B-cell Chronic Lymphocytic Leukaemia
Application of TABO8 for the treatment of B-cell chronic lymphocytic leukaemia (B-CLL)
Despite clinical benefits from chemotherapy or monoclonal antibody therapy, B-CLL is an incurable disease and the development of novel immunotherapies for the treatment of B-CLL is highly requested by hemato-oncologists. TAB08 represents a novel class of immunomodulatory antibodies and has the potential to be effective in the treatment of B-CLL.
Several features of B-CLL suggest that immune-based strategies have therapeutic potential. Despite expression of high levels of major histocompatibility complex (MHC) class I and II molecules, CLL B-cells are ineffective antigen-presenting cells (APC). This is due at least in part to their lack or reduced expression of important costimulatory surface molecules such as CD80 (B7.1) and CD86 (B7.2), which are necessary for cytoxic T-cell activation.
In addition to the functional (qualitative) deficiency of major immune effector cells, a quantitative imbalance between T- and CLL B-cells plays a significant role in the pathogenesis and clinical course of B-CLL. Due to the accumulation of the leukaemic B-cells, T-lymphocytes are proportionately reduced. Furthermore, T-cell function and numbers are profoundly impaired by chemotherapeutic, highly cytotoxic agents.
In order to provide preclinical proof of this concept in the contest of B-CLL, a series of in-vitro, ex-vivo and indirect in-vivo experiments have been conducted. For in-vitro and ex-vivo studies, peripheral blood mononuclear cells (PBMC) of healthy donors as well as primary blood samples of a broad spectrum of B-CLL patients were used.
In-vitro direct effects of TAB08 on T-cells include significant increase in T-cell proliferation and the induction of blastogenesis and enhance expression of the activation markers CD71, Ox40 and CD25 and CTLA-4. It has been demonstrated that CD40L expression on activated T-cells triggers CLL B-cells to express enhanced amounts of costimulatory molecules (CD80 and CD86) and to become more effective APCs. In addition to up-regulation of CD80 and CD80 on B-cells, a pronounced expression of the apoptosis-mediator CD95 (FAS-ligand) could be observed after ex-vivo culturing PBMC with TAB08. Finally, the cytolytic activity of TAB08 - activated T-cells against autologous leukaemic B-cells by flow cytometry using key markers of apoptosis.
In vivo, rapid recovery from T-lymphopenia has been demonstrated in a rat model. It could be shown that in lethally irradiated hosts, an agonistic antibody with specificity for rat CD28 was able to dramatically accelerate T-cell repopulation by a small inoculum of mature, allotype-marked T-cells. Expanded T-cells had a maintained repertoire diversity and were functional both in-vitro and in-vivo. A pronounced T-cell expansion was also observed in non-human primates (rhesus and cynomolgus monkeys) after treatment with TAB08. Since TAB08 is able to stimulate the T-cell pool to proliferate and doing so to aid immune reconstitution following myelo-ablative therapy, TAB08 could be extremely useful supplement to the physicians’ armory in the treatment of this condition, particularly as the newer products which have improved response rates in B-CLL seem to be associated with greater myelo suppression. Furthermore TAB08 is able to induce rapid recovery of lymphopenia following chemotherapy.
In summary, based on the results of preclinical ex-vivo studies using primary blood lymphocytes from B-CLL patients, it is expected that treatment of B-CLL with Humanized Agonistic Anti-CD28 Monoclonal Antibody will result in the following clinically relevant benefit for patients:
(1) Induction of T-cell proliferation and reversal of therapy-related T-lymphopenia;
(2) Induction of T-cell activation, including the induction of CD40L expression on T-cells;
(3) Up-regulation of co-stimulatory ligands CD80 and CD86 on normal and leukaemic B-cells;
(4) Improvement of the of antigen-presentingfunctionality of CLL B-cells ;
(5) Induction of a long-lasting anti-tumour T-cell response.