Engineered antibodies in the treatment of B cell lymphoma

Abstract

The incidence of lymphoma is rising, now representing 3% of cancers in the UK alone. Current treatments include chemotherapy and radiotherapy, but whilst significant remission is often observed, responses frequently prove not to be durable. Thus, alternative treatments are sought.

One such alternative is the use of bispecific antibodies (BsAb), which show dual specificity for both a target antigen on the tumour cell, and a cytotoxic trigger molecule on an effector cell.

To further investigate these issues, we have designed a panel of F(ab')₂ BsAb against a range of murine B cell lymphoma antigens (idiotype, MHC class II, CD19, CD22 and D40). We have assessed the relative merits in targeting both T cells and neutrophils against these antigens. In the first case, BsAb were directed towards the CD3 and CD2 molecules of the T cell receptor. In the second, a transgenic mouse was utilised, to investigate the therapeutic potential of targeting G-CSF primed neutrophils via human FcγRI. Extensive analysis of these derivatives both in vitro and in vivo has revealed that it is the nature of the tumor antigen itself that has most bearing on therapy.

This work indicates that effector mechanisms such as antibody-dependent cellular cytotoxicity, whilst certainly contributing to tumor removal, are not sufficient to eradicate the malignant clone. Instead, it appears likely that a combination of growth inhibitory signals, and generation of T cell immunity are more important to successful therapy. In light of this, Ab dimers were produced in an effort to increase the signalling potential of mAb. Following dimerisation, mAb were able to induce growth arrest and cell death in human lymphoma lines, as well as showing increased complement activation. Dimers were also able to protect against in vivo tumor challenge.

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