The contract manufacturing market for antibody-drug conjugates has huge potential, but an extraordinary range of capabilities is essential to be in the game. We spoke to some of the players to find out all about ADCs.

Today there are four commercial ADCs (Adcetris®, Kadcyla®, Besponsa® and Mylotarg®) on the market1 — though there is enormous potential up the pipeline. At the end of 2016, some 60 ADCs were in early-stage trials, with one undergoing regulatory review and two more in phase III trials.2 Despite many originators investing in manufacturing, contract development and manufacturing organizations (CDMOs) play a huge role in this industry. Some 40 CDMOs currently provide ADC-specific services, about 20 make cytotoxics and offer conjugation and 15 have relevant fill-finish capabilities, though few offer a true integrated capability.2 Research & Markets and Roots Analysis, who both published global market reports on ADCs in 2015, estimate that over 70% of ADC manufacturing is outsourced. The former projects the global market for contract manufacturing of ADCs at $1 billion by 2018, which is 36% of the forecast total market value of $2.8 billion.2 

In a high-potency compound, you are protecting the worker from the product; in a conjugation suite, you are working aseptically in aqueous systems and protecting the product from the worker, thoughalso vice versa in the case of a toxin. – Scott Miller, Ph.D., Carbogen Amcis

CDMOs Investing

CDMOs have also been investing in recent years to expand their facilities, buying companies with related expertise. Many of these originally expanded into ADCs from a core expertise in cytotoxics or HPAPIs in general; others come from the biologics or fill-finish sides of the business.

Lonza is a pioneer in ADCs, supplying the conjugates for both Adcetris and Kadcyla. Conjugation and related activities are based at Visp, Switzerland, where the company carries out both small molecule process development and scale-up and mammalian cell biomanufacturing for multiple highly potent biopharmaceuticals. Lonza now offers an ‘Easy Access ADC Program,’ including preparation of sample panels using linker, drug and mAb combinations. Later-stage capabilities are built on multipurpose cGMP plants dedicated to ADC drug substance at scales from 10 to 600 liters.

“ADCs are very complicated from the standpoint of the intermediates required to manufacture them,” says Tom Rohrer, Associate Director of Bioconjugate Commercial Development. Lonza, he adds, can make the antibody, the linker and the cytotoxin, both semi-synthetic or fully synthetic cytotoxins and can work with pretty much any linker. There is also investment in recruiting talent with experience in drug product development and manufacture, including bioconjugates. Because ADCs require a smaller amount of antibody due to their higher potency, Lonza has also expanded capacity at its Slough, UK site to make small batches. “This helps us tremendously because many companies coming to us may not have access to sufficient quantities of antibodies to execute their programs,” Rohrer says.

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Now part of Piramal Healthcare, the site at Grangemouth, UK has been active in ADCs since 2004. Piramal states that it has manufactured over 600 batches of ADCs, more than half to GMP and over 100 of them commercial. This work covers over 460 batches made of phase III/commercial ADCs.3 In September 2015, Piramal set a target of becoming the world leader in ADC contract manufacture by 2021. Earlier that year, it acquired Coldstream Laboratories, a specialized ADC fill-finish site in Lexington, Kentucky, which it described as “the final piece in the jigsaw puzzle.” It simultaneously launched a new ‘Proof of Concept’ service designed to speed the development of the most promising targets.4

Since then, says Mark Wright, Site Lead at Grangemouth, “Piramal has acquired Ash Stevens, a specialist in HPAPIs, has expanded the fill-finish capabilities at the Riverview, Michigan site and is now looking at upgrading the high-containment capabilities for ADC payload production. A plan should be presented to the board within months for an additional conjugation suite at Grangemouth to add larger-scale batch capacity.”

ADCs occupy a lot of personnel time, they are very complicated from an analytic standpoint and tend to tie up more personnel than a typical biologicor small molecule. – Thomas Rohrer, Lonza

Flexible Production

Novasep has been a contract service provider in the ADC arena for more than ten years. The company announced in June 2015 that it would build a fully integrated conjugation facility at its Le Mans site, with flexible GMP production suites equipped with 10 to 400-liter vessels, supported by process R&D, QC and production scale-up labs. Jean Bléhaut, President of the Novasep Synthesis business unit, has confirmed that this 2,000 m2, €11 million purpose-built facility is now operational. The investment complements existing capabilities in commercial-scale payloads, linkers, and antibodies. A €4 million plant extension for payload manufacturing was commissioned in 2014. “We are now ready to offer a full service for ADCs, but we are always looking to extend our scope of services either internally or through appropriate partnerships,” Bléhaut says.

