Anti-PD-L1-Based Bispecific Antibodies Targeting Co-Inhibitory and Co-Stimulatory Molecules for Cancer Immunotherapy.

Targeting PD-L1 via monospecific antibodies has shown durable clinical benefits and long-term remissions where patients exhibit no clinical cancer signs for many years after treatment. However, the durable clinical benefits and long-term remissions by anti-PD-L1 monotherapy have been limited to a small fraction of patients with certain cancer types. Targeting PD-L1 via bispecific antibodies (referred to as anti-PD-L1-based bsAbs) which can simultaneously bind to both co-inhibitory and co-stimulatory molecules may increase the durable antitumor responses in patients who would not benefit from PD-L1 monotherapy. A growing number of anti-PD-L1-based bsAbs have been developed to fight against this deadly disease. This review summarizes recent advances of anti-PD-L1-based bsAbs for cancer immunotherapy in patents and literatures, and discusses their anti-tumor efficacies in vitro and in vivo. Over 50 anti-PD-L1-based bsAbs targeting both co-inhibitory and co-stimulatory molecules have been investigated in biological testing or in clinical trials since 2017. At least eleven proteins, such as CTLA-4, LAG-3, PD-1, PD-L2, TIM-3, TIGIT, CD28, CD27, OX40, CD137, and ICOS, are involved in these investigations. Twenty-two anti-PD-L1-based bsAbs are being evaluated to treat various advanced cancers in clinical trials, wherein the indications include NSCLC, SNSCLC, SCLC, PDA, MBNHL, SCCHN, UC, EC, TNBC, CC, and some other malignancies. The released data from clinical trials indicated that most of the anti-PD-L1-based bsAbs were well-tolerated and showed promising antitumor efficacy in patients with advanced solid tumors. However, since the approved and investigational bsAbs have shown much more significant adverse reactions compared to PD-L1 monospecific antibodies, anti-PD-L1-based bsAbs may be further optimized via molecular structure modification to avoid or reduce these adverse reactions.

Design, synthesis and in vitro evaluation of amidoximes as histone deacetylase inhibitors for cancer therapy.

Amindoximes are geometric isomers of N-hydroxyamidines which are bioisosteres of hydroxamates. Since amindoxime group is capable of chelating transition metal ions including zinc ion, amindoximes should possess histone deacetylases (HDACs) inhibitory activity. In this work, we designed and synthesized a series of amindoximes, examined their inhibitory activities against HDACs, and investigated their cytotoxicity to human cancer cells. Preliminary results demonstrated that amindoximes possessed submicromolar HDACs inhibitory activity, with noteworthy enhancement compared with hydroxamates. Furthermore, the amindoximes arrested HCT116 and A549 cells in G2/M phase and showed good efficacy in inducing cells death. We provided a proof-of-concept that amindoximes could be used as HDACs inhibitors and hold great promise as epigenetic drugs.

Synthesis and evaluation of novel isoxazolyl chalcones as potential anticancer agents.

A series of novel isoxazolyl chalcones were synthesized and evaluated for their activities in vitro against four types of human non-small cell lung cancer cells, including H1792, H157, A549 and Calu-1 cells. The preliminary biological screening showed that compounds 5d and 5f-i exhibited significant cytotoxicity, particularly, compounds 5f and 5h were identified as the most potent anticancer agents with IC50 values 1.35-2.07 µM and 7.27-11.07 µM against H175, A549 and Calu-1 cell lines, respectively. Compounds 5f-i could induce apoptosis in A549 cells by death receptor 5 (DR5) mediated extrinsicpathways. The preliminary structure-activity relationship study showed that compounds bearing electron withdrawing groups (EWG) at the 2-position of the phenyl ring in Ar group were more effective than those with EWG at 4-position. These results further demonstrated that the scaffolds designed in this work might lead to the discovery of novel anti-lung cancer agents.

Modulating the toxicity of engineered nanoparticles by controlling protein corona formation: Recent advances and future prospects.

