All Antibodies are the same- think again!

New anti-CD20 monoclonal antibodies for the treatment of B-cell lymphoid malignancies.Robak T, Robak E. BioDrugs. 2011;25:13-25.

Over the last few years, new generations of anti-CD20 monoclonal antibodies (mAbs) have been developed for potential benefits over the classical, first-generation mAb rituximab. Compared with rituximab, new mAbs have enhanced antitumor activity resulting from increased complement-dependent cytotoxicity (CDC) and/or antibody-dependent cellular cytotoxicity (ADCC) and increased Fc binding affinity for the low-affinity variants of the FcγRIIIa receptor (CD16) on immune effector cells.

The second-generation mAbs, which include ofatumumab, veltuzumab, and ocrelizumab, are humanized or fully human to reduce immunogenicity, but with an unmodified Fc region.

Ofatumumab is a fully human anti-CD20 IgG1 mAb in clinical development for haematological malignancies and autoimmune diseases.

Ofatumumab specifically recognizes an epitope encompassing both the small and large extracellular loops of CD20 molecule, and is more effective than rituximab at CDC induction and killing target cells.

Veltuzumab (IMMU-106, hA20) is a humanized anti-CD20 mAb with complementarity-determining regions similar to rituximab. This antibody has enhanced binding avidities (strength of binding to the target of individual Fab is the avidity…strength of the binding of the two Fab in the antibody molecule is the affinity) and a stronger effect on CDC compared with rituximab.

Ocrelizumab is a humanized mAb with the potential for enhanced efficacy in lymphoid malignancies compared with rituximab due to increased binding affinity for the low-affinity variants of the FcγRIIIa receptor.

The third-generation mAbs are also humanized mAbs, but in addition they have an engineered Fc to increase their binding affinity for the FcγRIIIa receptor. The third-generation mAbs include AME-133v, PRO131921 and GA-101. AME-133v (LY2469298) is a type I, humanized IgG1 mAb with enhanced affinity for FcγRIIIa receptor and an enhanced ADCC activity compared with rituximab.

PRO131921 is a humanized anti-CD20 mAb engineered to have improved binding to FcγRIIIa and better ADCC compared with rituximab.

GA-101 (RO5072759) is a fully humanized, type II, IgG1 mAb derived from humanization of the parental B-Ly1 mouse antibody and subsequent glycoengineering using GlycoMab® technology. GA-101 was designed for enhanced ADCC and superior direct cell-killing properties, in comparison with currently available type I antibodies.

TRU-015 is a small modular immunopharmaceutical (SMIP) derived from key domains of an anti-CD20 antibody. TRU-015 represents a novel biological compound that retains Fc-mediated effector functions and is smaller than mAbs.

This week we have had a worry about the capacity to work following fingolimod treatment. The inference is that alemtuzumab does not kill white blood cells in the lymph glands because it kills by antibody dependent cellular cytotoxicity (ADCC) requiring phagocytes to bind to the Fc region via Fc receptors and release their products to kill the target. This is compared to complement fixation, which is activation of a cascade of blood/tissue pro-enzymes that are activated to punch holes in the target and to kill them.

The bioengineers can change an antibody to have different properties ,such that it depletes or does not deplete their targets and it can change the way they deplete.

The cells required for ADCC occur at low levels in the lymph glands. so Alemtuzumab does not kill the target cells in the lymph glands compared to killing them in the blood. If you can engineer alemtuzumab to kill in the lymph glands then maybe fingolimod would not stop alemtuzumab working.

There are second generation alemtuzumab antibodies being developed but those relating to anti-CD20 B cell depleting agents are more developed.

You may have heard of rituximab which is part human and part (the Fab regions) mouse. Oreclizumab is largely human except for the target binding region called the complementarity determining region. Ofatumumab is totally human. This means the human immune system is less likely to reject the antibody as it can recognise the mouse bits as being foreign to the body.

Theorectically ocrelizumab could have the same issues as alemtuzumab treatment after fingolimod because it depletes or perhaps doesn’t deplete in the same way as alemtuzumab (However I would like to see the data on the use of ocrelizumab in human CD20 transgenic mouse to see how it depletes in lymph glands and bone marrow…prod, prod).

But you can see you can betterer and betterer depleting antibodies than rituximab or ocrelizumab. expect to see some of them appear once ocrelizumab gets licenced.

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  • I do not think of rituximab as depleting the lymphocytes in the same way alemtuzumab does – at least not in the doses used for RA treatment( which presumably are the doses used in MS). Lymphopenia is not very high on the list, but the ratios of lymphocyte subpopulations change.

  • don't be coy: name a few – "but you can see you can betterer and betterer depleting antibodies than rituximab or ocrelizumab. expect to see some of them appear once ocrelizumab gets licenced."

  • So can there be production of NABs in Ocrelizumab and Rituximab as well?
    Then Ofatumumab would not offer this risk of rejection?
    And is there any given Alemtuzumab post Natalizumab in the SPMS?

    • NABS after ocrelizumab is about 0.5-1% pwMS, rituximab is 5-15%. I dont know about ofatumumab but as they are planning on injecting it subcutaneously which to my mind is a sensitizing route, I predict we will see them, possibly more than the infusions.

      As for Nabs with Natalizumab there are about 6-9% and for alemtuzumab there is a whopping 80-90% who get neutralizing antibodies…IS this news to you?…Not surprsing that they forgot to mention it in the pivotal clinical trials and although Cambridge published on binding antibodiesm and how to reduce their occurance, they have largely kept their mouths shut about the neutralizing antibodies or been told to keep them shut.
      There was a throw-away sentence by ProfC saying that they can be a problem in some people.

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