Immunoconjugates--monoclonal antibodies (mAbs) coupled to highly toxic agents, including radioisotopes and toxic drugs (ineffective when administered systemically alone)--are becoming a significant component of anticancer treatments. By combining the exquisite targeting specificity of mAbs with the enhanced tumor-killing power of toxic effector molecules, immunoconjugates permit sensitive discrimination between target and normal tissue, resulting in fewer toxic side effects than most conventional chemotherapeutic drugs. Two radioimmunoconjugates, ibritumomab tiuxetan (Zevalin) and tositumomab-131I (Bexxar), and one drug conjugate, gemtuzumab ozogamicin (Mylotarg), are now on the market. For the next generation of immunoconjugates, advances in protein engineering will permit greater control of mAb targeting, clearance and pharmacokinetics, resulting in significantly improved delivery to tumors of radioisotopes and potent anticancer drugs. Pre-targeting strategies, which separate the two functions of antibody-based localization and delivery or generation of the toxic agent into two steps, also promise to afford superior tumor targeting and therapeutic efficacy. Several challenges in optimizing immunoconjugates remain, however, including poor intratumoral mAb uptake, normal tissue conjugate exposure and issues surrounding drug potency and conditional release from mAb carriers. Nonetheless, highly promising results from preclinical models will continue to drive the clinical development of this therapeutic class.

Arming antibodies: prospects and challenges for immunoconjugates

Natural products have inspired chemists and physicians for millennia. Their rich structural diversity and complexity has prompted synthetic chemists to produce them in the laboratory, often with therapeutic applications in mind, and many drugs used today are natural products or natural-product derivatives. Recent years have seen considerable advances in our understanding of natural-product biosynthesis. Coupled with improvements in approaches for natural-product isolation, characterization and synthesis, these could be opening the door to a new era in the investigation of natural products in academia and industry.

Lessons from natural molecules

Natural products to drugs: natural product derived compounds in clinical trials

An antibody-drug conjugate (ADC) provides the possibility of selectively ablating cancer cells by combining the specificity of a monoclonal antibody (mAb) for a target antigen with the delivery of a highly potent cytotoxic agent. ADC target antigens are typically highly expressed on the surface of cancer cells compared to normal cells. The tumor target, the cytotoxic agent, and the manner in which the agent is attached to the antibody are key determinants of clinical activity and tolerability. Recently, several clinical trials have demonstrated that ADCs achieve higher clinical response rates than unconjugated mAbs targeting the same cell surface antigen. Brentuximab vedotin represents one such ADC that has recently been approved for the treatment of relapsed Hodgkin and systemic anaplastic large cell lymphomas--both characterized by high expression of the target antigen, CD30, on the surface of malignant cells. This review summarizes key characteristics of current, clinically active ADCs and highlights recent clinical data illustrating the benefit of antibody-targeted delivery of cytotoxic agents to cancer cells.

Antibody-Drug Conjugates in Cancer Therapy

In the year 2003 there was a 17% increase in the number of publications citing work performed using optical biosensor technology compared with the previous year. We collated the 962 total papers for 2003, identified the geographical regions where the work was performed, highlighted the instrument types on which it was carried out, and segregated the papers by biological system. In this overview, we spotlight 13 papers that should be on everyone's 'must read' list for 2003 and provide examples of how to identify and interpret high-quality biosensor data. Although we still find that the literature is replete with poorly performed experiments, over-interpreted results and a general lack of understanding of data analysis, we are optimistic that these shortcomings will be addressed as biosensor technology continues to mature.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jmr.753

Survey of the year 2003 commercial optical biosensor literature

Purpose: Linking a cytotoxic anticancer drug to an antibody that recognizes a tumor-associated antigen can improve the therapeutic index of the drug. We asked whether a conjugate of the cytotoxic antibiotic N -acetyl γ calicheamicin dimethyl hydrazide (CalichDMH) and an antibody recognizing Lewis y (Le y ) antigen could eliminate carcinomas that express Le y . Because Le y is highly expressed on carcinomas of colon, breast, lung, ovary, and prostate, a CalichDMH conjugate targeting Le y could provide a treatment option for various cancers. Experimental Design: The humanized anti-Le y antibody hu3S193 was conjugated to CalichDMH via the bifunctional AcBut linker. Selectivity and avidity of the conjugate (hu3S193-CalichDMH) for Le y -BSA or Le y+ cells was tested by BIAcore or flow cytometry. Cytotoxicity of hu3S193-CalichDMH was compared with toxicity of a control conjugate on monolayers of Le y+ and Le y− carcinoma cells. Inhibition of tumor growth by hu3S193-CalichDMH was assessed on three types of s.c. xenografts. Results: Hu3S193-CalichDMH had similar selectivity as hu3S193. The conjugate had lower affinity for Le y -BSA but not for Le y+ cells. When tested on monolayers of human Le y+ carcinoma cells, hu3S193-CalichDMH was more cytotoxic than a control conjugate. This difference in efficacy was not noted on Le y− cells. Efficacy of hu3S193-CalichDMH depended on the expression of Le y and on the sensitivity of the cells to CalichDMH. In vivo , hu3S193-CalichDMH inhibited growth of xenografted human gastric (N87), colon (LOVO), and prostate carcinomas (LNCaP). When used against N87 xenografts, hu3S193-CalichDMH arrested tumor growth for at least 100 days. Conclusion: Hu3S193-CalichDMH can specifically eliminate Le y+ tumors. These results support development of this conjugate for treatment of carcinomas.

