The setbacks were many over the 40 years of development. OKT3g1(Ala-Ala) was developed in 1986. They came down to three core issues: five different companies with varying degrees of commitment, poor clinical trial design, and lack of a champion in the industry.

The drug started as a collaboration with Ortho Pharmaceutical/J&J, built on the background of OKT3. The work involved two scientists, Bob Zivin and Linda Jolliffe, with humanization by John Adair at Celltech. Unfortunately, Ortho decided to give up monoclonal antibodies as therapeutics. Even after they acquired Centocor, there was no interest in moving forward.

This cost us 10 years, although I was able to get access to the drug and make product for early phase I studies and phase II trials supported by the Immune Tolerance Network, with support from NIAID and JDRF. Kevan Herold was essential, as he conducted the clinical trial.

We then licensed the drug to MacroGenics. They were very engaged and motivated to develop it. In partnership with Lilly, MacroGenics started a phase III trial in stage 3, or recent-onset, type 1 diabetes. At the same time, a second company, Tolerx, was developing a similar Fc receptor non-binding, low-toxicity anti-CD3 monoclonal antibody.

The competition led to a large, complex clinical trial that required 300 sites and 500 patients in multiple arms, including sites and patients in India and Eastern Europe. The trial failed to meet its primary endpoint, and Lilly immediately terminated the partnership. However, further post-hoc analysis suggested that the primary endpoint was met if the analysis was limited to US patients.

At that point, MacroGenics agreed to out-license teplizumab to another company or a new company. But, not being a business development person, I found it very difficult.

By a stroke of luck, I met Leni Ramos, a previous chief medical officer at the Immune Tolerance Network, in New Orleans. She was at a meeting with members of her leadership team from a new company, Provention Bio. I suggested they might be interested in teplizumab. After multiple meetings and a meeting of the minds with the CEO at MacroGenics, teplizumab was licensed to Provention Bio.

In the process of replicating the phase III trial, data became available from a stage 2, "prevention" trial conducted by TrialNet, a consortium supported by NIDDK. The results showed that teplizumab could delay disease onset in high-risk stage 2 patients for two to three years. These data led to the approval of teplizumab in November 2022, some 35 years after development.

More recently, the results of the stage 3 new-onset trial led to a label expansion for this population, making the drug available to more people with early-stage disease or a recent diagnosis.¹

As for the next wave, this was the first disease-modifying immunotherapy for type 1 diabetes. In many ways, it has opened the floodgates. Approaches include novel anti-CD3 monoclonal antibodies, in one case given intranasally; antigen-based peptide therapies; antibodies against novel targets such as CD40L; and potentially tolerogenic cell therapies, including CAR- and TCR-Tregs and CD19 CAR-T cells.

Treg cell therapies are a new field, and there are many areas where these therapies can be improved to provide greater access. This includes the potential for allogeneic therapies, assuming the immunogenicity issue can be resolved; more efficient manufacturing using automation and shorter or more efficient culture conditions; and even the potential for in vivo gene therapy, using novel approaches to ensure that expression of the target receptor, CARs or TCRs, is limited to Tregs.

Vie Ventures is committed to supporting companies in the autoimmune and inflammatory space, including startups and companies with drug candidates that need resources to tackle autoimmunity. One key aspect is that we look for innovative therapies that tackle core pathobiological pathways likely to be shared by multiple autoimmune diseases, not unlike anti-CD3, Tregs and similar approaches. Tolerance remains the Holy Grail for these treatments, but Vie is not restricted to tolerogenic approaches.

Multiple autoimmune diseases are in the mix for early intervention, given recent data identifying patients with disease before major clinical manifestations. These include rheumatoid arthritis, celiac disease, autoimmune Addison's disease, systemic lupus erythematosus, systemic sclerosis and autoimmune thyroid disease.