Enhancement of the complement activating capacity of 17-1A mAb to overcome the effect of membrane-bound complement regulatory proteins on colorectal carcinoma

Abstract

Adjuvant immunotherapy with 17‐1A mAb directed against colorectal carcinoma is found to be effective in patients. However, 52 % of the patients treated with mAb 17‐1A showed recurrence within 7 years. This high recurrence rate might be due to inhibition of complement activation by membrane‐bound complement regulatory proteins (mCRP). The effect of these complement regulatory proteins might be reduced by blocking mCRP, or be overcome by activating more complement at the tumor cell membrane. In this study the complement‐activating capacity of the 17‐1A mAb was enlarged by conjugating it to cobra venom factor (CVF) or C3b. The most important C3 regulatory protein, CD55, was blocked using a bispecific mAb directed against the 17‐1A / Ep‐CAM antigen and CD55. Up to a 13‐fold increase in C3 deposition was observed due to 17‐1A‐CVF and 17‐1A‐C3b, as compared to 17‐1A. CD55 was shown to partly inhibit complement activation by these conjugates. The effect of the bispecific anti‐17‐1A / Ep‐CAM*anti‐CD55 mAb was compared with 17‐1A conjugates with CVF or C3, and bispecific mAb were shown to be equally or more efficient in complement activation than the 17‐1A‐CVF or 17‐1A‐C3b conjugates. Therefore, 17‐1A conjugates and anti‐17‐1A / EpCAM*anti‐CD55 bispecific mAb may be promising immunotherapeutic agents for patients with colorectal cancer.

Is complement good or bad for cancer patients? A new perspective on an old dilemma

“…Although the role of complement in the immune surveillance of malignant neoplasms has not yet been clarified, the successful use of mAbs to treat cancer has motivated researchers to attempt to increase the activation of complement, as a supplement to antibody immunotherapy [69–71]. In fact, several in vitro and animal studies have demonstrated that an approach of this kind can improve the effectiveness of mAbs in killing tumor cells.…”

The Role of Complement in the Mechanism of Action of Rituximab for B-Cell Lymphoma: Implications for Therapy

“…2). This effect was achieved in vitro by either anti-epithelial cell adhesion molecule-CVF heteroconjugates targeted to colorectal cancer cells [92] or anti-GD2-CVF heteroconjugates targeted to neuroblastoma cells [93,94]. Additionally, an antibody against iC3b was demonstrated to increase iC3b deposition, which allowed it to interact with effector cells containing both Fc and complement receptors, and therefore significantly enhancing rituximab-mediated killing of Raji and DB cells in a cynomologous monkey model [95] (Fig.…”

Engineering therapeutic monoclonal antibodies

“…These proteins can protect both normal and tumor cells from lysis mediated by the complement system. Bispecific mAbs that are antagonists for mCRPs and tumor antigen are therefore being developed (141)(142)(143).…”