Genmab Synaffix: Advancing ADC Potential in Oncology

Antibody-drug conjugates (ADCs) have emerged as a promising approach in oncology, combining the specificity of monoclonal antibodies with the potency of cytotoxic drugs. By delivering chemotherapy directly to cancer cells while minimizing damage to healthy tissue, ADCs offer a targeted and potentially less toxic alternative to traditional treatments. Their effectiveness depends on precise engineering to ensure stability, controlled drug release, and efficient tumor targeting.

Genmab’s acquisition of Synaffix expands its ADC development capabilities by integrating innovative conjugation technologies, enhancing efficacy and safety profiles.

Principles of Antibody–Drug Conjugate Engineering

ADC design requires balancing stability, specificity, and therapeutic potency. Each component—the monoclonal antibody, cytotoxic payload, and linker—must be engineered to ensure the drug remains inactive in circulation while effectively targeting cancer cells. The antibody serves as the guiding mechanism, recognizing tumor-associated antigens with high affinity to maximize selective delivery. Off-target binding can lead to systemic toxicity and reduced efficacy.

Antibody selection depends on antigen expression levels, internalization rates, and tumor heterogeneity. Ideal targets are highly expressed on malignant cells but absent or minimally present on normal tissues. HER2-targeting ADCs like trastuzumab deruxtecan have demonstrated efficacy in HER2-positive breast and gastric cancers by leveraging this differential expression. Additionally, modifying the antibody’s Fc region can enhance pharmacokinetics, reduce immune clearance, or improve tumor penetration.

The conjugation strategy significantly impacts ADC stability and function. Traditional methods, such as lysine- or cysteine-based approaches, often create heterogeneous mixtures with variable drug-to-antibody ratios (DARs), affecting therapeutic consistency. Site-specific conjugation techniques, including engineered cysteine residues or enzymatic ligation, produce homogeneous ADCs with defined DARs, improving batch-to-batch reproducibility and pharmacokinetic predictability. Optimized DARs—typically in the range of 2 to 4—enhance efficacy while minimizing premature drug release and systemic toxicity.

Synaffix Conjugation Platform

Genmab’s acquisition of Synaffix introduces a suite of site-specific conjugation technologies designed to improve ADC stability, DAR uniformity, and therapeutic performance. Traditional conjugation methods often produce heterogeneous ADC populations, but Synaffix addresses this with its GlycoConnect™, HydraSpace™, and toxSYN™ technologies.

GlycoConnect™ modifies the antibody’s Fc glycan sites for precise drug attachment, ensuring a homogeneous DAR and reducing premature drug release. Clinical studies show ADCs with controlled DARs exhibit improved pharmacokinetics and reduced systemic toxicity compared to conventional conjugation methods. Leveraging naturally occurring glycan structures preserves antibody integrity while optimizing payload delivery.

HydraSpace™ enhances ADC solubility and reduces aggregation, a common challenge in formulation. Poor solubility can lead to rapid clearance or unwanted immune activation. By incorporating hydrophilic linkers, HydraSpace™ improves circulation time and tumor penetration, increasing therapeutic windows and prolonging half-lives.

The toxSYN™ platform strengthens ADC potency by integrating highly potent cytotoxic payloads with optimized linker chemistry. Balancing drug potency with systemic tolerability is crucial, and toxSYN™ provides a range of payloads, including microtubule inhibitors and DNA-damaging agents, tailored to different cancer types. Combined with GlycoConnect™ and HydraSpace™, toxSYN™ enables ADCs with superior therapeutic indices, expanding treatment possibilities.

Linker Chemistry and Payload Attachment

The linker chemistry tethering the cytotoxic payload to the antibody is critical to ADC success. Linkers must withstand systemic circulation while ensuring precise drug release in the tumor microenvironment. They are categorized as cleavable or non-cleavable, each with advantages based on tumor biology and intracellular processing.

Cleavable linkers exploit tumor-specific conditions—such as acidic pH, high glutathione concentrations, or lysosomal enzymes—to trigger payload release. This controlled mechanism enhances bystander effects, allowing the cytotoxic payload to diffuse into adjacent tumor cells, benefiting heterogeneous tumors. Linkers using pH-sensitive hydrazone bonds or enzyme-cleavable dipeptides like valine-citrulline demonstrate high plasma stability while ensuring efficient intracellular drug liberation.

Non-cleavable linkers, like the thioether bond in trastuzumab emtansine (T-DM1), prevent premature payload release, reducing systemic toxicity but requiring complete antibody degradation within tumor cells to activate the drug.

Linker hydrophilicity also plays a pivotal role in ADC pharmacokinetics. Highly hydrophobic linkers can lead to aggregation, rapid clearance, and off-target toxicities. Advances in linker design, such as incorporating polyethylene glycol (PEG) or polysarcosine spacers, improve solubility while maintaining conjugate stability. This enhances tumor penetration and reduces non-specific plasma protein interactions, leading to better biodistribution.

Mechanisms of Drug Release

Once an ADC reaches its target, efficient drug release determines therapeutic impact. The cytotoxic payload must be selectively liberated to destroy tumor cells while limiting off-target effects. Release strategies exploit intracellular conditions unique to malignant cells, such as elevated enzymatic activity, acidic vesicles, or reductive environments.

Cleavable linkers often rely on lysosomal proteases like cathepsin B, overexpressed in many cancers, to trigger drug release. This enzymatic degradation ensures rapid payload activation upon internalization. Disulfide-based linkers use high intracellular glutathione concentrations in tumor cells to break bonds and release the drug. These mechanisms enable efficient intracellular drug accumulation, leading to controlled cytotoxicity and improved therapeutic windows.

Tissue Targeting in ADC Technology

ADC effectiveness depends on efficient tumor penetration and distribution. Solid tumors present challenges such as heterogeneous antigen expression, high interstitial pressure, and dense extracellular matrices that can impede ADC infiltration. Optimizing antibody affinity, molecular size, and binding kinetics is essential to maximize tumor exposure while minimizing systemic circulation time.

Selecting antigens with high internalization rates ensures rapid ADC uptake and intracellular drug release. ADCs targeting rapidly internalizing receptors, such as HER2 and TROP2, demonstrate superior intracellular drug accumulation. Additionally, adjusting antibody binding strength influences tumor penetration. ADCs with excessively high affinity may become trapped at the tumor periphery, failing to reach deeper malignant cells. Engineering antibodies with moderate affinity improves distribution, increasing the likelihood of uniform drug delivery across the tumor mass.