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Previous syntheses of palaeoclimate and archaeological data from the Kashmir Valley have proposed that climate changes drove prehistoric settlement of the valley, based on the adaptation of West Asian winter crops to mid-Holocene warm-humid conditions ca. 5000 BP. It has been argued that these conditions enabled population growth that became unsustainable following the onset of a cold-arid phase ca. 3000 BP, with these cycles of growth and collapse again repeating ca. 2000 and 1000 BP. Here we present multi-proxy palynomorph, charcoal and sediment data indicating that from ca. 4500-1500 BP the environment of the valley was characterised by drier conditions, comparable to other regional records indicating weakening Westerly precipitation over Central Asia. Considering recent archaeobotanical data indicating the presence of both West Asian winter crops and East Asian summer millets in the valley as early as 4500 BP, we argue that rather than Malthusian cycles of growth and collapse in Kashmir, early populations likely drew on a broad range of available domesticates and varied ecotopes across the valley to allow a Boserupian response to changing Holocene climate conditions. These adaptations were likely more oriented towards flexible systems of agro-pastoralism practiced throughout the Inner Asian mountains, rather than towards developing large urban settlements as was the case in the river basins and plains south of Kashmir.

A next generation multiscale quantitative systems pharmacology (QSP) model for antibody drug conjugates (ADCs) is presented, for preclinical to clinical translation of ADC efficacy. Two HER2 ADCs (trastuzumab-DM1 and trastuzumab-DXd) were used for model development, calibration, and validation. The model integrates drug specific experimental data including in vitro cellular disposition data, pharmacokinetic (PK) and tumor growth inhibition (TGI) data for T-DM1 and T-DXd, as well as system specific data such as properties of HER2, tumor growth rates, and volumes. The model incorporates mechanistic detail at the intracellular level, to account for different mechanisms of ADC processing and payload release. It describes the disposition of the ADC, antibody, and payload inside and outside of the tumor, including binding to off-tumor, on-target sinks. The resulting multiscale PK model predicts plasma and tumor concentrations of ADC and payload. Tumor payload concentrations predicted by the model were linked to a TGI model and used to describe responses following ADC administration to xenograft mice. The model was translated to humans and virtual clinical trial simulations were performed that successfully predicted progression free survival response for T-DM1 and T-DXd for the treatment of HER2+ metastatic breast cancer, including differential efficacy based upon HER2 expression status. In conclusion, the presented model is a step toward a platform QSP model and strategy for ADCs, integrating multiple types of data and knowledge to predict ADC efficacy. The model has potential application to facilitate ADC design, lead candidate selection, and clinical dosing schedule optimization.

The relationships between societal and environmental changes have long attracted strong interest amongst scientists. Each of these systems has their own internal dynamics such as the adaptability and social systems built by people; and the feedbacks and controls on environmental systems. North west Xinjiang presents a challenging topographic and climate setting for people. Yet existing evidence shows Bronze Age populations settled into the Bortala Valley as early as the third millennium BCE. The harshness of the region provides a test case for exploring how environmental changes and societal changes may have intertwined. Near the town of Wenquan there is an extensive wetland which contains a sedimentary record covering the last 10,400 years. The early to mid-Holocene is marked by desert and a lake at Wenquan, but there is little evidence for human activity. By 4500 cal year BP the climate became more humid and soon peak humidity occurred when a regional steppe was developed and small numbers of trees were present on the mountains, also the lake shallowed to become a marsh and peatland. The uplands saw a slight increase in tree cover after this, probably as a result of moisture increase due to some cooling. Later changes in the archaeological record seem to be independent of the timing of any environmental changes, and human impacts on the wetland were small until historical times. In short, the major change from desert to steppe may have enabled people to settle the region, but later changes in the environment were too small to be revealed in the Wenquan sediment data, with the adaptability of societies overcoming any environmental challenges and with land-use practices being too small or localized to impact the palaeoenvironmental record.

The nature of economies and the movement of agricultural crops across Eurasia in the Bronze Age have been the subject of significant research interest in recent years. This study presents and discusses new results of flotation, radiocarbon and carbon stable isotope analyses from the seed assemblage at the Adunqiaolu site (northwestern Xinjiang), in combination with archaeological evidence. Archaeobotanical evidence, including carbonized foxtail millet, broomcorn millet, and naked barley, documents the diversity of local cereal consumption during the mid-second millennium BC. Our results suggest that crops were not grown locally, however, but in the lower Boertala Valley, supporting the argument that Adunqiaolu was a winter camp. These new sets of data constitute an important contribution to the discussion on cereal dispersal across the Tianshan Mountains in the Bronze Age.

