Challenges in bioconjugate drug development

Bioconjugate therapeutics have undergone significant changes and advancements over time. They have evolved from simple protein-polymers to complex, multifunctional molecules that can be tailored for a variety of applications, including drug delivery, imaging, and diagnostics. In recent years, we have seen novel bioconjugates emerge that consist of alternative protein modalities and non-traditional payloads, such as nucleic acids, peptides, and imaging agents. On top of that, novel conjugation chemistries now enable more controlled and site-specific linkages, driving the development of new and improved bioconjugate drugs.


Despite bringing new promising approaches, this diversification can also lead to considerable challenges in development, given that the success of these complex therapeutics is often not readily predictable and depends on the delicate interplay between the protein, the payload and the linker.

Complex Manufacturing processes

The complexity of the manufacturing process can also prove challenging. Bioconjugate manufacturing requires robust technologies, specialized equipment and varied expertise. Regulatory agencies also have more specific requirements for the safety and efficacy of bioconjugates therapeutics in response to innovating new technologies in a regulatory framework constantly evolving and developing. Thus, it’s better to take them into consideration as early as possible in the development process.

Overcoming these Challenges

Our early development team's goal is to help you navigate this evolving technology landscape and find a uniquely tailored solution that best fits your requirements. There is no one-fits-all solution for the different modalities of each protein and payload, so that’s why we help you identify the right combinations that match your goals. We will also accompany you right from the beginning straight through to clinical and commercial manufacturing.

The Lonza Bioconjugation Toolbox

The Lonza Bioconjugation Toolbox is a uniquely developed concept that offers a variety of conjugation technologies, linkers, and payloads. To complement Lonza’s own intellectual property on site-specific conjugation, we decided to partner up with leading bioconjugation technology providers to offer state-of-the-art solutions. Importantly, we always put each of our toolbox technologies to the test in our development labs to ensure their robustness, scalability, and ease of transfer into GMP. Based on scientific rationale and our experience, we choose the technology which fits best your drug concept and product requirements. By building on scalable and proven solutions, we can de-risk the development of your drug from the very beginning by preventing pitfalls and deadends in later development stages.

State-of-the-art bioconjugate technologies

Our innovation partners have developed state-of-the art conjugation technologies that overcome key challenges in the field. They provide solutions for attaching a payload to a specific site on the protein, generating more homogeneous and more stable conjugates than could be achieved with conventional approaches. We now offer solutions for conjugation to native, off-the-shelf antibodies, as well as other protein modalities, such as antibody fragments, nanobodies and cytokines, which are becoming increasingly important in the biologics pipeline.

Besides conjugation methodologies, the area of payloads and linkers is also experiencing an innovation boom. As such, we are always on the lookout for collaborations with tech companies that are developing novel mode-of-action payloads for cytotoxic bioconjugates, immunostimulants, chelators, and linkers with improved hydrophilic properties or highly specific release mechanisms.

With the support of our technology partners, we are empowered to tackle the challenges associated with bioconjugate drug development, and are ready to provide you with your own tailored solution. Bioconjugation is in a constant state of innovation, so we continuously re-assess the need for novel technologies and expand our capabilities to stay ahead of the game.

Overview of our toolbox technologies and their key features

Lonza-owned technology:

Synaffix (a Lonza Company)
Site-specific glycan remodeling with Synaffix` GlycoConnect™
Synaffix developed with GlycoConnect™ a technology platform which uses glycan remodelling followed by a metal free click reaction to yield in stable and homogeneous antibody-conjugates. Highlights of the technology are:
  • Native antibody can be used
  • Stable bond formed between protein and payload
  • Site-specific conjugation with access to highly homogeneous DAR 1, 2 & 4 products
  • Retention of antibody functionality: using the glycan pocket as conjugation side does not interfere with its binding or specificity.
  • Improved therapeutic index compared to earlier generation ADCs

Our partners' technologies:

Below, we delve into more detail on our current technology partners, giving a brief description of their technology as well as highlighting some key features.


