An Introduction to the Regulatory and Nonclinical Aspects of the Nonclinical Development of Antibody Drug Conjugates.

Antibody drug conjugates (ADCs) are promising therapies currently in development for oncology with unique and challenging regulatory and scientific considerations. While there are currently no regulatory guidelines specific for the nonclinical development of ADCs, there are harmonized international guidelines (e.g., ICHS6(R1), ICHM3(R2), ICHS9) that apply to ADCs and provide a framework for their complex development with issues that apply to both small and large molecules. The regulatory and scientific perspectives on ADCs are evolving due to both the advances in ADC technology and a better understanding of the safety and efficacy of ADCs in clinical development. This paper introduces the key scientific and regulatory aspects of the nonclinical development of ADCs, discusses important regulatory and scientific issues in the nonclinical to clinical dose translation of ADCs, and introduces new concepts in the areas of pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation.

Genetic diversity in Carthamus tinctorius (Asteraceae; safflower), an underutilized oilseed crop.

UNLABELLED: • PREMISE OF THE STUDY: Underutilized crops are potentially valuable resources for meeting increasing food demands. Safflower, an oilseed crop, is an example of one such underutilized crop that thrives in moisture-limited areas. Characterization of the genetic diversity maintained within the gene pools of underutilized crops such as safflower is an important step in their further development.• METHODS: A total of 190 safflower individuals, including 134 USDA accessions, 48 breeding lines from two private North American safflower breeding companies, and eight wild safflower individuals, were genotyped using 133 single nucleotide polymorphism (SNP) markers. We then used the resulting data to assess the amount and distribution of genetic diversity within and among these collections of safflower.• KEY RESULTS: Although just a modest reduction in gene diversity was observed in the commercial breeding lines (relative to the other safflower groupings), safflower domestication was accompanied by a significant decrease in allelic richness. Further, our results suggest that most safflower breeding lines originated from a single pool of diversity within the Old World safflower germplasm.• CONCLUSIONS: Taken together, our results suggest that both the safflower germplasm collection and related, wild species harbor previously undocumented genetic diversity that could help fuel future improvement efforts. Paired with analyses of functional diversity, the molecular resources described herein will be thus be useful in the continued development of safflower as an oilseed crop.

Ecological patterns and genetic analysis of post-dispersal seed predation in sunflower (Helianthus annuus) crop-wild hybrids.

Crop-wild hybridization has been documented in many cultivated species, but the ecological and genetic factors that influence the likelihood or rate that cultivar alleles will introgress into wild populations are poorly understood. Seed predation is one factor that could mitigate the spread of otherwise advantageous cultivar alleles into the wild by reducing seedling recruitment of crop-like individuals in hybrid populations. Seed predation has previously been linked to several seed characters that differ between cultivated and wild sunflower, such as seed size and oil content. In this study, seed morphological and nutritional characters were measured in a segregating population of sunflower crop-wild hybrids and wild and cultivated lines. Seed predation rates among lines were then assessed in the field. The relationship between seed predation and seed characters was investigated and quantitative trait loci (QTL) were mapped for all traits. There was no effect of seed type (hybrid vs. parents) on seed predation, although a trend toward more early predation of wild seeds was observed. Within the hybrids, seed predators preferred seeds that contained more oil and energy but were lower in fibre. The relationship between seed predation and oil content was supported by co-localized QTL for these traits on one linkage group. These results suggest that oil content may be a more important determinant of seed predation than seed size and provide molecular genetic evidence for this relationship. The cultivar allele was also found to increase predation at all QTL, indicating that post-dispersal seed predation may mitigate the spread of cultivar alleles into wild populations.

Extensive chromosomal repatterning and the evolution of sterility barriers in hybrid sunflower species.

New species may arise via hybridization and without a change in ploidy. This process, termed homoploid hybrid speciation, is theoretically difficult because it requires the development of reproductive barriers in sympatry or parapatry. Theory suggests that isolation may arise through rapid karyotypic evolution and/or ecological divergence of hybrid neospecies. Here, we investigate the role of karyotypic change in homoploid hybrid speciation by generating detailed genetic linkage maps for three hybrid sunflower species, Helianthus anomalus, H. deserticola, and H. paradoxus, and comparing these maps to those previously generated for the parental species, H. annuus and H. petiolaris. We also conduct a quantitative trait locus (QTL) analysis of pollen fertility in a BC2 population between the parental species and assess levels of pollen and seed fertility in all cross-combinations of the hybrid and parental species. The three hybrid species are massively divergent from their parental species in karyotype; gene order differences were observed for between 9 and 11 linkage groups (of 17 total), depending on the comparison. About one-third of the karyoypic differences arose through the sorting of chromosomal rearrangements that differentiate the parental species, but the remainder appear to have arisen de novo (six breakages/six fusions in H. anomalus, four breakages/three fusions in H. deserticola, and five breakages/five fusions in H. paradoxus). QTL analyses indicate that the karyotypic differences contribute to reproductive isolation. Nine of 11 pollen viability QTL occur on rearranged chromosomes and all but one map close to a rearrangement breakpoint. Finally, pollen and seed fertility estimates for F1's between the hybrid and parental species fall below 11%, which is sufficient for evolutionary independence of the hybrid neospecies.