A semimechanistic pharmacokinetic (PK)/receptor occupancy (RO) model was constructed to differentiate a next generation anti‐NKG2A monoclonal antibody (KSQ mAb) from monalizumab, an immune checkpoint inhibitor in multiple clinical trials for the treatment of solid tumors. A three‐compartment model incorporating drug PK, biodistribution, and NKG2A receptor interactions was parameterized using monalizumab PK, in vitro affinity measurements for both monalizumab and KSQ mAb, and receptor burden estimates from the literature. Following calibration against monalizumab PK data in patients with rheumatoid arthritis, the model successfully predicted the published PK and RO observed in gynecological tumors and in patients with squamous cell carcinoma of the head and neck. Simulations predicted that the KSQ mAb requires a 10‐fold lower dose than monalizumab to achieve a similar RO over a 3‐week period following q3w intravenous (i.v.) infusion dosing. A global sensitivity analysis of the model indicated that the drug‐target binding affinity greatly affects the tumor RO and that an optimal affinity is needed to balance RO with enhanced drug clearance due to target mediated drug disposition. The model predicted that the KSQ mAb can be dosed over a less frequent regimen or at lower dose levels than the current monalizumab clinical dosing regimen of 10 mg/kg q2w. Either dosing strategy represents a competitive advantage over the current therapy. The results of this study demonstrate a key role for mechanistic modeling in identifying optimal drug parameters to inform and accelerate progression of mAb to clinical trials.

Bronze Age agro-pastoralist populations with economies and materials that are generally consistent with the Andronovo Culture—but with localised variations—are known throughout the mountains bordering the Eastern Eurasian Steppe. Recently, evidence for this tradition has also been found in north-west Xinjiang, China, although many questions remain about the production, use and significance of ceramics here. The authors’ analyses of a sample of pottery from sites across the Bortala Valley permit the reconstruction of the ceramic chaine operatoire and offer two distinct stories: one of cultural connectivity with regional networks of Eurasian pastoralists, and another about self-expression through small-scale local ceramic production.

The Valley of Kashmir in the western Himalayas holds a large number of Neolithic sites that are part of a loosely affiliated group of prehistoric cultures occupying mountains and valleys in the north of the Indian subcontinent – the Northern Neolithic. Despite extensive excavations at several sites in the 20th century, full reports on key sites are still lacking. As a result of this a number of issues have arisen, including a poorly resolved internal chronology based in part on relative dating of ceramics, as well as unclear or speculative links to neighbouring cultures. This study reports new absolute dates, botanical materials and ceramic analyses resulting from preliminary survey and testing work aimed at rectifying these problems. A thorough synthesis of previously reported excavation data is also provided, and considered alongside the newly reported material. This has allowed us to contextualise the development of the Neolithic in Kashmir against a growing number of recent studies on the spread of early dry-farming agricultural villages in the mountain zones of South Asia. The long term cultural and economic stability of the Northern Neolithic in Kashmir has allowed us to situate it as an important niche within a wider network of agriculturalist-pastoralist exchange taking place between the mountain zones and the settled areas of Inner Asia during the 3rd- 2nd millennia BCE.

This paper outlines current knowledge about the early Bronze Age in Xinjiang, discussing evidence for external influences and indigenous cultural development. It identifies three cultural clusters, Qiemu'erqieke, Tianshanbeilu (Linya) and Xiaohe, showing how the general origins of the first two can be broadly defined. For the third, Xiaohe, for which archaeological evidence of its origins is highly ambiguous, the paper offers a theoretical hypothesis based on Island Biogeography Theory.

We report here the discovery and optimization of a novel T cell retargeting anti-GUCY2C x anti-CD3ε bispecific antibody for the treatment of solid tumors. Using a combination of hybridoma, phage display and rational design protein engineering, we have developed a fully humanized and manufacturable CD3 bispecific antibody that demonstrates favorable pharmacokinetic properties and potent in vivo efficacy. Anti-GUCY2C and anti-CD3ε antibodies derived from mouse hybridomas were first humanized into well-behaved human variable region frameworks with full retention of binding and T-cell mediated cytotoxic activity. To address potential manufacturability concerns, multiple approaches were taken in parallel to optimize and de-risk the two antibody variable regions. These approaches included structure-guided rational mutagenesis and phage display-based optimization, focusing on improving stability, reducing polyreactivity and self-association potential, removing chemical liabilities and proteolytic cleavage sites, and de-risking immunogenicity. Employing rapid library construction methods as well as automated phage display and high-throughput protein production workflows enabled efficient generation of an optimized bispecific antibody with desirable manufacturability properties, high stability, and low nonspecific binding. Proteolytic cleavage and deamidation in complementarity-determining regions were also successfully addressed. Collectively, these improvements translated to a molecule with potent single-agent in vivo efficacy in a tumor cell line adoptive transfer model and a cynomolgus monkey pharmacokinetic profile (half-life>4.5 days) suitable for clinical development. Clinical evaluation of PF-07062119 is ongoing.