Site-specific conjugation with Singzyme's ligases

Singzyme developed a proprietary set of peptide ligases for the site-specific conjugation of different payloads to give stable and homogeneous bioconjugates. Their technology comes with a few key advantages, such as:

  • One-step conjugation
  • Site-specific, homogeneous bioconjugate products obtained
  • Control of DAR by conjugation to N- or C-termini (or both)
  • Highly efficient, stable bond formed between protein and payload (amide bond)
  • Fast conjugation (20'000x faster than Sortase A), high yield up to 95%
  • Minimal footprint on final product due to short three-amino acid recognition sequence
  • Broad applicability (antibodies, fragments, protein-RNA/DNA conjugates, protein-protein conjugates)
  • Capable of conjugating two different payloads on the same antibody scaffold


Cysteine rebridging technology with McSAF InsideTM platforms

McSAF developed cysteines rebridging technology platforms conjugating the payload to the target protein at the native interchain disulfides. Highlights of the technology include:

  • Native antibodies can be used without the need for engineering
  • Site-specific bioconjugation
  • 100% chemical process
  • Stable bond formed between protein and linker
  • ADC obtained with access to defined DAR conjugates
  • Synthesis of drug-linker straightforward
  • Applicable to different IgG subtypes, mAb fragments, proteins & peptides, linkers and payloads


Affinity-based, site-selective conjugation with AbTis' AblickTM platform

The AbClickTM utilizes a cyclic peptide that binds to a specific site of the mAb leading to a traceless proximity driven reaction of the linker to the mAb. Key highlights of the technology include:

  • Site-selective ADC obtained with controllable DAR and improved homogeneity
  • Native antibody can be used without need for engineering
  • Stable isopeptide bond formed between protein and linker
  • Simple process 2-step process with high yield
  • Applicable to different IgG subtypes

Cristal Therapeutics

Metal-free click technology with Cristal Therapeutics CliCrTM reagent

Cristal Therapeutics offers with CliCrTM a powerful metal-free click chemistry reagent. The key advantages of the technology are:

  • Shorter reaction times than all other marketed copper-free click reagents, hence attractive cost of goods (CoG)
  • More hydrophilic than other strained alkynes
  • Highly selective, site-specific conjugation
  • High stability in a broad range of reaction conditions; with tunable release of payload if preferred
  • High variability of linkers and payloads can easily be attached to the reagent


ADC Payloads from Cyanobacteria

Simris produces highly potent and safe cyanobacterial toxins which can be functionalized for easy conjugation and tailored structurally towards improved hydrophobicity, potency, selectivity/safety and labelling. Available from Simris are known and novel nonribosomal peptide toxins from cyanobacteria, including microcystins, dolastatins (auristatins), cryptohycins, and many more. Through structural optimization, Simris makes these toxins available as promising ADC payloads. Simris’ microcystin platform, for example, offers a pool of analogues that exhibit a novel multimodal mode of action of high potentcy combined with an excellent safety profile:

  • Cyclic heptapeptides, produced by different genera with huge structural diversity (> 300 natural structural analogs) and easy to modify for conjugation, lead optimization and labeling
  • Comprehensive in-vitro and in-vivo data are available, incl. mode of action (MoA), structure-activity-relationships (SAR), hepatic uptake and hepatotoxicity
  • Potent inhibition of two protein phosphatases supported by reactive oxygen species (ROS) mediated apoptosis
  • Only expresses toxicity after active cell uptake: non-toxic for healthy tissues mediating an excellent safety profile for ADCs
  • In-vitro/in-vivo proof-of-concept for diverse microcystin-ADCs revealing high efficacy and tolerability (MTD)


We follow an ‘Innovation through collaboration’ approach and aim to facilitate access to next-generation conjugation technologies, with the greater vision of supporting and accelerating the development of superior biotherapeutics for much-needed treatments.

As our customer, you will benefit from access to a repertoire of scalable and robust technologies that are well established in our conjugation facilities. It is crucial to keep a keen eye on manufacturability and facility fit during the process design of a bioconjugate early on; doing so will ensure as smooth a journey as possible when moving through the development stages towards your First-in-human (FIH) trials.

Ready to solve your bioconjugate challenges?

Find out more about our Early Development Bioconjugate Services and get solutions that are specifically tailored to your therapeutic needs. Alternatively, speak to our friendly experts here to help streamline your process development and manufacturing.

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