Combating non-Hodgkin lymphoma by targeting both CD20 and HLA-DR through CD20–243 CrossMab

Abstract

Although rituximab has revolutionized the treatment of hematological malignancies, the acquired resistance is one of the prime obstacles for cancer treatment, and development of novel CD20-targeting antibodies with potent anti-tumor activities and specificities is urgently needed. Emerging evidence has indicated that lysosomes can be considered as an "Achilles heel" for cancer cells, and might serve as an effective way to kill resistant cancer cells. HLA-DR antibody L243 has been recently reported to elicit potent lysosome-mediated cell death in lymphoma and leukemia cells, suggesting that HLA-DR could be used as a potential target against lymphoma. In this study, we generated a bispecific immunoglobulin G-like antibody targeting both CD20 and HLA-DR (CD20-243 CrossMab) through CrossMab technology. We found that the CrossMab could induce remarkably high levels of complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and anti-proliferative activity. Notably, although HLA-DR is expressed on normal and malignant cells, the CrossMab exhibited highly anti-tumor specificity, showing efficient eradication of hematological malignancies both in vitro and in vivo. Our data indicated that combined targeting of CD20 and HLA-DR could be an effective approach against malignancies, suggesting that CD20-243 CrossMab would be a promising therapeutic agent against lymphoma.

WITHDRAWN: Effective suppression of Rituximab-resistant B-cell lymphoma by a comb-like anti-CD20 mAb nanocluster

“…As we all know, cancer is usually multifactorial in nature, involving various redundant disease-mediating ligands and receptors, as well as crosstalk between signal cascades [40,41]. Thus, targeting only one or two pathways may not completely shut off a hallmark capability of cancer, allowing some malignant cells to survive until they or their progeny eventually adapt to the selective pressure imposed by the applied therapeutic agents [25,26]. Therefore, the activation of multiple tumor suppression pathways may result in improved therapeutic index and reduced drug resistance.…”

“…Phase I/II studies with either epratuzumab (a humanized antibody targeting the CD22) or galiximab (a chimeric antibody targeting the costimulatory ligand CD80) in combination with Rituximab demonstrate safety and clinical responses greater than single agent [22][23][24]. Previously, our research group constructed an IgG-like bispecific fusion protein targeting both CD20 and Flt3 (CD20-Flex BiFP) and a bispecific mAb targeting both CD20 and HLA-DR (CD20-243 CrossMab) by using CrossMab technology; both exhibit excellent in and ex vivo anti-lymphoma activities [25,26].…”

Double attack strategy for leukemia using a pre-targeting bispecific antibody (CD20 Ab×mPEG scFv) and actively attracting PEGylated liposomal doxorubicin to enhance anti-tumor activity

“…According to previous studies, nanoparticles may accumulate and be retained in solid tumors through the enhanced permeation and retention (EPR) effect [7,8]. However, the EPR effect is present in tumors of more than ~ 100 mm 3 in volume and hampers the use of nanoparticles for targeting small or unvascularized metastases [9]. We hypothesized that the lack of an improvement in outcome of PLD against leukemia may due to the non-speci c targeting cytotoxicity and a reduced EPR effect.…”

“…Rituximab, is a chimeric monoclonal antibody (mAb) that binds to CD20. It is expressed on the membrane of up to 90% of late pre-B and mature B-cells as well as in the majority of B-cell lymphoproliferative disorders [2,3], and can activate complement-dependent cytotoxicity (CDC) via the Fc domain of Rituximab and antibodydependent cellular cytotoxicity (ADCC) based on the additional contact to Fcγ receptors [2]. In the clinic, the use of doxorubicin hydrochloride combined with Rituximab is an effective therapy for relapsed and refractory leukemia [4].…”

Development of novel monoclonal antibodies to dog leukocyte antigen DR displaying direct and immune‐mediated cytotoxicity toward canine lymphoma cell lines

“…Other CL surface target molecules considered for CL therapy are Class II MHC antigens . Anti‐HLA‐DR antibodies engineered alone or in combination with anti‐CD20 or anti‐CD19 have been successfully used in experimental therapies for human lymphoma and leukaemia . In both humans and dogs, MHC II DR is expressed on most lymphoid neoplasms from the precursor cells at levels higher than CD20 but dedicated, species‐specific and high affinity monoclonal antibodies to the canine MHC II DR are missing.…”