Anti-idiotypic antibody (Ab2) vaccines: Coupling of Ab2 BR3E4 to KLH increases humoral and/or cellular immune responses in animals and colorectal cancer patients

Abstract

The colorectal carcinoma (CRC)-associated CO17-1A/GA733 antigen (Ag) has been the target of a phase II/III randomized trial of passive immunotherapy with monoclonal antibody CO17-1A (Ab1), and phase I active immunotherapy trials with polyclonal anti-idiotypic antibodies (Ab2) mimicking the CO17-1A or GA733 epitope of the Ag. However, monoclonal rat Ab2 BR3E4 directed against Ab1 CO17-1A was superior to polyclonal Ab2 in inducing antigen-specific humoral and cellular immune responses in mice and rabbits. Various forms of Ab2 BR3E4, i.e., BR3E4-F(ab')2 precipitated with aluminum-hydroxide (alum), BR3E4-F(ab')2 coupled to KLH and precipitated or non-precipitated with alum, and BR3E4-IgG in alum or incomplete Freund's adjuvant were compared for their capacity to induce in rabbits anti-anti-idiotypic antibodies (Ab3) that specifically bind to the CO17-1A Ag. BR3E4-F(ab')2 coupled to KLH and precipitated with alum was shown to induce the highest Ab3 titers, followed by Ab2 BR3E4-IgG in alum. Therefore Ab2 BR3E4 as intact IgG (IgG group) or as F(ab')2 coupled to KLH (KLH group), was administered in a phase I trial to 45 patients with CRC, stage Dukes'D (UICC stage IV), with the goal to modulate patients' immune responses to their tumors. Fifteen of 23 patients in the IgG group developed Ab3 binding specifically to Ab2, and in four of these patients the Ab3 also specifically bound to Ag-positive CRC cells. Lymphoproliferative responses to Ab2 and/or GA733-2E Ag stimulation were observed in three of these patients. Eighteen of the 22 KLH group patients tested developed Ab3 and the Ab3 bound specifically to CRC cells in eight patients. Five of the 15 KLH group patients tested developed lymphoproliferative responses to Ab2 and/or GA733-2E Ag. Thus, there was a trend for the KLH group demonstrating higher immune response rates than the IgG group. Clinical responses were rare in these patients with liver metastases.

Anti-idiotype antibodies in cancer treatment

“…Over about 20 years, scientists at the Wistar Institute have tenaciously brought to sequential clinical application passive immunotherapy with murine CO17-1A mAb and active immunotherapy with polyclonal goat anti-Id antibodies produced against the same CO17-1A mAb, which mimics the CRC-associated antigen above (Birebent et al, 2001a, b). Results of the former approach were substantially modest, whereas with the latter strategy anti-anti-Id humoral immune responses were systematically documented ever since the first trial was concluded, and encouraging partial responses were also described.…”

“…Once again, the actual clinical impact of the strategy could not be completely ascertained, inasmuch as all patients had undergone primary tumor and lymph node metastases surgical removal before receiving immunotherapy (Somasundaram et al, 1995). More recently, a rat mAb directed against CO17-1A has shown clear superiority over the goat polyclonal antibodies above in inducing antigen-specific, humoral and cellular immune responses; these responses also benefited of conjugation of such a mAb with keyhole limpet hemocyanin (Birebent et al, 2001a, b). Subsequent studies have also proved that when molecularly cloned in a baculovirus, the GA733 epitope is more immunogenic than its mimicking anti-Id mAb counterpart, both in terms of humoral and cellular immune responses elicited (Birebent et al, 2001a, b).…”

“…More recently, a rat mAb directed against CO17-1A has shown clear superiority over the goat polyclonal antibodies above in inducing antigen-specific, humoral and cellular immune responses; these responses also benefited of conjugation of such a mAb with keyhole limpet hemocyanin (Birebent et al, 2001a, b). Subsequent studies have also proved that when molecularly cloned in a baculovirus, the GA733 epitope is more immunogenic than its mimicking anti-Id mAb counterpart, both in terms of humoral and cellular immune responses elicited (Birebent et al, 2001a, b). These results have also been independently confirmed by scientists at Karolinska Institute, who have showed that Ep-CAM protein induces more pronounced and longer lasting, specific humoral and cellular immune responses compared with a human anti-Id mimicking Ep-CAM, when both immunogens are administered in combination with GM-CSF (Mosolits et al, 2004).…”

Loss of Sialic Acid Binding Domain Redirects Protein σ1 to Enhance M Cell-Directed Vaccination

“…Original strategies involved the coupling of vaccines to anti-Ig antibodies (Abs) [1] or MHC class II molecules [2] to develop an adjuvant-free method to enhance vaccine uptake. More recently, using Abs to target dendritic cells (DCs), as with DEC205 mAb, has enhanced immunogenicity to HIV [3] and plague LcrV [4].…”

“…Both the described Ab- [1]–[5] and DC-targeting methods [3]–[7] adopt a targeting strategy for a specific host cell receptor. To improve mucosal immunity, strategies also have focused on targeting microfold (M) cells [8], a specialized epithelium present on the luminal surface of the Peyer's patches (PPs) or nasal-associated lymphoid tissue (NALT).…”