Conjugation Services

We offer personalized design & synthesis solutions for the conjugation of small molecules such as drugs, metabolites, and labelled compounds with synthetic or natural polymers for specific applications. Our conjugation services include:

Many chemotherapeutics are characterized by a limited therapeutic efficacy, often due to severe side effects at higher doses or rapid elimination from the body. Conjugation of small therapeutics to polymers can enhance efficacy by improving pharmacokinetic and pharmacodynamic properties by reducing plasma protein binding, reducing toxicity, or by improving stability.

Drug conjugates are under development for cardiovascular disease, acute invasive fungal infections, immune modulation, etc. Conjugation is also being explored as a means of synergistic drug and gene delivery by conjugating a drug with a cationic polymer such as PEI, which is capable of complexing with negatively charged DNA. The polyplexes thus formed, after internalization into a cell, release the DNA and the drug molecule.

In addition, drug conjugation offers the important commercial advantage of extending the patent life of a drug.

Research is ongoing for the development of new drug delivery systems for targeted drug delivery.  Equipping polymer-drug conjugates with target cell specific ligands like EGF and RGD peptides can provide a solution for selective and targeted chemotherapy.

The largest class of conjugated drug products under development is the antibody-drug conjugate (ADC).  Antibody-drug conjugates combine a drug with a monoclonal antibody which provides selective targeting for tumoral cell masses or lymphomas.  The drug is released by enzymatic cleavage of the linker under physiological conditions.

One such ADC, Mylotarg (gemtuzamab ozogamicin), was approved by the FDA, but later voluntarily withdrawn from the US market.

Another ADC has been submitted for approval and at least 15 antibody conjugates are currently being investigated in clinical trials. The high selectivity greatly reduces the toxic side effects of traditional chemotherapy, and also makes possible the use of newer actives with a high toxicity profile.

TARGETED IMAGING

The conjugation approach is being strategically investigated for targeted imaging to achieve a large contrast enhancement at the diseased site.  Conjugation of a targeting ligand such as RGD or EPR and a radio-ligand chelator such as DOTA with a polymer has added a new dimension to diagnostic imaging (PET, MRI etc.) for targeted tumor mapping.

ANALYTICAL

Dalton has the analytical tools and experience that are critical for this field.  The analytical requirements for supporting the manufacture, testing as well as regulatory safety and efficacy of drug conjugates are technically challenging.  The biological or polymeric carrier can be coupled to the drug through site-specific linking or through random linking (involving multiple sites of similar reactivity).  The stoichiometry (i.e. the mean ratio of the carrier to the drug) may reasonably characterize the conjugate in the case of site-specific linking.  When the linking is random, the product is not homogeneous, and the mean ratio is a reflection of the distribution of conjugate subpopulations. 

The conjugation reaction may produce by-products, or may be incomplete, leaving residues of carrier, drug, and linker.  Sophisticated analytical methods must be used to follow the often difficult purification steps.  Sensitive analytical tools are needed to investigate stability, to characterize the end product, and to ensure batch to batch consistency.

Conjugation leverages Dalton’s extensive experience in both small molecules and large biopolymers.  This includes synthesis, analysis, purification, cGMP manufacturing, and aseptic filling (see next section).

Our wide expertise in synthetic organic chemistry includes complex chemistry, chiral compounds, hydrogenation, natural products chemistry, organometallic chemistry, nucleotide and amino acid production, stable isotope synthesis, fluorescent probes, inert atmosphere chemistry, steroids, opiods, and cannabinoids.

Dalton’s custom small molecules synthesis and fine chemicals department has broad experience in the synthesis of low volume, high value molecules for biotech and pharmaceutical applications.  This includes APIs, pharmaceutical intermediates, drug intermediates, drug metabolites, drug analogs, analytical standards, reference standards, certified reference materials, chemical intermediates, chemical standards, and pharmaceutical impurities.

We are a full service peptide company which manufactures peptides for clients by solid phase synthesis or solution phase chemistry on a custom basis.  Pre or post synthesis operations and the chemistry itself can incorporate natural amino acids, modified amino acids, and unnatural amino acids.  Post synthesis modifications include biotinylation and a wide range of conjugation reactions.

GMP ASEPTIC FILLING

Conjugation products developed at Dalton can be seamlessly prepared for preclinical and early stage clinical trials in our fully integrated GMP Class 100 Aseptic Filling Manufacturing Facility.  Our capability includes sterile filling of liquid-in-vial injectable drugs, aseptic filling and stoppering of liquid prefilled syringes, and aseptic filling and capping of powders.  We provide our clients with full regulatory compliance support.  Dalton has the capabilities to develop, create, and execute validation protocols in accordance with current Guidelines (HPFBI, FDA, EP, ICH, WHO) and acceptable formats (prospective, retrospective, and concurrent).

• Sterile Liquid Injectables: validated for 3, 5, and 20 ml vials up to 20,000 units per run.
• Aseptic Powder Fill: validated for 20 ml vials up to 1800 units per run.
• Aseptic Syringe Fill: capacity 2, 3, 5, 10, and 20 ml; validated for 2 ml syringes up to 20,000/batch

In the typical arrangement, the client identifies the drug and the linkage requirement, and provides the carrier molecule.  In some cases the client will provide a proprietary drug.  Dalton Pharma Services obtains or synthesizes the required link, develops the linkage method, uses appropriate analytical tools to characterize the product, and works with the client to optimize the drug conjugate for the intended clinical use. It is likely that the client will elect to have Dalton manufacture clinical trial material using the company’s aseptic filling capabilities, since it is well known that going to another vendor for manufacturing usually involves significant inefficiencies.