Get your TOX off: Piramal looks to next generation of ADCs

Non-cytotoxic payloads, immune-stimulating antibody conjugates, and peptide-delivery mechanisms all form part of the new drug-conjugate landscape, says Piramal Pharma Solutions.

It has been over 20 years since the first antibody-drug conjugate (ADC) hit the market. However, the sector has only taken off over the past three years with six US FDA approvals tallying the total number of marketed ADCs to 11, the latest being ADC Therapeutics’ Zynlonta (loncastuximab tesirine).

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Piramal Pharma Solutions (PPS) is a contract development and manufacturing organization (CDMO) that works in the space. According to chief operating officer John Fowler, recent approvals mean “the future for ADCs is bright,” with a next generation of products beginning to move through the clinic.

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We (metaphorically) sat down with Fowler to find out more.

BPI: Can you give any insights into what is driving growth in the sector?

John Fowler: Speed to the clinical market is being driven by a better understanding of the early generation of ADCs, as well as progress in technologies in areas ranging from molecular design to design and understanding of TOX studies to CDMO experience and know-how. The toolbox is continuously expanding with a wider range of new and novel chemistries, drugs, linkers, as well as antibodies or antibody format.

Why is your company so excited about this target class – what do you foresee?

PPS has always been a leader in working with ADCs, evidenced by our position as the first CDMO to support the development and manufacture of ADCs back in the early 2000s. PPS has incrementally invested in its facilities and technologies to support ADCs and bioconjugates development, characterization, and manufacture, not only in its bioconjugation core unit, but also via integration of a fill-finish operation, plus the internal capability to supply both cytotoxic and non-cytotoxic linker payloads.

Has the success of ADCs triggered R&D into other conjugated therapies?

In the last five years, we have seen an expansion into bioconjugation beyond “pure” ADCs to conjugates with non-cytotoxic payloads for therapeutic applications in both oncology and also to many other new fields. For example, one new exciting area is the development of new immune-stimulating antibody conjugates. A lot of learning from experience with ADCs can easily translate to these new modalities, and from PPS’ perspective the broad knowledge accumulated over more than 15 years of experience in the field of ADCs is of real benefit for de-risking and speeding up the development of non-ADC bioconjugates.

Are oncology targets still dominating or are you seeing any diversification into other therapeutic indications?

Oncology does remain the primary target, but new therapeutic indications are being investigated to bring solutions to existing problems and a few products started to filter through our doors. Potential applications outside oncology include antibacterial or anticoagulant bioconjugates. Other applications outside therapeutic use also exist; for example, bioconjugate products for radio imaging.

Can you comment on the numbers of different types of conjugated therapies being developed?

PPS has taken over 40 distinct bioconjugate molecules through GMP manufacture. In the early days, these were exclusively ADCs. The landscape has now changed. We started working on the first non-ADC approximately five years ago; this was an antibody chelator conjugate for radioimmunotherapy. Since then, the proportion of non-cytotoxic ADCs we have seen has steadily increased, reaching around 30-40% of the projects we are currently working on.

What are the benefits in conjugating non-antibody molecules to payloads?

Targeted therapy is not limited to the antibody; there are many classes of non-antibody molecule carriers of the cytotoxic payloads. Each class of molecule has its own benefits and can become additional weaponry against cancer or other illnesses. There is also a lot of work being done in all areas; for example. from small peptide or various antibody fragments to large liposomes. Some of these technologies at the extreme of size variants do require specific manufacturing and/or analytical skills in addition to those presented by classical antibody conjugates, but the conjugation and development activity principles remain similar.

With approximately 70% of manufacturing outsource, how are CDMOs supporting the drug conjugate space and how does an end-user go about working with the right partner?

You’ll always benefit from an experienced CDMO, which will bring all its technical expertise and systems built across multiple projects, particularly around risk management and speed to manufacture. The PPS bioconjugation team is dedicated to bioconjugation and has faced many common challenges in development and learned the ways to avoid them. The company’s processes are robust, scalable, and designed to de-risk and deliver consistent product quality throughout. The same is true for the company’s well-characterized analytical methods. PPS has also substantial experience with the specifics of process characterization studies needed to bring a product to commercial.

As a CDMO moving towards the manufacturing of more commercial products, the scale of facilities needs to be adjusted to the various products. The variety of indications and targets means that we need to be flexible to be able to accommodate very variable product demand, for example, with regard to equipment size. The one-size fixed equipment facility approach does not work. Typically we can accommodate from tens of grams to multiple kilogram scale.