With the rapid development and widespread application of engineered nanoparticles (ENPs), understanding the fundamental interactions between ENPs and biological systems is essential to assess and predict the fate of ENPs in vivo. When ENPs are exposed to complex physiological environments, biomolecules quickly and inevitably adsorb to ENPs to form a biomolecule corona, such as a protein corona (PC). The formed PC has a significant effect on the physicochemical properties of ENPs and gives them a brand new identity in the biological environment, which determines the subsequent ENP-cell/tissue/organ interactions. Controlling the formation of PCs is therefore of utmost importance to accurately predict and optimize the behavior of ENPs within living organisms, as well as ensure the safety of their applications. In this review, we provide an overview of the fundamental aspects of the PC, including the formation mechanism, composition, and frequently used characterization techniques. We comprehensively discuss the potential impact of the PC on ENP toxicity, including cytotoxicity, immune response, and so on. Additionally, we summarize recent advancements in manipulating PC formation on ENPs to achieve the desired biological outcomes. We further discuss the challenges and prospects, aiming to provide valuable insights for a better understanding and prediction of ENP behaviors in vivo, as well as the development of low-toxicity ENPs.

Synthesis, physical properties and cytotoxicity of stilbene-triazine derivatives containing amino acid groups as fluorescent whitening agents.

A series of novel stilbene-triazine derivatives containing amino acid groups were synthesized and screened to evaluate their cytotoxicity. The UV absorptions of the derivatives were in the range of 240-450 nm. The absorption peaks of the cis-isomers and trans-isomers were in 281-291 nm and 353-361 nm, respectively. Their fluorescence emission peaks of the derivatives were located in the range of 400-650 nm. The whiteness data indicated that all the stilbene-triazine-amino acid derivatives showed excellent whitening effect on cotton fiber compared to untreated cotton. The preliminary cytotoxicity of these derivatives on a mouse fibroblast cell line (L-929 cells) was also investigated. The results showed that the compounds (7a-h) were nontoxic to L-929 cells as fluorescent whitening agents.

Nanomaterial-Based Drug Delivery Systems for Pain Treatment and Relief: From the Delivery of a Single Drug to Co-Delivery of Multiple Therapeutics.

The use of nanomaterials in drug delivery systems for pain treatment is becoming increasingly common. This review aims to summarize how nanomaterial-based drug delivery systems can be used to effectively treat and relieve pain, whether via the delivery of a single drug or a combination of multiple therapeutics. By utilizing nanoformulations, the solubility of analgesics can be increased. Meanwhile, controlled drug release and targeted delivery can be realized. These not only improve the pharmacokinetics and biodistribution of analgesics but also lead to improved pain relief effects with fewer side effects. Additionally, combination therapy is frequently applied to anesthesia and analgesia. The co-encapsulation of multiple therapeutics into a single nanoformulation for drug co-delivery has garnered significant interest. Numerous approaches using nanoformulation-based combination therapy have been developed and evaluated for pain management. These methods offer prolonged analgesic effects and reduced administration frequency by harnessing the synergy and co-action of multiple targets. However, it is important to note that these nanomaterial-based pain treatment methods are still in the exploratory stage and require further research to be effectively translated into clinical practice.

Accelerating the multifunctionalization of therapeutic nanoparticles by using a multicomponent reaction.

Simpler and faster! Multifunctionalized nanoparticles are crucial for nanobiomedical applications, but their syntheses are tedious and time-consuming. A multicomponent reaction on nanostructures is an excellent way to prepare such nanomaterials. The gold nanosystem illustrated in the scheme was built and shown to enhance cancer cell targeting and killing by combining the effects of a therapeutic drug with X-ray radiation.

Enhancing cell recognition by scrutinizing cell surfaces with a nanoparticle array.

We report a dual-ligand nanoparticle array approach for discerning cells that have different surface receptor profiles surrounding a common primary receptor expressed at high or low levels. The achieved differentiation provides nanoparticles the ability for potential applications in treatment of patients at a personalized medicine level for drug delivery and radiation therapy with a much better safety profile.

Leading neuroblastoma cells to die by multiple premeditated attacks from a multifunctionalized nanoconstruct.

To conquer complex and devastating diseases such as cancer, more coordinated and combined attack strategies are needed. We suggest that these can be beautifully achieved by using nanoconstruct design. We present an example showing that neuroblastoma cells are selectively killed by a nanoconstruct that specifically targets neuroblastoma cells, pushes cells to the vulnerable phase of the cell cycle, and greatly enhances radiation-induced cell death. The success of this multipronged attack approach launched by cell-embedded nanoconstructs demonstrates the power and flexibility of nanotechnology in treating cancer, a difficult task for a small molecule.