In 2013, Carbogen Amcis announced two key investments: the $4 million, 100 m2 cleanroom clinical supply facility dedicated to drug conjugates at the main Bubendorf site, and a $950,000 upgrade of the sterile manufacturing area at its fill-finish site in Riom, France. The firm moved into conjugation from high potency, explains Dr. Scott Miller, Senior Scientific Adviser. “Because we made linkers and toxins, customers asked if we could also do conjugation and that led to expanding in this area.”

Key features at Bubendorf include aseptic and safe handling of highly potent material at occupational exposure limits (OELs) of <1 µg/m3 over an eight-hour time-weighted average (8h-TWA). There are separate areas for reagent and buffer preparation, equipment sterilization, and for cGMP conjugation, purification and packaging, separated by a system of pressure cascades and air locks for material and personnel. At Riom, Carbogen Amcis installed a vaporized hydrogen peroxide disinfection system and two aseptic filling isolators operating under nitrogen atmosphere and at a regulated temperature, expanding the Grade A manufacturing capability at OELs of <1 µg/m3 8h-TWA and allowing a maximum batch size of up to 5,000 units in 2 mL vials.

“Having Riom means we can do the linker and the chemistry, take the antibody, do the conjugation and also do the fill for clinical trials,” Miller says. “Traditionally, you did the chemistry and the conjugation, then threw it over the wall to a formulator. We can integrate a lot of that internally and it should shorten the pathways, which is critical when supplying clinical trials.”

“Carbogen Amcis can carry out most ADC-related services in-house, barring some parts of the analytical side, such as mass spectrometry (MS) for the whole conjugate,” adds Miller. “One of the things unique to our service, perhaps, is having knowledge from the Design of Experiments (DoE) approach of how to bring a product from bench top to commercial,” he says.

Cerbios-Pharma, similarly, expanded into ADCs based on over 20 years’ expertise in handling HPAPIs to SafeBridge Category 4 at the Lugano, Switzerland site, which has now expanded from cytotoxics into linkers and conjugation. “Toxin production and conjugation both need the highest containment level,” says CEO Gabriel Haering. “The two cGMP production lines we have are perfect for manufacturing since we can cover batches from a few grams up to 2 kg.”

Cerbios has invested at the R&D level with additional HPAPI laboratories. “For ADCs, only investments in analytical equipment were required to complete the biological QC lab; toxin, linker and toxicology and clinical batch capacities are already adequate,” Haering says. An additional suite has been designed and will be ready for commercial production in the next year. 

Some of the payloads do not crystallize and remain as oils or foams. The only way to purify them is by chromatography and it is cGMP for the supply of clinical and commercial material. This is a unique capability we have. – Gabriel Haering, Ph.D., Cerbios-Pharma 

Alliances Formed

There have also been collaborations in the field by CDMOs seeking to offer a complete package. Even before being acquired by Piramal, Coldstream was working with Goodwin Biotechnology. Piramal also has a long-standing partnership with Fujifilm Diosynth Biotechnologies to supply mAbs.

“This is more than just an alliance — our scientists and Fujifilm’s collaborate closely, leading to both time and efficiency savings for clients,” says Wright. Moreover, where before clients were more likely to take an existing mAb and then evaluate it for conjugation, now they are increasingly making the mAb with the specific intention of conjugating it.

As of March 2016, Novasep formed a partnership with its French compatriot GTP Technology for preclinical and early clinical mAb production. “We can also leverage a couple of other partners to develop a cell line and are now in several projects where we develop mAbs for customers from scratch, GTP can take us to the non-GMP stage and we take over again with GMP manufacturing,” says Bléhaut.

PAQ417_VP_icon1.svgDrivers to Outsource

ADC developers outsource for various reasons. Some seek flexibility or to avoid capital investment in highly specialized facilities that risk low utilization, while others are put off by the complex operations required. Whether customers, in general, prefer the proverbial one-stop shop that can offer all or nearly all operations under a single roof is an open question.

“Biotechs like it that we have everything in-house and to have somebody who can do it all,” says Miller. “We can manage the whole process and they don’t need to worry about getting different materials moved between different vendors, and it’s all managed by one person. Big Pharma firms know the game already and are more willing to outsource multiple steps to different partners.”

