Scaffold-Drug Conjugates (SDCs)

Scaffold-Drug Conjugates (SDCs)

Scaffold-drug conjugates (SDCs) are drug conjugates in which drug molecules are attached to scaffold molecules. Scaffold molecules serve as carriers for drugs, helping to target them to specific cells or tissues and improving their stability and pharmacokinetic properties. SDCs have emerged as a promising method of targeted drug delivery, particularly in cancer treatment, where they can help improve the efficacy of chemotherapy drugs and reduce side effects. BOC Sciences is a leading provider of development services for antibody-drug conjugates (ADCs), offering a range of solutions to support the design, synthesis and optimization of these novel therapeutics, including scaffold-drug conjugates (SDCs).

What are Scaffold-Drug Conjugates?

SDCs are a class of therapeutic molecules that combine the advantages of small molecule drugs and biologics. Small molecule drugs are attached to larger scaffold molecules, which can provide multiple advantages, including improved stability, enhanced targeting, and improved efficacy. Scaffolds tend to be smaller than 6-21 kDa antibody fragments, can be expressed in E. coli , and have greater stability. Currently, most are used in imaging and receptor/ligand inhibition. A recent commercial analysis of the field revealed 84 unique scaffold-drug conjugates in development, 82% of which are in the preclinical/discovery stage and 40% for oncology.

Illustration of alternative scaffold-drug conjugatesFig. 1. Illustration of alternative scaffold-drug conjugates (Antibodies (Basel). 2018, 7(2): 16).

SDCs can be engineered to target specific disease pathways or cell types, making them highly versatile and suitable for a wide range of therapeutic applications. They can be used to treat a variety of conditions, including cancer, autoimmune diseases, and infectious diseases. SDCs offer several advantages over traditional small molecule drugs, including:

  • Enhanced stability: Scaffold molecules can protect drugs from degradation, increase their stability, and extend their half-life in the body.
  • Improved targeting: Scaffold molecules can be designed to target specific receptors or cell types, increasing the specificity of drugs and reducing off-target effects.
  • Improved therapeutic efficacy: By optimizing drug-stent conjugation, SDC can deliver higher concentrations of drugs to target sites, thereby improving therapeutic efficacy.
  • Reduced toxicity: SDCs can minimize the exposure of healthy tissue to drugs, reduce the risk of adverse reactions, and improve patient safety.

Scaffold-Drug Conjugates Development Services

BOC Sciences is a leading provider of ADC development services, offering comprehensive solutions to support the design, synthesis and optimization of these innovative therapies. We have a team of experienced chemists, biologists and pharmacologists at the forefront of developing cutting-edge SDCs for a variety of therapeutic applications.

Screening of Small Molecule Cytotoxins

The first step in the SDC production process is drug selection. Drug molecules are selected based on their therapeutic properties and their ability to target specific cells or tissues. With strong supply capabilities in the field of small molecule cytotoxins, BOC Sciences can provide a comprehensive range of high-quality cytotoxic products. If our existing stock products do not meet your needs, we also support one-stop synthesis services for novel small molecule cytotoxins.

Design of Scaffold Molecules

Once a drug molecule is selected, the scaffold molecules are designed to optimize the delivery of the drug to its target site. Scaffold molecules must be biocompatible, stable, and able to bind to drug molecules. Our bioscientists have extensive experience in modification and conjugation of antibodies and small molecule antibody fragments, and can support the coupling of a variety of engineered small molecule scaffolds such as Affibodies, Centyrins, Knottins, DARPins, and Abdurins.

Synthesis of Linker Molecules

After selecting the drug and scaffold molecules, the linker molecules are synthesized. Linker molecules are designed to connect the drug and scaffold molecules and control the release of the drug. The linker molecule must be stable, biodegradable, and able to release the drug in a controlled manner. We also have extensive synthetic capabilities in the linker area, including cleavable linkers and non-cleavable linkers.

SDC Conjugation Support

Once the drug, scaffold, and linker molecules are prepared, they are conjugated together to form the SDC. The conjugation process involves chemically linking drug molecules to scaffold molecules via linker molecules. This step requires precise control of reaction conditions and careful monitoring of reaction progress. BOC Sciences can design and synthesize custom SDCs targeting specific therapeutic targets or disease pathways. Utilizing state-of-the-art synthetic chemistry techniques, we can create novel SDCs with enhanced stability, targeting, and efficacy.

Purification and Characterization of SDC

After SDC synthesis, purification is performed to remove any impurities or by-products that may be formed during the conjugation process. Purification is often performed using chromatographic techniques such as high performance liquid chromatography (HPLC) or size exclusion chromatography. BOC Sciences can optimize the pharmacokinetic and pharmacodynamic properties of SDC through detailed characterization studies. By evaluating drug-stent conjugation, stability, and bioactivity to ensure the development of safe and effective SDCs.