Small molecules as antagonists of co-inhibitory pathways for cancer immunotherapy: a patent review (2018-2019).

INTRODUCTION: Therapeutic antibodies blocking co-inhibitory pathways do not attack tumor cells directly, but instead bind to their targeted proteins and mobilize the immune system to eradicate tumors. However, only a small fraction of patients with certain cancer types can benefit from the antibodies. Additionally, antibodies have shown serious immune-related adverse events in certain patients. Small-molecule antagonists may be a complementary and potentially synergistic approach to antibodies for patients with various cancers. AREAS COVERED: The authors review the small molecules as antagonists of co-inhibitory pathway proteins, summarize their preliminary SARs, discuss biochemistry assays used in patents for the development of small molecules as novel antagonists. EXPERT OPINION: The disclosed pharmacophores of small molecules as co-inhibitory pathway antagonists are represented by biphenyl derivatives, biaryl derivatives, teraryl derivatives, quateraryl derivatives, and oxadiazole/thiadiazole derivatives. However, these antagonists are still inferior to therapeutic antibodies in their inhibitory activities due to relatively flat of human co-inhibitory pathways proteins. Allosteric modulators may be an alternative approach. The more safety and efficacy evaluation trials of small-molecule antagonists targeting co-inhibitory pathways should be performed to demonstrate the proof-of-principle that small-molecule antagonists can result in sustained safety and antitumor response in the near future.

Mesoporous silica-coated gold nanostars with drug payload for combined chemo-photothermal cancer therapy.

Combined chemo-photothermal therapy is attracting increasing attention in the treatment of cancers. In this work, PEGylated mesoporous SiO2-coated gold nanostars (GNS@mSiO2-PEG) were synthesised without using the cytotoxic surfactant cetyltrimethylammonium bromide as the template. Mesoporous nanostructures were obtained by poly(vinylpyrrolidone) protection of the outer silica shell and NaOH etching of the inner shell. GNS@mSiO2-PEG exhibited good dispersity in medium and excellent photothermal effects. Loading capacity for the anticancer drug doxorubicin (DOX) was ∼17.9%, and the drug release profile was pH- and light-responsive. In vitro studies revealed that the as-prepared nanocomposites featured good biocompatibility. Furthermore, the nanocomposites were readily internalised by cancer cells, and a combined chemo-photothermal therapy assay revealed that DOX-loaded GNS@mSiO2-PEG have a higher therapeutic efficiency than individual therapies, demonstrating suitable synergistic effects.

PD-1/PD-L1 Inhibitors for Immuno-oncology: From Antibodies to Small Molecules.

BACKGROUND: The recent regulatory approvals of immune checkpoint protein inhibitors, such as ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab ushered a new era in cancer therapy. These inhibitors do not attack tumor cells directly but instead mobilize the immune system to re-recognize and eradicate tumors, which endows them with unique advantages including durable clinical responses and substantial clinical benefits. PD-1/PD-L1 inhibitors, a pillar of immune checkpoint protein inhibitors, have demonstrated unprecedented clinical efficacy in more than 20 cancer types. Besides monoclonal antibodies, diverse PD- 1/PD-L1 inhibiting candidates, such as peptides, small molecules have formed a powerful collection of weapons to fight cancer. METHODS: The goal of this review is to summarize and discuss the current PD-1/PD-L1 inhibitors including candidates under clinical development, their molecular interactions with PD-1 or PD-L1, the disclosed structureactivity relationships of peptides and small molecules as inhibitors. RESULTS: Current PD-1/PD-L1 inhibitors under clinical development are exclusively dominated by antibodies. The molecular interactions of therapeutic antibodies with PD-1 or PD-L1 have been gradually elucidated for the design of novel inhibitors. Various peptides and traditional small molecules have been investigated in preclinical model to discover novel PD-1/PD-L1 inhibitors. CONCLUSION: Peptides and small molecules may play an important role in immuno-oncology because they may bind to multiple immune checkpoint proteins via rational design, opening opportunity for a new generation of novel PD-1/PD-L1 inhibitors.

Small Molecules as PD-1/PD-L1 Pathway Modulators for Cancer Immunotherapy.

