Antibody-drug conjugates: the paradigm shifts in the targeted cancer therapy

Cancer is one of the deadliest diseases, causing million of deaths each year globally. Conventional anti-cancer therapies are non-targeted and have systemic toxicities limiting their versatile applications in many cancers. So, there is an unmet need for more specific therapeutic options that will be effective as well as free from toxicities. Antibody-drug conjugates (ADCs) are suitable alternatives with the right potential and improved therapeutic index for cancer therapy. The ADCs are highly precise new class of biopharmaceutical products that covalently linked a monoclonal antibody (mAb) (binds explicitly to a tumor-associated surface antigen) with a customized cytotoxic drug (kills cancer cells) and tied via a chemical linker (releases the drug). Due to its precise design, it brings about the target cell killing sparing the normal counterpart and free from the toxicities of conventional chemotherapy. It has never been so easy to develop potential ADCs for successful therapeutic usage. With relentless efforts, it took almost a century for scientists to advance the formula and design ADCs for its current clinical applications. Until now, several ADCs have passed successfully through preclinical and clinical trials and because of proven efficacy, a few are approved by the FDA to treat various cancer types. Even though ADCs posed some shortcomings like adverse effects and resistance at various stages of development, with continuous efforts most of these limitations are addressed and overcome to improve their efficacy. In this review, the basics of ADCs, physical and chemical properties, the evolution of design, limitations, and future potentials are discussed

Antibody-drug conjugates: the paradigm shifts in the targeted cancer therapy

Cancer is one of the deadliest diseases, causing million of deaths each year globally. Conventional anti-cancer therapies are non-targeted and have systemic toxicities limiting their versatile applications in many cancers. So, there is an unmet need for more specific therapeutic options that will be effective as well as free from toxicities. Antibody-drug conjugates (ADCs) are suitable alternatives with the right potential and improved therapeutic index for cancer therapy. The ADCs are highly precise new class of biopharmaceutical products that covalently linked a monoclonal antibody (mAb) (binds explicitly to a tumor-associated surface antigen) with a customized cytotoxic drug (kills cancer cells) and tied via a chemical linker (releases the drug). Due to its precise design, it brings about the target cell killing sparing the normal counterpart and free from the toxicities of conventional chemotherapy. It has never been so easy to develop potential ADCs for successful therapeutic usage. With relentless efforts, it took almost a century for scientists to advance the formula and design ADCs for its current clinical applications. Until now, several ADCs have passed successfully through preclinical and clinical trials and because of proven efficacy, a few are approved by the FDA to treat various cancer types. Even though ADCs posed some shortcomings like adverse effects and resistance at various stages of development, with continuous efforts most of these limitations are addressed and overcome to improve their efficacy. In this review, the basics of ADCs, physical and chemical properties, the evolution of design, limitations, and future potentials are discussed

Thermal plasticity in postembryonic life history traits of a widely distributed Collembola: Effects of macroclimate and microhabitat on genotypic differences

Life history traits in many ectotherms show complex patterns of variation among conspecific populations sampled along wide latitudinal or climatic gradients. However, few studies have assessed whether these patterns can be explained better by thermal reaction norms of multiple life history traits, covering major aspects of the life cycle. In this study, we compared five populations of a Holarctic, numerically dominant soil microarthropod species, Folsomia quadrioculata, sampled from a wide latitudinal gradient (56–81°N), for growth, development, fecundity, and survival across four temperatures (10, 15, 20, and 25°C) in common garden experiments. We evaluated the extent to which macroclimate could explain differences in thermal adaptation and life history strategies among populations. The common garden experiments revealed large genotypic differences among populations in all the traits, which were little explained by latitude and macroclimate. In addition, the life history strategies (traits combined) hardly revealed any systematic difference related to latitude and macroclimate. The overall performance of the northernmost population from the most stochastic microclimate and the southernmost population, which remains active throughout the year, was least sensitive to the temperature treatments. In contrast, performance of the population from the most predictable microclimate peaked within a narrow temperature range (around 15°C). Our findings revealed limited support for macroclimate‐based predictions, and indicated that local soil habitat conditions related to predictability and seasonality might have considerable influence on the evolution of life history strategies of F. quadrioculata. This study highlights the need to combine knowledge on microhabitat characteristics, and demography, with findings from common garden experiments, for identifying the key drivers of life history evolution across large spatial scales, and wide climate gradients. We believe that similar approaches may substantially improve the understanding of adaptation in many terrestrial ectotherms with low dispersal ability