In vitro and in vivo Testing of SDC

BOC Sciences can perform comprehensive in vitro and in vivo testing to evaluate the effectiveness and safety of SDC. Utilizing cell-based assays, animal models, and pharmacokinetic studies, BOC Sciences can evaluate the therapeutic potential of SDCs and guide further development.

Our SDC Development Capabilities

Affibody-Drug Conjugates

Affibody is a small triple helix protein (~7 kDa) derived from the z domain of staphylococcal protein A. Serum half-life of about 20 min, about 20 years of development history. Affibody is easy to express in E.coli and can be used for ligand display technology, such as phage display and cell display. In addition, the simplicity of the scaffold makes solid-phase peptide synthesis possible. Chemical coupling can be achieved by specifically modifying cysteine residues at sites in the tolerance modification region of the scaffold.

Centyrins-Drug Conjugates

Centyrins are small (~10 kDa) cysteine-free scaffolds based on the 10th type III fibronectin domain of human fibronectin. These scaffolds contain multiple rings, which are structurally similar to the complementarity determining (CDR) region of IgG and confer target specificity. They contain only one domain without disulfide bonds and can be easily expressed in various expression systems. At present, site-specific introduction of cysteine residues and maleimide linkers are still the most commonly used conjugation strategies for this scaffold.

Cystine Knot-Drug Conjugates

Knottins are polypeptides of 30-50 amino acid residues (3-6 kDa) in length. Due to its highly compact structure, it has significant chemical stability, protease stability and thermal stability. These scaffolds form a compact three-dimensional (3D) structure, which consists of at least three disulfide bonds and can be designed to bind to multiple targets. The most common way to produce cystine knots is solid-phase peptide synthesis, followed by oxidative folding. Although Knottins contain multiple disulfide bonds, disulfide-bridged chemicals have not yet been explored. Through copper-free click chemistry, azide residues can effectively and specifically bind to the sites of Knottins.

DARPin-Drug Conjugates

The designed ankyrin repeat protein (DARPins) is a scaffold based on Akyrin repeat (~18 KD). Typical DARPins are composed of 4-6 repeat units, each of which is about 33 amino acids in length. These scaffolds can be selected by phage display or ribosome display and can be expressed by E.coli. Through the site-specific binding of cysteine residues to the scaffold and then reacting with the maleimide linker, site-selective binding to DARPins can be achieved. The incorporation of azide and alanine into the n-terminus of DARPin can easily use azide cycloaddition click chemistry for chemical conjugation.

Abdurin-Drug Conjugates

Unlike most binding scaffolds, Abdurins is a scaffold based on engineered IgG CH2 domain, which retains the ability to bind to FcRn receptors and has the ability to prolong serum half-life. It is only 1/10 (~15 kDa) in size and has thermal stability. It has three rings and can form a binding library in diversity.

Case Study

Researchers extend the circulation time of Z(HER2:4)-MMAE targeted cancer therapy by self-assembling a nanomicelle, an affibody-based nanoagent (Z(HER2:4)-MMAEADCM) that is HER2-positive in vivo Ovarian and breast tumor models showed excellent anti-tumor activity, almost eradicating both small solid tumors (approximately 100mm3) and established large tumors (more than 500mm3). The relative tumor proliferation inhibition rates of both models reached 99.8%.

Schematic representation of Z-M ADCN for targeted cancer therapyFig. 2. Schematic representation of Z-M ADCN for targeted cancer therapy (Nano-micro letters. 2021,14(1): 33).


1. What is a drug scaffold?

A drug scaffold is a molecular framework or core structure that serves as the basis for the design and development of new drug compounds. It is a key component of drug molecules and is responsible for the overall shape and function of the molecule. Drug scaffolds are often used as a starting point for medicinal chemists to modify and optimize a drug's properties, such as its potency, selectivity, and pharmacokinetic characteristics.

2. What is an antibody scaffold?

Antibody scaffolds are structural frameworks that provide stability and support to the variable regions of antibody molecules. It usually consists of a constant region that provides stability and a variable region that is responsible for binding to a specific antigen. Antibody scaffolds can be engineered to improve antibody stability, solubility, and binding affinity for a variety of applications such as diagnostics, therapy, and research.


  1. Deonarain, M.P. et al. Small-Format Drug Conjugates: A Viable Alternative to ADCs for Solid Tumours? Antibodies (Basel). 2018, 7(2): 16.
  2. Xia, X. et al. Self-Assembled Nanomicelles of Affibody-Drug Conjugate with Excellent Therapeutic Property to Cure Ovary and Breast Cancers. Nano-micro letters. 2021, 14(1): 33.
* Only for research. Not suitable for any diagnostic or therapeutic use.
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