Galderma

John Armstrong

What’s your sign?

Personalized therapy for cancer is generally based on the identification of a single, molecular biomarker expressed by a patient’s tumor. On the other hand, personalizing therapy for immune-mediated inflammatory disorders (IMIDs) is not so straightforward and requires a complex, translational medicine approach. IMIDs include diseases such as rheumatoid arthritis, psoriasis, Crohn’s Disease, asthma, and others. How these inflammatory diseases are driven (and hence, can be controlled) can differ from patient to patient. While genomics and proteomics play a role, we gain insight into each patient’s inflammatory drivers primarily by looking at patterns of mRNA expression from blood, biopsies, tape strips, and other sampling technologies. In 1970, we were asked “What’s your sign”, and our answers were ‘Aquarius’, ‘Gemini’, ‘Virgo’ and the like. Half a century later, those of us still around but now in translational medicine don’t want your astrological sign but your transcriptional signature. With this information our chances are better that you can be prescribed the most appropriate antibody-based therapy for your IMID, whether that’s a disease of the skin, the joints, the gut, the lungs, or the nervous system.

Why mAbs?

Monoclonal antibodies (mAbs) have become the therapy of choice for severe IMIDs for a number of reasons, not the least of which is their exquisite specificity. Generally speaking, small molecular entity (SME)-based therapies also can be very specific, but for the treatment of an IMID, they aren’t often capable of targeting a single, terminal effector cytokine, such as IL-17 for psoriasis. Instead, they are often used for targetingintracellular, inflammatory pathway intermediates, such as JAK kinases. When administered orally, as one would do for a severe IMID, they can bring unwanted, off-target downstream effects more often than when relying on mAbs.

Antibody Discovery and Engineering

Because mAb technology evolves so rapidly, it can be challenging for any established Biopharma company to have the latest tools at its disposal, and outsourcing is the answer to this challenge. Antibody discovery and engineering (D&E) firms make their living developing and delivering high affinity, extremely specific mAbs – often targeting soluble, effector cytokines as discussed above, but they can also provide mAbs targeting surface receptors on the specific cells driving disease. Antibody D&E firms are not the only source of therapeutic antibodies, though, as biologics partners and platforms relying on engineered mice obviate the need for the affinity maturation services of a D&E firm but can still provide antibodies of the same high quality to biopharma companies, and sometimes they can do so with shorter development timelines.

“As antibodies become applied more commonly in personalized medicine approaches to the treatment of IMIDs, we will see the bars raised in the field of Immunology and Inflammation both in terms of safety and efficacy”

Putting antibodies together with other things in cocktails, bsAbs, immunotoxins, and ADCs

In biopharma we often use antibodies just as they are, but new approaches to biologic therapy for IMIDS sometimes involves combining two antibodies in a cocktail in an effort to increase clearance of an IMID that is driven, for instance, by more than one primary inflammatory driver. Conjugating two or more antibodies of different specificities serves the same purpose but does so in a single biologic entity known as a bispecific antibody (bsAb). Improvements in therapeutic efficacy can also come from conjugating antibodies to other things. Sticking a sidechain of the extremely poisonous Ricin molecule onto a tumor antigen-specific antibody makes an immunotoxin capable of eliminating cancer cells. I used to make these reagents myself in graduate school, and they are not only very effective, but because they are based on antibodies, they are also highly specific. Swapping out that toxin sidechain for a normal chemo drug to form an antibody-drug conjugate (ADC) is another commonly used approach for the same purpose.

Taking antibodies apart

We can also take antibodies apart and use their pieces to improve efficacy even further in novel, highly creative therapeutic approaches. For instance, if we replace a killer T cell’s antigen receptor with an antibody, we get a Chimeric Antigen Receptor-, or CAR-, T cell. With the specificity of an antibody, CAR-T cells can eliminate cancer cells but gain the advantage of being self-replicating, thus providing a onedose regimenthat delivers continuous treatment whenever the body needs it: in essence, a cure. Also, a version of CAR-T cells now has been developed for IMIDs, but this is only possible because the autoantigen that drives the skin disease known as Pemphigus Vulgaris (PV) has been identified. Because of that breakthrough, Chimeric Auto-Antigen Receptor-T (CAAR-T) cells are being used successfully to target autoreactive B cells in PV in the kind of curative approach seen in cancer with CAR-T therapy.

Antibodies as the building blocks of cures

As antibodies become applied more commonly in personalized medicine approaches to the treatment of IMIDs, we will see the bars raised in the field of Immunology and Inflammation both in terms of safety and efficacy, just as we have witnessed in the field of oncology. Antibodies are both diverse and specific, and they likely represent not only the most powerful tool in the armamentarium of Biopharma companies but their most likely chance bringing cure-like effects to complex diseases like IMIDs. Personalized therapy approaches are necessary to achieve these goals, and antibodies can make that happen. What it comes down to is this: If amino acids are the building blocks of proteins, antibodies are the building blocks of cures.