The mountainous areas of Inner Asia are now well established as a vector for the transmission of a number of crop plants between their centres of domestication in West and East Asia. Recent studies have indicated that agro-pastoralist populations in these mountains translocated wheat and barley to northwest China by as early as 5200 BP, while archaeobotanical and isotopic evidence from Kazakhstan indicates the use of East Asian millets by around 4500 BP. The Kashmir Valley in the western Himalayas is home to a Neolithic culture that developed possibly as early as 5000 BP, with stronger evidence for agriculture based on wheat and barley established by 4500 years ago. This brief report presents new evidence for directly dated West Asian wheat, barley and lentils as well as East Asian broomcorn millets, indicating their presence in the Kashmir Valley as early as 4400 BP. These new dates represent a significantly early movement and mixing both West and East Asian crops outside of their centres of domestication and have implications for early contacts between West, South, East and Central Asia.

Fire is an intrinsic aspect of Zoroastrian ritual and religious traditions. Akchakhan-kala can be conclusively linked with pre-Sasanian Zoroastrian practice through evidence from the recent discovery of murals depicting Avestan deities. Close similarities in apparently ritual features suggest that Tash-k’irman-tepe can also be linked to such traditions. Both sites also have a rich array of fire features which can be linked to respect for, and veneration of, fire in a variety of forms. This paper discusses these features, how they might fit into the wider picture of pre-Sasanian Zoroastrian development, and their significance for a deeper understanding of the history of Ancient Chorasmia.

This paper reports on the recent discovery in western Xinjiang of three Late Bronze Age walled sites located on high hilltops, with a fourth on a terrace above a river bed. The hilltop sites contain very small clusters of residential structures and overlook one of the richest areas of seasonal pasture in the upper Bortala Valley, in the western Tian Shan. The walls do not fully encircle the residential structures but protect the most vulnerable points of access to the hilltops, and in particular protect against direct access from the pastures. The discovery of these walled sites in the western Tian Shan is surprising and significant in terms of regional patterns of increased social complexity in the Eurasian Late Bronze Age. It is suggested that the walled hilltop sites were lookout posts, with a small garrison of herders prepared to defend the area in the event of attack by rival pastoralist groups, and that in the Late Bronze Age the Upper Bortala Valley was home to a number of pastoralist groups who contested access to the best pastures.

The reconstruction of fruit collection and cultivation based on plant remains plays an important role in understanding the subsistence strategies of ancient societies. Here, we report the identification of fossil charcoal from eight sites in the Hexi Corridor to give a clue to the early exploitation of fruit resources in the period 2300–400 bc. Charcoal assemblages show that millet farmers may have collected some tree fruits including bird cherry (Padus sp.), pear (Pyrus sp.) and whitebeam (Sorbus sp.) in the period 2300–2000 bc. From 2000 to 1500 bc there was continuing utilization of Padus sp., Sorbus sp. and cotoneaster (Cotoneaster sp.), at a time when cereal agriculture of wheat and barley had been introduced from outside. Based on analysis of ecological distribution, reproductive biology and the history of utilization, we infer that these fruits were gathered from the wild rather than cultivated. Later, the cultivation of non-native mulberry (Morus alba) began around 1500 bc in the context of an established high-yield wheat agriculture, probably indicating the earliest sign of horticulture in the Hexi Corridor. As with the beginning of agriculture, the horticulture is associated with cultivation of non-native species. In short, the variations in the presence of charred wood of fruit trees indicate that people might have collected wild fruits over a period of time, and that horticulture occurred much later than the spread of a variety of cereal and other crops in the Hexi Corridor.

Based on identification of fossil charcoals from 11 sites in the Hexi Corridor, we reconstruct the local vegetation community and human impact on it in the period from 4300 to 2400 cal. yr BP. More...

