Aims of the current proposal
I. what is the best configuration of bispecific antibodies (BsAb)? II. what is the best way to produce bulk amounts of BsAb?
III. what is the optimal delivery regimen of BsAb in B cell malignancies?
B lymphoid malignancies are a heterogeneous group of hematologic tumors, presenting themselves in blood, lymph nodes or bone marrow, and often disseminated throughout the body. Antigenically they share most normal B cell markers, such as CDl9, CD20 and CD22, and appear to represent cells "frozen" at one stage in the normal differentiation pathway. The incidence of Non Hodgkin,s Lymphoma (NHL) is about 15 per 100,000. Chemotherapy can induce a complete remission in the majority of new cases of NHL, but relapse is the usual outcome. This bleak outlook demands novel methods of treatment. One new approach involves engineered BsAb which can re-target a patient's own immune system (T cells) against the malignant (B) cells. Using a BsAb which expresses dual specificity for a trigger molecule on T cells (e.g. CD3) and a target molecule on the malignant B cells (e.g. CDl9), cytotoxic T cells can be re-targeted, irrespective of the antigen specificity or MHC restriction of the T cells. Mouse studies and preliminary clinical results confirm this model. As co-activating molecules such as CD28 and Fc receptors play an important role in BsAb mediated T cell activation, BsAb recognising these molecules and other B cell antigens may enhance this specific cytotoxicity.
It is widely agreed that B cell malignancies present the best clinical setting in which to study the therapeutic efficacy of BsAb, as B and T cells represent the most extensively studied system of cellular interaction in biology, and because many of the inherent drawbacks seen with solid tumors (poor vasculature, antigen negative variants, no clear cell specific antigens present) are largely avoided in B cell malignancies. In addition, this group of tumors is the best forerunner for studying the activation of therapeutically useful T cells in-vivo. Furthermore, they provide a model system which may lead to applications in many, more widespread cancers and even other medical conditions. These would include a.o. vaccinology (presentation of antigens to antigen presenting cells by BsAb, obviating the need of adjuvantia), infectiology (presentation of pathogens to phagocytic cells) and haemostasis (presentation of thrombolytic agents to haemostatic plugs, increasing the speed and local specificity of the desired thrombolytic process). Clearly the field of BsAb treatment potentially pertains to an immense group of (European) citizens of all age groups.
The institutes participating in this application (EURO-BATH; European bispecific antibody therapy-group) represent many of the accepted world leaders in the field of immunotherapy. This is evidenced also from a literature search, showing that half of the pertinent references, and all clinical studies, have emerged from this group.
Further, the Utrecht based coordinator of this Network is now organising the 5th International Conference on Bispecific Antibodies (1997), where all various aspects of above will be reviewed. End points of current programme include the selection and production of a (series of) BsAb, suitable to enable multicenter clinical studies (in itself not included within this programme) in NHL and acute lymphoblastic leukemia (ALL). One (industrial) partner of this project (a SME) will produce this material under GMP rules. Other (scientific) partners have intensive contacts with various pharmaceutical companies (Glaxo-Wellcome, Medarex/Europe), which altogether form the extended audience.
Funding SchemeCSC - Cost-sharing contracts
6202 AZ Maastricht
9747 AN Groningen
9713 GZ Groningen
CB2 1QP Cambridge
SO16 6YD Southampton