https://clincancerres.aacrjournals.org/content/clincanres/10/13/4538.full.pdf

Antibody-Targeted Chemotherapy with the Calicheamicin Conjugate hu3S193-N-Acetyl γ Calicheamicin Dimethyl Hydrazide Targets Lewisy and Eliminates Lewisy-Positive Human Carcinoma Cells and Xenografts

Purpose: Mortality due to acute myeloid leukemia (AML) remains high, and the management of relapsed or refractory AML continues to be therapeutically challenging. The reapproval of MYLOTARG, an anti-CD33-calicheamicin antibody-drug conjugate (ADC), has provided a proof-of-concept for an ADC-based therapeutic for AML. Several other ADCs have since entered clinical development of AML but have met with limited success. We sought to develop a next-generation ADC for AML with a wide therapeutic index that overcomes the shortcomings of previous generations of ADCs. Experimental Design: We compared the therapeutic index of our novel CD33-targeted ADC platform to other currently available CD33-targeted ADCs in preclinical models of AML. Next, using this next-generation ADC platform, we performed a head-to-head comparison of two attractive AML antigens: CD33 and CD123. Results: Our novel ADC platform offered improved safety and therapeutic index when compared to certain currently available ADC platforms in preclinical models of AML. Differentiation between the CD33- and CD123- targeted ADC was observed in safety studies conducted in cynomolgus monkeys. The CD33-targeted ADC produced severe hematological toxicity, whereas minimal hematological toxicity was observed with the CD123-targeted ADC at the same doses and exposures. The improved toxicity profile of an ADC targeting CD123 over CD33 was consistent with the more restricted expression of CD123 in normal tissues. Conclusions: We optimized all components of ADC design (i.e., leukemia antigen, antibody, and linker-payload) to develop an ADC that has the potential to translate into an effective new therapy against AML.

/pdf/development-of-highly-optimized-antibody-drug-conjugates-2vx3j15w2f.pdf

Development of Highly Optimized Antibody-Drug Conjugates against CD33 and CD123 for Acute Myeloid Leukemia.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9832108

Developing a multiepitope vaccine for the prevention of SARS-CoV-2 and monkeypox virus co-infection: A reverse vaccinology analysis

Antibiotic resistance is the greatest challenge for the treatment of Staphylococcus aureus (S. aureus) infection under the global antibiotic resistance crisis. With the bottleneck period of the development of new antibiotics, novel alternative agents are urgently in need. In this study, the small molecule amentoflavone is identified as a dual‐action inhibitor of Hla, a pore‐forming virulence determinant particularly important for S. aureus pathogenicity and Toll‐like receptor 2 (TLR2) signaling, which triggers inflammation response upon recognizing pathogen‐associated molecular patterns. Amentoflavone treatment conferred effective protection against S. aureus pneumonia through this dual‐action mechanism. Mechanically, amentoflavone effectively inhibited Hla pore formation, thereby reducing Hla‐mediated cytotoxicity and tissue damage; at the same time, amentoflavone suppressed TLR2‐mediated inflammatory response by blocking the interaction between TLR2 and its adapter myeloid differentiation primary response gene 88 (MyD88). Surprisingly, TLR2 signaling induced by synthetic bacterial TLR2 agonists and other heat‐killed gram‐positive bacteria is also blocked by amentoflavone. In summary, these results presented amentoflavone as a potential antibiotic alternative that curbed S. aureus infection by simultaneously suppressing host‐damaging virulence determinants derived from bacteria and the detrimental effect of excessive inflammation derived from the host rather than bacteria viability.

Fan Jiang

Papers

Antibody-Targeted Chemotherapy with the Calicheamicin Conjugate hu3S193-N-Acetyl γ Calicheamicin Dimethyl Hydrazide Targets Lewisy and Eliminates Lewisy-Positive Human Carcinoma Cells and Xenografts

Development of Highly Optimized Antibody-Drug Conjugates against CD33 and CD123 for Acute Myeloid Leukemia.

Developing a multiepitope vaccine for the prevention of SARS-CoV-2 and monkeypox virus co-infection: A reverse vaccinology analysis

A Dual‐Action Molecule Suppresses S. aureus Infection as an Inhibitor Targeting Hla Pore Formation and TLR2 Signaling