T time …..Another way that influences of T cells inhibit MS?..or is it T blinker time?

T

CD40 is a costimulatory protein (needed for activation of cells in addition to signalling via the antigen receptor) found on antigen-presenting cells including B cells, macrophages and dendritic cells. EBV induces B cell activation as it produces molecules that mimics the activation of B cell receptor (meaning that the B cell doesnt need to see its target for activation) and mimics the activation of CD40.

CD40 is activated by binding of CD154 (CD40L). The CD40 ligand (CD40 binding molecule) is expressed by activated (typically CD4) T celsl so it is a way that T cells can stimulate B cells or macrophages/dendritic cells. So if you block CD40L you can block B cell activation and effects on antigen presenting cells. It also blocks other targets that bind to molecules produced in inflammed blood vessels. So by blocking this you block B cell maturation and germial centre formation, which is the place where antibody producing cells are formed. So a depleting CD40L antibody would kill T cells (T-time), a blocking CD40L would block B cell function (B time). Academia will be depleting T cells, but which way have pharma actually gone?

Safety and Immune Effects of Blocking CD40 Ligand in Multiple Sclerosis.Fadul CE, Mao-Draayer Y, Ryan KA, Noelle RJ, Wishart HA, Channon JY, Kasper IR, Oliver B, Mielcarz DW, Kasper LH.Neurol Neuroimmunol Neuroinflamm. 2021 Oct 15;8(6):e1096. doi: 10.1212/NXI.0000000000001096.

Background and objectives: Costimulation by CD40 and its ligand CD40L (CD154) is important for the functional differentiation of T cells. Preclinical studies have recognized the importance of this costimulatory interaction in the pathogenesis of experimental models of multiple sclerosis (MS). To determine safety, pharmacokinetics, and immune effect of a humanized monoclonal antibody (mAb) against CD40 ligand (toralizumab/IDEC-131) in patients with relapsing-remitting MS (RRMS).

Methods: This single-institution open-label dose-escalation study (phase I) enrolled 12 patients with RRMS to receive 4 doses of 1, 5, 10, or 15 mg/kg of humanized αCD40L (toralizumab) IV infusion every other week. Patients were followed up to 18 weeks, annually, and finally at 5 years. In addition to safety and pharmacokinetics, other secondary and exploratory measurements are immune effects, clinical, MRI, laboratory, and neuropsychological evaluations.

Results: Fifteen adverse events, all of mild to moderate severity, were considered to be of possible or of unknown relationship to treatment. No serious adverse events, including thromboembolic events, occurred during the 18-week defined study period. Annual and long-term follow-up at 5 years revealed no delayed toxicity. Pharmacokinetics were nonlinear between the 5 and 10 mg/kg dose groups. The serum half-life of toralizumab was consistent between the dose groups with a mean of 15.3 days (SD = 1.9). Flow cytometry revealed no depletion of lymphocyte subsets. An increase in the CD25+/CD3+ and CD25+/CD4+ ratio and a shift toward an anti-inflammatory cytokine response were seen after treatment.

Discussion: Our study suggests that blocking CD40L is safe and well tolerated in patients with RRMS while increasing CD25 + T cells and anti-inflammatory cytokine profile. These findings support further studies to assess the efficacy of blocking CD40L as a potential treatment of RRMS.

Therefore the approach is blocking and not depleting, therefore it is clear pharma is putting its money on targeting B cells…..but no……this acts via a T cell effect. That is according to this paper. Why?. Because this study is being done by academics and not pharma

However, before we get too excited, we have to say we have been here before with an antibody called 5c8, which was developed….and dropped because it caused platelet issues, where blood clots were formed. These can block blood vessels. This was due to effects of IgG1 antibody tail and by engineering this, it is possible to make it more blocking and reducing the risks of clotting. However, the big problem, it seems is that even toralizumab been dropped too, as it has been indicated that trials were halted because of the blood clotting problem. This view is supported by comments in the paper

In this current study it was indicated that there was a clinical effect at the higher doses and so this says….you guessed it…yep an important mechanism of anti-CD40L would be via “the induction of an effective T regulatory response in the absence of inducing circulating CD3+/CD4+/CD8+ depletion“.

OK it was suggested that B cells may not present antigen to T cells in the above diagram, but there was no interest in B cells as the authors focused on T cells, T cells, T cells…….Thhis is because in their head T cells are the problem in MS. They don’t do experiments to disprove the idea they do experiments that in their head confirms their views. This cinderella science leads to people pushing and idea into a place where it does not belong, like the ugly sisters trying to get their size 15 feet into Cinderella’s glass slipper.

Now if this paper does show an effect, it argues that EBV that mimics CD40 signalling in B cells is not the problem in MS because if it was then there would be no impact from blocking CD40 as the EBV effect is down stream of this. However in terms of the data presented here that argues for an imporant role for T cells does not exclude that B cells are the important issue.

What happens in the future, we have to wait and see. However, there is another version in development that has had the antibody tail engineered so it will not kill or bind to macrophages or other cells, to block B cells. Is that going to work? We will see.

COI None relevant

General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

About the author

MouseDoctor

Add comment

By MouseDoctor

Translate

Categories

Recent Posts

Recent Comments

Archives