Data from: Thermal plasticity in postembryonic life history traits of a widely distributed Collembola: Effects of macroclimate and microhabitat on genotypic differences

Life history traits in many ectotherms show complex patterns of variation among conspecific populations sampled along wide latitudinal or climatic gradients. However, few studies have assessed whether these patterns can be explained better by thermal reaction norms of multiple life history traits, covering major aspects of the life cycle. In this study, we compared five populations of a Holarctic, numerically dominant soil microarthropod species, Folsomia quadrioculata, sampled from a wide latitudinal gradient (56–81°N), for growth, development, fecundity, and survival across four temperatures (10, 15, 20, and 25°C) in common garden experiments. We evaluated the extent to which macroclimate could explain differences in thermal adaptation and life history strategies among populations. The common garden experiments revealed large genotypic differences among populations in all the traits, which were little explained by latitude and macroclimate. In addition, the life history strategies (traits combined) hardly revealed any systematic difference related to latitude and macroclimate. The overall performance of the northernmost population from the most stochastic microclimate and the southernmost population, which remains active throughout the year, was least sensitive to the temperature treatments. In contrast, performance of the population from the most predictable microclimate peaked within a narrow temperature range (around 15°C). Our findings revealed limited support for macroclimate-based predictions, and indicated that local soil habitat conditions related to predictability and seasonality might have considerable influence on the evolution of life history strategies of F. quadrioculata. This study highlights the need to combine knowledge on microhabitat characteristics, and demography, with findings from common garden experiments, for identifying the key drivers of life history evolution across large spatial scales, and wide climate gradients. We believe that similar approaches may substantially improve the understanding of adaptation in many terrestrial ectotherms with low dispersal ability

Life history traits

Life history trait

A Multiple Life-History Trait–Based and Time-Resolved Assessment of Imidacloprid Effects and Recovery in the Widely Distributed Collembolan Folsomia quadrioculata

Life-history traits determine individual fitness and the fate of populations. Imidacloprid, a widely used neonicotinoid insecticide, which persists in soil for more than 100 d at biologically relevant levels, may affect nontarget and ecologically important species, such as collembolans. In the present study, we determined the sublethal effects of short-term imidacloprid exposure and postexposure recovery in the collembolan Folsomia quadrioculata, which occurs abundantly across the northern hemisphere. We assessed survival, egg production, and hatching success in adult springtails exposed for 14 d through the diet to imidacloprid, followed by a 28-d postexposure phase. Survival and hatching success were high throughout the experiment in all the treatments, with no clear concentration dependence. However, egg production declined during the exposure phase and nearly stopped between 8 and 14 d in all the treatments (except the control) but resumed during the postexposure phase. Moreover, the resumption of egg production showed a concentration-dependent delay. Our findings suggest that low imidacloprid exposures can restrict reproduction, with potentially severe consequences for the population, notwithstanding the partial recovery in egg production

High sensitivity to dietary imidacloprid exposure in early life stages of Folsomia quadrioculata (Collembola) populations from contrasting climates