The economy of the Western Tianshan Mountains from prehistory to present has been almost exclusively focused on transhumant pastoralism. Settlement sites are located in a variety of different ecological zones, but the location does not always provide a clear indication of the original season of occupation. Other tools for identifying seasonality of occupation for prehistoric pastoral sites presently rely largely on analysis of faunal and botanical data which may produce ambiguous results. In this paper we correlate an ethnographic study based on data from local informants with a NDVI-based model on vegetation cycles to analyze why and how modern herders in the Western Tianshan select their range lands, and whether these patterns are applicable to Bronze Age land use in the same region. Micro-climates play an important role in the choice of optimal locations for any given season, and despite small climatic fluctuations the data strongly suggest that the seasonality of the Bronze Age sites in the Bortala (Bo'ertala) Valley can be correlated with modern land use. Thus pasture analysis applied to the location of prehistoric sites in the Tianshan can provide significant insights on seasonal use.

The east Jordan badia is a fascinating but difficult landscape, an attribute that has protected the record of its historic and prehistoric past to an extraordinary degree. It is rich in rock art, graves hunting traps, seasonal settlements and fortified sites that have remained almost undisturbed for thousands of years. Archaeological exploration of this region has also been slow, primarily due to the challenges of work in this rocky, semiarid region. However, the past few decades have seen a surge in new research that continues to uncover unexpected and remarkable aspects of the history of the badia. This article outlines the history of exploration and research in the badia and its historical significance.

Bronze Age social and cultural interconnections across the Eurasian steppe are the subject of much current debate. A particularly significant place is occupied by the Andronovo Culture or family of cultures. Important new data document the most easterly extension of Eurasian Bronze Age sites of Andronovo affinity into western China. Findings from the site of Adunqiaolu in Xinjiang and a new series of radiocarbon dates challenge existing models of eastward cultural dispersion, and demonstrate the need to reconsider the older chronologies and migration theories. The site is well preserved and offers robust potential for deeper study of the Andronovo culture complex, particularly in the eastern mountain regions.

A significant body of recent research shows that the first east–west transmission of cereal crops, Triticum spp. (wheat) and Hordeum spp. (barley) from the west and millets (Setaria italica, foxtail millet, and Panicum miliaceum, common millet) from the east, took place sometime around the start of the 5th millennium bp, with part of the most likely route lying along the Tianshan mountains in northern Xinjiang, China. Here the dominant economic adaptation is, and was in prehistory, not crop-based agriculture but transhumant pastoralism. The site of Luanzagangzi (ca. 3,300–2,900 cal bp) on the northern slope of the Tianshan is one of only a handful of Bronze Age sites in Xinjiang with evidence for well-established crop cultivation. In this paper, we report on ten samples collected for phytolith analysis from a 4 m deep profile at Luanzagangzi. The results show evidence that a range of cereal crops was being grown (multi-cropping), Triticum spp., Hordeum spp., Setaria italica and Panicum miliaceum. Pooideae, Paniceae woody plants, Phragmites (reed) and Cyperaceae (sedges) were presumably also exploited for subsistence purposes in this area. We speculate that the strategy of growing a range of crops, wheat/barley, common millet and foxtail millet was adopted by the Bronze Age population in this region as a supplement to herding. The findings of this study help us to understand the dispersal of cultivation strategies across the Eurasian steppe via the Xinjiang region, and the communication between China and the West in the late Bronze Age.

This research presents age class and gender ratio for 13 horses from burial 15 of the Kalasu cemetery in Habahe County, Aletai Region, Xinjiang, western China. Through the identification of horse age and gender and examination of abnormalities revealed on teeth, vertebrae, and limb bones, the authors analyzed possible strategies practiced by prehistoric society for the selection of horses for burials and also confirmed the evidence of horseback riding shown on skeletal morphologies. By zooarchaeological research at the first time in this area, this research provides important evidence for horse exploitation strategies of nomads in the early Iron Age in northern Xinjiang, China.

This paper presents compositional results for six faience beads from Adunqiaolu, an Early Bronze Age site in western Xinjiang, China. It is shown that all analysed samples were made of mixed-alkali flux with sodium oxide 8–10% and potassium oxide 5–9%. The microstructure of samples indicates that cementation glazing was used. The analytical results, together with the typology of the faience beads were then compared with data of Bronze Age faience beads found in Europe and East Asia. There are clear similarities in both typological and technological features. As the earliest faience objects discovered in China so far, the Adunqiaolu beads set an essential starting point for the further discussion on the early exchange network evidenced by faience products and long distance transmission of technologies and knowledge. This observation is of significance for deepening our understanding of prehistoric exchange between West and East across the Eurasian continent by providing another element in addition to metallurgy, cereal crops and herding animals.

