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

Abstract

Background Tumor-targeted nanoparticles hold great promise as new tools for therapy of liquid cancers. Furthermore, the therapeutic efficacy of nanoparticles can be improved by enhancing the cancer cellular internalization. Methods In this study, we developed a humanized bispecific antibody (BsAbs: CD20 Ab-mPEG scFv) which retains the clinical anti-CD20 whole antibody (Ofatumumab) and is fused with an anti-mPEG single chain antibody (scFv) that can target the systemic liquid tumor cells. This combination achieves the therapeutic function and simultaneously “grabs” Lipo-Dox® (PEGylated liposomal doxorubicin, PLD) to enhance the cellular internalization and anticancer activity of PLD. Results We successfully constructed the CD20 Ab-mPEG scFv and proved that CD20 Ab-mPEG scFv can target CD20-expressing Raji cells and simultaneously grab PEGylated liposomal DiD increasing the internalization ability up to 60% in 24 h. We further showed that the combination of CD20 Ab-mPEG scFv and PLD successfully led to a ninefold increase in tumor cytotoxicity (LC50: 0.38 nM) compared to the CD20 Ab-DNS scFv and PLD (lC50: 3.45 nM) in vitro. Importantly, a combination of CD20 Ab-mPEG scFv and PLD had greater anti-liquid tumor efficacy (P = 0.0005) in Raji-bearing mice than CD20 Ab-DNS scFv and PLD. Conclusion Our results indicate that this “double-attack” strategy using CD20 Ab-mPEG scFv and PLD can retain the tumor targeting (first attack) and confer PLD tumor-selectivity (second attack) to enhance PLD internalization and improve therapeutic efficacy in liquid tumors.

Polyethylene Glycol Immunogenicity: Theoretical, Clinical, and Practical Aspects of Anti-Polyethylene Glycol Antibodies

“…Several excellent reviews cover PEG chemistry, , assay of pegylated compounds, and immunogenicity of pegylated medicines. ,− In the present review, we aim to clear up some misconceptions about PEG immunogenicity, realistically assess the impact of anti-PEG antibodies on pegylated medicines, and describe the specificity and binding behavior of anti-PEG antibodies. We survey the literature as well as draw from personal experience over the past 20 years on creating anti-PEG monoclonal antibodies, developing anti-PEG antibody assays, − assaying and discovering genetic markers for anti-PEG antibodies, , investigating the effects of anti-PEG antibodies on pegylated medicines, ,− and creating recombinant anti-PEG receptors and targeting molecules − to provide a framework to understand what makes a pegylated drugs immunogenic, how anti-PEG antibodies affect the efficacy and safety of pegylated medicines, and some experience with how anti-PEG antibodies behave in practice.…”

Targeted internalization and activation of glycosidic switch liposomes by an EphA2 PEG engager increases therapeutic efficacy against lung cancer

“…Importantly, the antitumor activity of the targeted GSL was signi cantly greater than non-targeted GSL, resulting in the cure of more than half of the treated mice. E cient internalization of lysosomotropic drugs or mRNA [45] as well as drugs against liquid tumors [22,46] are increasingly important challenges in modern medicine. In the case of liquid tumors, such as leukemia or lymphoma, the effective internalization of drugs into cancer cells is crucial for targeted and precise treatment.…”

“…We previously developed bispeci c antibody-like molecules called PEG engagers to target pegylated nanomedicines to cancer cells [19][20][21][22], the similar PEG engagers strategies also described by other research groups [23][24][25]. The typical PEG engager format fuses an antibody fragment with speci city to the PEG backbone or terminal methoxy group on PEG to another antibody fragment with speci city to a tumor antigen expressed on the cancer cell surface.…”

PEGylated liposomes enhance the effect of cytotoxic drug: A review

“…The recent strategy was reported by Ho (2021) reported “double attack “strategy for anticancer using CD20 Ab-mPEG scFv and PEGylated liposomal doxorubicin which incresase cellular internalization of doxorubicin form36.6%–83.6% and enhanced cellular cytotoxicity by 11-fold [ 54 ] ( Fig. 5 ).…”