Survival of early life stages is critical for population growth. Understanding the vulnerability of these sensitive stages can therefore improve ecological risk predictions. The globally-used neonicotinoid insecticide imidacloprid does not degrade easily in soil and occurs at concentrations potentially toxic to non-target soil organisms, such as Collembola. Here, we studied the effects of dietary exposure to imidacloprid on the survival of juveniles in an arctic and a temperate population of Folsomia quadrioculata (Collembola), a commonly-occurring litter-dwelling species in the Northern Hemisphere. The exposure lasted from <24 h to 30 days since hatching at 15 °C. We assessed whether (1) the arctic population of the test species with faster development rates could be more vulnerable than the temperate population, (2) cumulative mortality could increase substantially with exposure time, and (3) the mortality risk experienced during the juvenile stage could be greater than that experienced by the adults. We found a strong concentration-dependent decline in survival in both populations, with small but significantly different LC50s, despite large differences in multiple life-history traits. Applying a General Unified Threshold model for Survival (GUTS) showed a low threshold for effects, slow damage dynamics, a 6–11-fold decrease in LC50 from 14 to 30 days of exposure, and saturation of damage at the three highest concentrations. In addition, exposure starting soon after hatching caused much more mortality than that starting in the adult stages. Our findings suggest that toxicity tests not emphasizing the neonate stages or not lasting long enough can underestimate the implications for populations of naturally abundant non-target organisms

Pesticide effects on the abundance of springtails and mites in field mesocosms at an agricultural site

The use of pesticides to protect crops often affects non-target organisms vital to ecosystem functioning. A functional soil mesofauna is important for decomposition and nutrient cycling processes in agricultural soils, which generally have low biodiversity. To assess pesticide effects on natural soil communities we enclosed intact soil cores in situ in an agricultural field in 5 cm wide mesocosms. We used two types of mesh lids on the mesocosms, allowing or preventing migration of mesofauna. The mesocosms were exposed to the insecticide imidacloprid (0, 0.1, 1, and 10 mg/kg dry soil) and left in the field for 20 days. Overall, regardless of lid type, mesocosm enclosure did not affect springtail or mite abundances during the experiment when compared with undisturbed soil. Imidacloprid exposure reduced the abundance of both surface- and soil-living springtails in a concentration-dependent manner, by 65–90% at the two highest concentrations, and 21–23% at 0.1 mg/kg, a concentration found in some agricultural soils after pesticide application. Surface-living springtails were more affected by imidacloprid exposure than soil-living ones. In contrast, neither predatory nor saprotrophic mites showed imidacloprid-dependent changes in abundance, concurring with previous findings indicating that mites are generally less sensitive to neonicotinoids than other soil organisms. The possibility to migrate did not affect the springtail or mite abundance responses to imidacloprid. We show that under realistic exposure concentrations in the field, soil arthropod community composition and abundance can be substantially altered in an organism-dependent manner, thus affecting the soil community diversity

Novel solid-phase strategy for the synthesis of ligand-targeted fluorescent-labelled chelating peptide conjugates as a theranostic tool for cancer

In this article, we have successfully designed and demonstrated a novel continuous process for assembling targeting ligands, peptidic spacers, fluorescent tags and a chelating core for the attachment of cytotoxic molecules, radiotracers, nanomaterials in a standard Fmoc solid-phase peptide synthesis in high yield and purity. The differentially protected Fmoc-Lys-(Tfa)-OH plays a vital role in attaching fluorescent tags while growing the peptide chain in an uninterrupted manner. The methodology is versatile for solid-phase resins that are sensitive to mild and strong acidic conditions when acid-sensitive side chain amino protecting groups such as Trt (chlorotrityl), Mtt (4-methyltrityl), Mmt (4-methoxytrityl) are employed to synthesise the ligand targeted fluorescent tagged bioconjugates. Using this methodology, DUPA rhodamine B conjugate (DUPA = 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid), targeting prostate specific membrane antigen (PSMA) expressed on prostate, breast, bladder and brain cancers and pteroate rhodamine B, targeting folate receptor positive cancers such as ovarian, lung, endometrium as well as inflammatory diseases have been synthesized. In vitro studies using LNCaP (PSMA +ve), PC-3 (PSMA −ve, FR −ve) and CHO-β (FR +ve) cell lines and their respective competition experiments demonstrate the specificity of the newly synthesized bioconstructs for future application in fluorescent guided intra-operative imaging