Complete eradication of human B-cell lymphoma xenografts using rituximab in combination with the immunocytokine L19-IL2

Abstract

The antibody-mediated delivery of therapeutic agents to sites of angiogenesis is an attractive strategy for anticancer therapy, but is largely unexplored in hematologic malignancies. In the present study, we show that the extra domain B (EDB) of fibronectin, a marker of angiogenesis, is expressed in B-cell non-Hodgkin lymphoma (NHL) and that the human monoclonal anti-EDB antibody L19 can selectively localize to the lymphoma-associated subendothelial extracellular matrix. In vivo, the preferential accumulation of the antibody at the tumor site was confirmed by quantitative biodistribution analyses with radioiodinated antibody preparations. The fusion protein L19-IL2, which mediates the delivery of interleukin-2 (IL-2) to the neovasculature, displayed a superior antilymphoma activity compared with unconjugated IL-2 in localized and systemic xenograft models of NHL. When coadministered with rituximab, L19-IL2 induced complete remissions of estab- IntroductionConventional cytotoxic therapies of cancer often do not discriminate between tumor and normal tissues. To achieve therapeutically relevant concentrations in the tumor mass, large drug doses have to be administered to the patient, leading to a poor therapeutic index and unacceptable toxicities to healthy tissues. The selective delivery of therapeutic agents to the tumor site using antibodies against tumor-associated antigens represents a promising strategy to overcome the disadvantages of conventional cancer therapies. 1-3 Antigens expressed in the tumoral neovasculature are especially attractive targets for antibody-based pharmacodelivery applications due to their inherent accessibility for blood-borne agents. [4][5][6] The efficacy of targeting either tumor endothelial cells or the modified subendothelial extracellular matrix has been demonstrated in a variety of animal models of solid cancers using antibodies functionalized with different effector moieties, 4,[7][8][9][10][11][12][13][14] leading to the clinical development of immunocytokines and radioimmunoconjugates for the therapy of solid tumors. 6,15 Tumortargeting strategies based on the preferential accumulation of biopharmaceuticals around new blood vessels could also be conceivable for the therapy of leukemias and lymphomas, since the dependence of hematologic malignancies on a functional neovasculature has been highlighted already a decade ago. 16,17 Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy, with now more than 60 000 new cases being diagnosed each year in the United States. 18 The approval of rituximab, a chimeric monoclonal immunoglobulin G1 (IgG1) antibody specific to CD20, represented a major step toward a more selective and effective therapy of NHLs of B cell origin. While first shown to be effective in relapsed follicular lymphoma, anti-CD20 immunotherapy is nowadays incorporated in front-line therapy schemes of follicular and diffuse large B-cell lymphoma. 18 However, in spite of the unquestionable clinical effectiveness of rituximab, a high percentage of patients ...

The antibody‐based targeted delivery of interleukin‐4 and 12 to the tumor neovasculature eradicates tumors in three mouse models of cancer

“…12,39,40 As for the previous two models, a quantitative biodistribution study and an ex vivo immunofluorescence analysis following intravenous administration confirmed a preferential accumulation of F8-IL4 around tumor neovascular structures (Figs. 6a and 6b).…”

Pegfilgrastim Enhances the Antitumor Effect of Therapeutic Monoclonal Antibodies

“…An immunocytokine fusion protein combining IL2 with an antifibronectin antibody in combination with rituximab was found to eradicate B-cell lymphoma xenografts (32). Antibodies directed against the inhibitory Kir molecules expressed by NK cells have been evaluated in combination with rituximab (33).…”

Interfering with pH regulation in tumours as a therapeutic strategy

“…The alternatively spliced domains extra domain A (EDA) and extra domain B (EDB) of fibronectin, which are targeted by the F8 and L19 antibodies, respectively, exhibit a high level of conservation among species and are virtually undetectable in normal tissues; however, they are abundantly expressed in the stroma and neovasculature of most aggressive types of human cancers 96,[102][103][104][105][106][107][108][109][110] . Similarly, systematic chemical proteomics studies 107,[111][112][113] have recently shown that another component of the extracellular matrix, periostin, exists in several splice isoforms that are abundantly found in most types of cancers [111][112][113][114] .…”