Blockade of PD-1/PD-L1 interactions using PD-1/PD-L1 pathway modulators has shown unprecedented clinical efficacy in various cancer models. Current PD-1/PD-L1 modulators approved by FDA are exclusively dominated by therapeutic antibodies. Nevertheless, therapeutic antibodies also exhibit several disadvantages such as low tumor penetration, difficulty in crossing physiological barriers, lacking oral bioavailability, high manufacturing costs, inaccessible to intracellular targets, immunogenicity, immune-related adverse events (irAEs). Modulation of PD-1/PD-L1 pathway using small molecules may be an alternative approach to mobilize immune system to fight against cancers. In this review, we focus on summarizing the recently disclosed chemical structures and preliminary structure-activity relationships (SARs) of small molecules as PD-1/PD-L1 modulators for cancer immunotherapy.

Enhancing both CT imaging and natural killer cell-mediated cancer cell killing by a GD2-targeting nanoconstruct.

Although nanomaterials have been widely investigated for drug delivery, imaging and immunotherapy, their potential roles in triggering innate cellular immune responses while simultaneously serving as imaging enhancer remain unexplored. In this work, gold nanoparticles (GNPs) conjugated to the tumor-targeting anti-GD2 antibody hu14.18K322A, namely HGNPs, were designed and synthesized to specifically enhance computerized tomography (CT) imaging contrast and to stimulate the attack of neuroblastoma and melanoma cells by natural killer (NK) cells. The HGNPs specifically targeted GD2-positive neuroblastoma (NB1691) and melanoma (M21) cells, with an enhancement of CT contrast images of the HGNP-labeled cell pellets by 5.27- and 7.66-fold, respectively, compared to images of unlabeled cell pellets. The HGNPs also triggered NK-mediated antibody-dependent cellular cytotoxicity (ADCC) in NB1691 and M21 cells with a two-fold higher efficacy compared to that elicited by hu14.18K322A alone, with no adverse effect to GD2-negative PC-3 cells. These results suggest that HGNPs are promising theranostic agents for neuroblastoma and melanoma cancers.

Novel 8-hydroxylquinoline analogs induce copper-dependent proteasome inhibition and cell death in human breast cancer cells.

An elevated level of copper (Cu), which is necessary for the growth and metastasis of tumor cells, has been found in many types of cancer, including breast, prostate, lung and brain. Although its molecular basis is unclear, this tumor-specific Cu elevation has been proposed to be a novel target for developing selective anti-cancer therapies. We previously reported that 8-hydroxylquinoline (8-OHQ) is able to form a Cu complex that inhibits the proteasome and induces apoptosis in cultured cancer cells. Toward the goal of discovering novel 8-OHQ analogs as potential anti-copper and anti-cancer drugs, in the current study we synthesized several 8-OHQ analogs and their copper complexes and evaluated their biological activities in human breast cancer cells. We report that when substitutions are made on the hydroxyl group of 8-OHQ, their copper mixtures have profound effects on the proteasome-inhibitory and apoptosis-inducing abilities in breast cancer MDA-MB-231 cells. In addition, the proteasome-inhibitory and apoptosis-inducing activities of 8-OHQ analog-copper mixtures are determined by both the polarity and position of the substituents. Finally, a synthetic complex of 8-OHQ analog-copper was able to inhibit the proteasome activity, induce cell death and suppress the growth selectively in breast cancer MDA-MB-231 cells, but not in normal immortalized human breast MCF-10A cells. Our results support the concept that human cancer cells and tissues, which contain an elevated copper level and are highly dependent on proteasome activity for their survival, should be sensitive to treatment with anti-copper drugs such as the novel 8-OHQ analogs described here.

Design, synthesis, and preliminary biological evaluation of 2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine derivatives.

We synthesized a series of novel small molecules, 2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine derivatives, by tandem reduction-oxirane opening of 2-nitroaroxymethyloxiranes in moderate or excellent yields. We investigated the effects of all of the compounds on HUVEC apoptosis and A549 cell growth. The results showed that 6,8-dichloro-2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine was the most effective small molecule in promoting HUVEC apoptosis and inhibiting A549 cell proliferation, but 6-amino-2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine could remarkably inhibit HUVEC apoptosis and might induce the formation of microvessel.