Haering agrees, noting that small biotech companies and start-ups “are definitely outsourcing 100% of their GMP production. Large biotechs, on the other hand, have certain competencies in-house and outsource only one or two elements of the ADC manufacturing,” he says.

All concur that the 70% figure for total outsourcing in the ADC market sounds reasonable in terms of total volume — and this will probably increase. “ADCs occupy a lot of personnel time, they are very complicated from an analytic standpoint and tend to tie up more personnel than a typical biologic or small molecule. So if companies are launching multiple programs, I would anticipate that, due to internal analytical needs, they will tend to put a lot of the programs out into the CMO network,” Rohrer says.

Wright notes that some drug companies have preclinical and/or phase I GMP capacity in-house, but relatively few have the capacity for phase II onwards. “There has been an increase in the number of ADCs but also in the number of CMOs trying to get involved. There is no bandwidth problem in terms of conjugation, but there might be a shortage of companies with real experience in it,” he explains.

The ADC supply chain is very complex, involving the antibody, linker and payload, related conjugation activities, testing and characterization, formulation and finishing, stability studies and the required regulatory package. This must all be brought together at the right time. Moreover, every ADC product is different and must be managed accordingly.5 For Haering, managing the supply chain is “definitely the key issue of ADC manufacturing,” he comments. “Customers using two or more PROVEO alliance partners
will benefit from the site-to-site shipment procedures already in place and from an integrated project management system headed by a ‘super coordinator,’” he adds.

Piramal has acquired AshStevens, a specialist in HPAPIs, has expanded the fill-finish capabilities at the Riverview, Michigan site and is now looking at upgrading the high-containment capabilities for ADC payload production. – Mark Wright, Ph.D., Piramal Healthcare

Complex Needs

Conjugation work on ADCs or any other conjugate is different from a CDMO viewpoint, Miller says. “In a high-potency compound, you are protecting the worker from the product; in a conjugation suite, you are working aseptically in aqueous systems and protecting the product from the worker, though also vice versa in the case of a toxin.”

Rohrer adds that special attention must be paid to personnel flows and ensuring the facility can be properly decontaminated. Seal design for the tanks and the rate of air changeover are key. “An ADC suite has to operate as an aseptic environment, which is one of the typical differences from a small molecule suite that isolates personnel from the product being manufactured.”

ADCs also call on complicated, sometimes unconventional, analytics at all stages of the process. CDMOs have invested accordingly. Lonza, for instance, has formed a dedicated ADC QC analytics team and has pulled personnel from traditional biologics and small molecule QC to support it. “You need much more equipment, technology and people for the analysis of ADCs than you would for classical chemistry,” Bléhaut says. “The analytics represent a significant part of our investment because you also need to have the right tools for the development phases and for routine cGMP commercial production, so we have invested in, for example, high-resolution MS.”

Cerbios, Haering says, draws on over ten years of experience in the analytical methods used in characterizing therapeutic proteins, applying them also to ADCs. “Moreover, the use of potent methodologies such as MS in our R&D allows a straightforward transfer to QC for method validation of ADC-related methods like drug-antibody ratio (DAR).”

“Purification of the payload with high-pressure chromatography is definitely important and essential,” Haering adds. “Some of the payloads do not crystallize and remain as oils or foams. The only way to purify them is by chromatography and it is cGMP for the supply of clinical and commercial material. This is a unique capability we have.” Like many others active in HPAPIs, Carbogen Amcis already had a very high analytical capability, so the level of support needed for ADCs was already in place. “Most methods we use are HPLC-based and it all fits in well with existing quality systems,” Miller says.

We are now ready to offer a full service for ADCs, but we are always looking to extend our scope of services either internally or through appropriate partnerships. – Jean Bléhaut, Novasep

Like many others active in HPAPIs, Carbogen Amcis already had a very high analytical capability, so the level of support needed for ADCs was already in place. “Most methods we use are HPLC-based and it all fits in well with existing quality systems,” Miller says. 

Oncology — and More?

ADCs are commonly oncology therapies. The panel agrees that this indication will remain a key driver but has heard of others on the horizon, notably in hematology and antivirals, though these mostly relate to biomolecules conjugated with small molecules.

Novasep, according to Bléhaut, has more in mind. “We think in terms of immunoconjugates, and even more generally conjugates, because we can couple a highly potent payload onto a polymer or a peptide as well. We definitely aim at covering these various possibilities, which offer applications that go beyond oncology,” he says.

