Functional antibodies: B-cell depleting antibodies

Lymphocytes are a type of white blood cell that perform major immune functions in the defense of the body against aggression by external agents. They are produced in the bone marrow and circulate in the blood and lymphatic vessels. There are several types of lymphocytes, of which two are the main ones, the B and the T categories.

What are B cells?

 

B cells, are responsible for the humoral specific immune response thanks to different molecules in their membrane, among which is surface immunoglobulin (sIg).

 

The "B" lymphocytes - so called for the "Bursa of Fabricius", organ in which they evolve in birds - mature in the bone marrow in humans. Their maturation involves the unique process of somatic V(D)J genes recombination, facilitating the specific recognition of an almost infinite number of antigens (1).

 

Once matured, B cells migrate to secondary lymphoid organs (bone marrow, lymph nodes and spleen) to meet with antigens for which they are specific. B cell receptor (BCR) binding, to either soluble or membrane bound antigen, triggers the simulation of B cells. When B cells are activated, some divide and differentiate into memory B cells and others into plasma cells, secreting immunoglobulins.

 

The interaction with helper T cells in germinal centres in the secondary lymphoid organs permit :

  • the increased affinity of the antibody for its target thanks to somatic hypermutation in the hypervariable regions, through the activity of cytidine deaminase,
  • the process of class-switch recombination (CSR) to other isotypes, so keeping the antigen specificity intact while modifying the heavy chain.

While plasma cells secrete antibodies to defend the body, memory B cells memorize the markers of the antigen in order to create a faster, more intense and more specific immune response if a second infection with the same antigen occurs. Because of their much longer life span than plasma cells, memory B cells can defend the body even years after a first infection or vaccination.

Monoclonal antibody depletion therapies (BCDTs)

B cell depletion therapies for cancer

 

As a potential consequence to proliferation and mutagenesis mechanisms, some B cells may develop into uncontrollable cancer cells. The idea then emerged to be able to neutralize these unwanted cells thanks to B cells removing treatment or B cell depletion therapies (BCDTs). The monoclonal antibody IDEC-C2B8 has been developed to specifically target CD20, a transmembrane glycoprotein molecule with four predicted hydrophobic motifs that cross the membrane and two extracellular loops (2), and rapidly became a blockbuster under the name Rituximab (MabThera).

 

B cell depletion therapies for autoimmune disorders

 

Regarding auto-immune diseases, B cells can cause unnecessary inflammations due to auto-antibodies targeting self antigens :

  • In systemic lupus erythematosus (SLE), nuclear antigens
  • In rheumatoid arthritis (RA), rheumatoid factor and citrullinated proteins
  • In myasthenia gravis, muscle-specific tyrosine kinase, and nicotinic acetylcholine receptor.

Consequently, the same approach as cancer treatment can be applied, and different monoclonal depleting treatments have been developed like anti-CD19, anti-BAFF (B lymphocyte stimulator, BlyS) or anti-BCMA.

 

B cell depletion therapies for transplantation

 

Finally, B cell depletion strategy can be applied to transplantation.

 

Graft-versus-host disease (GVHD) is the major complication of allogeneic stem cell transplantation and shares similarities with auto-immune diseases regarding autoantibodies generation. In this context, depleting antibodies may be used.

 

To address all B cell depletion needs, SYnAbs has developed monoclonal antibody references, which exhibit the ability to deplete murine or rat B cells in vivo, providing a valuable research tool for its biotech and pharma partners.

 

In fact, Chentoufi et al demonstrated that in adult mice sequential treatment with SYnAbs LO-MD anti-δ and then SYnAbs LO-MM anti-μ induces a complete depletion of B cells and xenoreactive natural antibodies (XNA) and represents a potential approach to induce xenograft tolerance (3).

 

In parallel, Bazin et al showed that anti-µ suppression was demonstrated to be effective on rat IgM, IgA, and IgG classes but also on IgD and IgE classes and on the four subclasses of IgG via the injection of SYnAbs MARM anti-μ and SYnAbs MARD anti-δ antibodies (4).

 

Finally, Soares et al concluded that the obtained data suggested that SYnAbs MARM anti-mu administration in adult rats results in the early arrest of B cell differentiation in the bone marrow, which causes the down-regulation of IgM production. Furthermore, anti-mu mAb administration directly or indirectly activates a particular subset of mature B cells, which differentiates into IgG2c-secreting cells (5).

 


(1)  Susumu Tonegawa – Biographical. NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1987/tonegawa/biographical/

(2)  D.G. Maloney, T.M. Liles, D.K. Czerwinski, C. Waldichuk, J. Rosenberg, A. Grillo-Lopez, R. Levy. Phase I Clinical Trial Using Escalating Single-Dose Infusion of Chimeric Anti-CD20 Monoclonal Antibody (IDEC-C2B8) in Patients With Recurrent B-Cell Lymphoma, Blood, Volume 84, Issue 8, 1994, Pages 2457-2466, ISSN 0006-4971, https://doi.org/10.1182/blood.V84.8.2457.2457.

(3)  Chentoufi, Aziz Alami; Nizet, Yannick; Havaux, Xavier; De La Parra, Bernardo; Cormont, Françoise; Hermans, Dominique; Bazin, Hervé; Latinne, Dominique DIFFERENTIAL EFFECTS OF INJECTIONS OF ANTI-μ AND ANTI-δ MONOCLONAL ANTIBODIES ON B-CELL POPULATIONS IN ADULT MICE, Transplantation: December 15, 1999 - Volume 68 - Issue 11 - p 1728-1736

(4)  Bazin H, Platteau B, Beckers A, Pauwels R. Differential effect of neonatal injections of anti-mu or anti-delta antibodies on the synthesis of IgM, IgD, IgE, IgA, IgG1, IgG2a, IgG2b, and IgG2c immunoglobulin classes. J Immunol. 1978 Nov;121(5):2083-7. PMID: 101595.

(5)  Soares M, Havaux X, Nisol F, Bazin H, Latinne D. Modulation of rat B cell differentiation in vivo by the administration of an anti-mu monoclonal antibody. J Immunol. 1996 Jan 1;156(1):108-18. PMID: 8598450.