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Boosting TRegs to target autoimmune disease

    Abbott Laboratories and Biotest Pharmaceuticals have entered into an agreement to co-develop BT-061, a humanized CD4-specific monoclonal antibody that is currently in Phase II trials for psoriasis and rheumatoid arthritis (RA). Under the agreement, Biotest will receive an upfront fee of US$85 million, with additional milestone payments potentially adding up to a total of $395 million, plus royalties on the sales of BT-061, if the drug is approved. The two companies will co-promote BT-061 in the five major European markets (Germany, France, the United Kingdom, Italy and Spain), and Abbott will have exclusive global rights to commercialize BT-061 outside these countries.

    The target, CD4, is a surface glycoprotein that functions as a co-receptor for the T cell receptor (TCR) on CD4+ T helper cells and regulatory T (TReg) cells. Several different CD4-specific antibodies have entered clinical trials for autoimmune diseases so far, and fall into two main categories: depleting and non-depleting. Depleting CD4-specific antibodies function by targeting autoreactive CD4+ effector T cells, but can suppress general immunity. By contrast, non-depleting antibodies such as BT-061 are thought to act by activating TReg cells, which have been found to malfunction in autoimmune diseases such as psoriasis and RA. As only natural regulatory mechanisms are activated in this process, BT-061 is thought to be particularly safe, as the immune system as a whole remains functional to fight infection.

    Michael Ehrenstein, Professor of Rheumatology at University College London, UK, expresses his excitement about the fact that a non-depleting CD4-specific approach has shown promising results in RA and psoriasis. “Inducing tolerance in autoimmune diseases is an attractive proposition, as it raises the possibility of administering the therapy for only a short period of time, until balance is restored. This contrasts with currently available conventional or biological therapies, which need to be administered continuously for conditions like RA.”

    How BT-061 works, and why it appears to affect TReg cells differently to other CD4+ T cell subsets, is not yet entirely clear. Ehrenstein points out that: “In an inflammatory milieu, TCR signalling is likely to be intense. Targeting CD4 would dampen TCR signalling and it is possible that in this context, TRegs are less sensitive than effector T cells to this inhibitory effect.” Alexander Rudensky, Professor at Memorial Sloan Kettering Cancer Center, New York, USA, explains that we now also know that a particular 'suboptimal' mode of T cell activation results in the generation of TReg cells. “In this regard, it is possible that during the ongoing recruitment of naive T cells into the chronic inflammatory response, BT-061 might facilitate the differentiation of new auto-antigen-specific TReg cells.” A further hypothesis is that the antibody selectively stimulates preformed TReg cells, at the expense of pathogenic effector T cells, but the mechanistic underpinnings of such a mechanism are not clear.

    The selective expansion or activation of TReg cells is a promising strategy in a range of autoimmune settings, and preclinical studies with BT-061 are underway to study its potential in immune-related disorders other than RA and psoriasis.

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    Boosting TRegs to target autoimmune disease. Nat Rev Drug Discov 10, 566 (2011).

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