Wright says that he has seen an increase in interest in anti-infectives using conjugation technology. “There could be potential for antimicrobial-resistant antibiotics and antivirals, whose development was hindered by toxicity issues, if they are made more targeted, possibly with the addition of selective turning-off of parts of the immune system.”

Miller adds: “I see some literature about other areas of research, but by the time anything gets to us it is in the clinical and early-phase area. For us, it has all been oncology and it will stay that way in the near term. I suspect the payback is faster and the clinical trials easier to set up in oncology.”

Rohrer adds that the application of targeted therapy will continue to broaden and is already being seen in combination vaccines and in antibiotics. Targeted antibodies and nanoparticles are also moving forward. “All of these require conjugation of a biological or targeting molecule with a small molecule or nanoparticle, so the market will broaden, there’s no question about that. Conjugation chemistry is the key, and the biology is tremendously complex. I think that conjugation technology will be deployed to slow the rate of clearance of small molecules,” he notes.

PAQ417_VP_icon2.svgNew Generation

Of course, like with all new drug development, there are challenges. “We all probably underestimated the biology involved in ADCs. We looked at it too simplistically and assumed that you can attach just about any small molecule cytotoxin as long as the linker is stable and expect a biological effect,” says Rohrer. “That doesn’t work,” he adds.

For Bléhaut, development is now focused on a new generation of ADCs, where the objectives are to control DAR and stability. “This is why we see a lot of new technologies arising, and also may be why a little more time is needed for ADCs to come onto the market,” he suggests.

Wright observes that many of the first generation of ADCs did not fare so well in later phases. Quite often, this was because although their standard toxicity profiles were reasonably good, specific issues related to the payloads were discovered only once they were exposed to a larger number of patients.

“The other driver is diagnostics and selection of patients,” Miller adds. “The ability to find the subset and genomic profile of the people who take it is crucial — different profiles exist for different nationalities and regions. Customization of the treatment is going to be critical going forward.”

All agree that success for future compounds will depend more on technologies than their intrinsic properties. Although cysteines and lysines still account for about 75% of the linkers used, the locations of these residues on the antibody vary, leading to heterogeneous conjugation. Technologies that offer more homogeneous conjugation can improve the therapeutic properties of the ADCs. Some coming forward are selective N-terminal conjugation and site-specific functionalization of glutamines and protein engineering, facilitating new conjugation chemistries like enzymatic ligation and click reactions.6

A number of platforms are developing in that area and it is hard to say which will become successful, but the nice thing is that there is a wide array of technologies for site-specific conjugation,” says Novasep’s Bléhaut. “We are currently doing some internal R&D work in this field, looking at process robustness studies.”

Rohrer confirms that Lonza is looking at various linker technologies. Site-specific conjugation, he adds, may have actually held back some development programs on second-generation candidates, because some companies watched to see technologies develop before committing themselves. “We have seen a lot of site-directed conjugation technology coming through, with stable coupling between the targeting agent and the small molecule,” he says. “This will be what pushes ADCs back into the limelight, and now we are seeing a lot of activity.”

Miller agrees that both technology and regulation are driving the market in this direction. “I am optimistic for conjugates in general, and there may be a breakthrough with a less expensive scaffold — a polymer, a monomer, a protein, a peptide or an antibody fragment,” he says.

References

  1. Dan Stanton. “New dosing regimen brings Mylotarg reapproval for Pfizer.” 5 Sept. 2017. Web
  2. ADC Contract Manufacturing Market (3rd edition), 2015-2025. Rep. Roots Analysis. 10 Dec. 2015. Web.
  3. “Global Network.” Piramal Pharma Solutions. Piramal Enterprises Ltd. Web.
  4. “Piramal Targets Becoming the Global Market Leader In Development & Manufacturing of Antibody Drug Conjugates (ADCs).” Outsourced Pharma. Piramal Enterprises Ltd. 29 Sept. 2015. Web.
  5. Cynthia Wooge. “Using a CMO for your ADC: Access Analytical and Manufacturing Platforms, Specialized Facilities, and Expertise.” Bioprocess International. 15 Oct. 2014. Web.
  6. Cynthia A. Challener. “Conjugation Chemistry with Highly Potent Compounds.” Pharmaceutical Technology. 2 Apr. 2012. Web.