the immune system while the checkpoint inhibitor removes the brakes that tumors use to suppress immune attack. Studies in patients receiving both ADCs and checkpoint inhibitors have shown expansion of cancer-targeting T cells, including cells that recognize tumor proteins the ADC itself does not target, suggesting the immune response diversifies over time.²⁰ The combination is being tested across numerous tumor types in clinical trials right now, though one concern is that amplifying immune activation also raises the risk of immune-related side effects.

Next-Generation Designs

Standard ADCs target a single protein. Bispecific ADCs, a newer class, carry antibodies that bind two different targets at once. The appeal is better selectivity: by requiring both targets to be present on the same cell before the ADC engages, the drug can distinguish tumor cells from healthy cells that express only one of the two targets.²¹ In preclinical models, a bispecific ADC targeting two proteins commonly co-expressed in colorectal cancer showed activity against tumors expressing both targets but spared tumors expressing only one.²² That kind of “AND gate” logic, requiring two signals rather than one, could dramatically reduce off-target toxicity if it translates to patients.

On the diagnostic side, companion tests are also getting more sophisticated. Newer multiplex panels can assess the levels of multiple biomarkers simultaneously on a single tissue sample, helping oncologists determine which ADC is the best match for a particular patient’s tumor profile.²³ As more ADCs become available targeting different proteins, matching the right drug to the right tumor becomes increasingly important.

Manufacturing Complexity

Making an ADC is considerably harder than making either a standard antibody or a standard small-molecule drug. The process involves producing the antibody through biological cell culture, separately synthesizing the linker-payload chemistry, then conjugating the two together under controlled conditions. Every step introduces variability: the antibody’s structure, the number of payloads attached, the position of attachment, and the stability of the final product all need to be tightly controlled.²⁴

Site-specific conjugation, where drug molecules are attached at defined positions on the antibody rather than randomly, has been an important advance. It produces a more uniform product, meaning every ADC molecule in the vial looks roughly the same. Older random conjugation methods created mixtures where some antibodies carried too many payloads and others too few, which led to inconsistent performance and unpredictable side effects. Modern manufacturing treats the upstream antibody production, the conjugation chemistry, and the downstream purification as an integrated system, where variability at any stage can compromise the final product.²⁵ This complexity is one reason ADCs are among the most expensive cancer drugs on the market.

Beyond Cancer

Almost all approved ADCs target cancers, but the core concept of using an antibody to deliver a toxic or functional payload to a specific cell type is not inherently limited to oncology. Researchers are now exploring ADCs for autoimmune diseases, inflammatory conditions, and infections.²⁶ In autoimmune disease, for example, the idea is to target and eliminate the specific immune cells driving the disease rather than broadly suppressing the entire immune system, as many current treatments do. The payloads in these cases do not necessarily need to be as potent as those used in cancer, since the goal is to deplete a specific cell population rather than destroy a solid tumor.

A related concept gaining traction is peptide-drug conjugates, or PDCs, which swap out the large antibody for a smaller peptide as the targeting molecule. The trade-off is that peptides are cleared from the body much faster, but they penetrate tissue more easily and are cheaper and simpler to manufacture.²⁷ Several PDCs are in clinical development, and the approach could open up targeted delivery strategies for diseases and tissue types where antibodies are too large to reach effectively. The broader trajectory across all of these conjugate platforms is toward increasingly precise delivery, using molecular engineering to put powerful drugs exactly where they are needed and nowhere else.