Drug‐Free Macromolecular Therapeutics Induce Apoptosis via Calcium Influx and Mitochondrial Signaling Pathway

Wang

et al. 2018

ACS Nano

Self Cite

Although the CD20-targeted monoclonal antibody rituximab (RTX) has revolutionized the therapeutic landscape for B-cell malignancy, relapsed and refractory disease due to RTX resistance continue to constitute major challenges, illustrating the need for better therapies. Here, we apply drug-free macromolecular therapeutics (DFMT) that amplifies CD20 cross-linking to enhance apoptosis in RTX-resistant cells. Bispecific engager (anti-CD20 Fab′ conjugated with oligonucleotide1) pretargets CD20 and the deletion of Fc-region minimizes its premature endocytosis in resistant cells that rapidly internalize and consume CD20/RTX complexes. Second-step delivery of multivalent polymeric effector (linear copolymer conjugated with multiple copies of complementary oligonucleotide 2) simultaneously hybridizes multiple CD20-bound engagers and strengthens CD20 ligation. Moreover, the restoration of CD20 expression by the pretreatment of cells with a polymer-gemcitabine conjugate, a CD20 expression enhancer, unleashes the full potential of DFMT in the CD20-deficient resistant cells. Hence, amplification of CD20 cross-linking is achieved by (1) the enhancement of surface CD20 accessibility, (2) the increase in CD20 expression, and (3) multimeric CD20 binding, which ultimately translates into the amplified activation of a wide range of innate apoptotic responses. We demonstrated that the altered molecular signaling pathway that originally results in RTX resistance could be circumvented and compensated by other DFMT-augmented pathways. Of note, our preliminary data provide proof-of-concept that CD20 cross-linking amplification emerges as an important strategy for overcoming RTX resistance.

Section: Resultsmentioning

confidence: 99%

“…21 2P-GEM was synthesized and characterized based on previous publication. 27 Details are included in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Amplification of CD20 Cross-Linking in Rituximab-Resistant B-Lymphoma Cells Enhances Apoptosis Induction by Drug-Free Macromolecular Therapeutics

Wang

et al. 2018

ACS Nano

Self Cite

“…In addition, our group demonstrated cell surface amplification of CD20 crosslinking overcomes rituximab resistance through augmenting numerous downstream pathways (e.g. calcium influx, NF-κB, mitochondrial pathway) [22][23][24]. In this regard, one prerequisite for optimal signal transduction that they share in common is the efficient clustering of these receptors.…”

Section: Introductionmentioning

confidence: 92%

“…Fab'-MORF1 and Fab'-MORF1-Cy5 were synthesized based on our previously published methods [22][23][24]. HSA-(MORF2) x and HSA-(MORF2) x -Cy3 with different valences were prepared by maleimide functionalization of HSA surface followed by thiol-ene reaction.…”

Section: Synthesis and Characterizationmentioning

confidence: 99%

Drug-free albumin-triggered sensitization of cancer cells to anticancer drugs

Journal of Controlled Release

Soodvilai

et al. 2019

Self Cite

Chemosensitization strategies have been used to sensitize cancer cells to conventional drugs, but their utility is often obstructed by additional off-target toxicity, limited access to intracellular targets and heterogeneous tumor pathogenesis. To address these challenges, we rationally developed a drug-free human serum albumin (HSA)-based therapeutic (KH-1) that functions extracellularly and exhibits pleiotropic effect on multiple intracellular signaling pathways. It is a two-step touch-trigger system that consists of a pretargeting anchor on surface receptor CD20 (anti-CD20 Fab' conjugated with a morpholino oligonucleotide 1) and a CD20 clustering actuator (HSA grafted with multiple copies of complementary morpholinooligonucleotide 2). The extracellular actuation by surface CD20 crosslinking boosts robust activations of numerous intracellular responses, and promotes cancer cell susceptibility to various anticancer drugs, including docetaxel (microtubule stabilizer), gemcitabine (nucleoside analogue) and GDC-0980 (PI3K/mTOR inhibitor). The broad applicability of KH-1 is demonstrated to result from simultaneous inhibition of survival pathways and augmentation of apoptotic pathways. In addition, KH-1 covalently conjugated with anthracycline anticancer agent, epirubicin, integrates the advantages of both chemosensitization function and improved intracellular drug delivery in a single system and takes effect on the same cell. Therefore, in the present study, we have provided mechanistic demonstration that crosslinking of surface receptors can be leveraged to elicit chemosensitization.

Inhibition of Immunosuppressive Tumors by Polymer‐Assisted Inductions of Immunogenic Cell Death and Multivalent PD‐L1 Crosslinking

et al. 2020

Adv Funct Materials

Self Cite

Checkpoint blockade immunotherapies harness the host's own immune system to fight cancer, but only work against tumors infiltrated by swarms of preexisting T cells. Unfortunately, most cancers to date are immune‐deserted. Here, a polymer‐assisted combination of immunogenic chemotherapy and PD‐L1 degradation is reported for efficacious treatment in originally nonimmunogenic cancer. “Priming” tumors with backbone‐degradable polymer‐epirubicin conjugates elicits immunogenic cell death and fosters tumor‐specific CD8+ T cell response. Sequential treatment with a multivalent polymer‐peptide antagonist to PD‐L1 overcomes adaptive PD‐L1 enrichment following chemotherapy, biases the recycling of PD‐L1 to lysosome degradation via surface receptor crosslinking, and produces prolonged elimination of PD‐L1 rather than the transient blocking afforded by standard anti‐PD‐L1 antibodies. Together, these findings establish the polymer‐facilitated tumor targeting of immunogenic drugs and surface crosslinking of PD‐L1 as a potential new therapeutic strategy to propagate long‐term antitumor immunity, which might broaden the application of immunotherapy to immunosuppressive cancers.