A modeling and simulation approach was used for quantitative comparison of a new generation HER2 antibody drug conjugate (ADC, PF-06804103) with trastuzumab-DM1 (T-DM1). To compare preclinical efficacy, the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of PF-06804103 and T-DM1 was determined across a range of mouse tumor xenograft models, using a tumor growth inhibition model. The tumor static concentration was assigned as the minimal efficacious concentration. PF-06804103 was concluded to be more potent than T-DM1 across cell lines studied. TSCs ranged from 1.0 to 9.8 µg/mL (n = 7) for PF-06804103 and from 4.7 to 29 µg/mL (n = 5) for T-DM1. Two experimental models which were resistant to T-DM1, responded to PF-06804103 treatment. A mechanism-based target mediated drug disposition (TMDD) model was used to predict the human PK of PF-06804103. This model was constructed and validated based on T-DM1 which has non-linear PK at doses administered in the clinic, driven by binding to shed HER2. Non-linear PK is predicted for PF-06804103 in the clinic and is dependent upon circulating HER2 extracellular domain (ECD) concentrations. The models were translated to human and suggested greater efficacy for PF-06804103 compared to T-DM1. In conclusion, a fit-for-purpose translational PK/PD strategy for ADCs is presented and used to compare a new generation HER2 ADC with T-DM1. Electronic supplementary material The online version of this article (10.1007/s10928-020-09702-3) contains supplementary material, which is available to authorized users.

CD3 bispecific antibody constructs recruit cytolytic T cells to kill tumor cells, offering a potent approach to treat cancer. T cell activation is driven by the formation of a trimolecular complex (trimer) between drugs, T cells, and tumor cells, mimicking an immune synapse. A translational quantitative systems pharmacology (QSP) model is proposed for CD3 bispecific molecules capable of predicting trimer concentration and linking it to tumor cell killing. The model was used to quantify the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of a CD3 bispecific targeting P-cadherin (PF-06671008). It describes the disposition of PF-06671008 in the central compartment and tumor in mouse xenograft models, including binding to target and T cells in the tumor to form the trimer. The model incorporates T cell distribution to the tumor, proliferation, and contraction. PK/PD parameters were estimated for PF-06671008 and a tumor stasis concentration (TSC) was calculated as an estimate of minimum efficacious trimer concentration. TSC values ranged from 0.0092 to 0.064 pM across mouse tumor models. The model was translated to the clinic and used to predict the disposition of PF-06671008 in patients, including the impact of binding to soluble P-cadherin. The predicted terminal half-life of PF-06671008 in the clinic was approximately 1 day, and P-cadherin expression and number of T cells in the tumor were shown to be sensitive parameters impacting clinical efficacy. A translational QSP model is presented for CD3 bispecific molecules, which integrates in silico, in vitro and in vivo data in a mechanistic framework, to quantify and predict efficacy across species. Electronic supplementary material The online version of this article (10.1208/s12248-019-0332-z) contains supplementary material, which is available to authorized users.

Palaeobotanical studies at Qasim Bagh, a site of the Northern Neolithic culture in the Kashmir Valley, India, have produced important new data on the spread of agriculture across Inner Asia, and on the cross-transmission of Chinese and West Asian cultivars. Directly dated broomcorn millet (Panicum miliaceum) and compact wheat (Triticum aestivum), and a series of charcoal dates suggest that the Valley of Kashmir was integrated into a wider network of crop exchange in the mountainous regions of South and Central Asia from at least the 5th/4th millennium BP transition. The evidence of Qasim Bagh supplements recent data from other Central Asian sites which suggest that exchange of East and West Asian cultivars took place earlier than previously believed.

In a recent special issue of The Holocene, Miller et al. review the evidence for the spread of millet ( Panicum miliaceum and Setaria italica) across Eurasia. Among their arguments, they contend that millet cultivation came to Eurasian regions with hot, dry summers when irrigation was introduced, as part of a region-wide shift toward agricultural intensification in the first millennium BC. This hypothesis seems to align with the pattern of agricultural change observed in the Khorezm oasis, a Central Asian polity of the first millennium BC and first millennium AD. While we wholeheartedly accept this hypothesis for its explanatory value regarding trends across Eurasia, in this paper we nevertheless suggest that the introduction of millet to Central Asia needs further explication. Specifically, we seek to address the underlying assumption that this introduction was predicated upon centrally organized, state-level land development, increased sedentism, and the rise of Mesopotamian-style social complexity. We describe how millet cultivation in Khorezm was preceded by multi-resource strategies that included the cultivation of summer crops, and emphasize that this earlier history mattered significantly to the evolution of Khorezmian society and agriculture in the first millennium BC. In contrast to the imperial systems of West Asia, in Khorezm the introduction of complex irrigation works supported the expansion and greater stratification of pre-existing agropastoral lifeways, and helped to buttress the rise of nomadic elites within an agrarian zone. We believe the example of Khorezm is important because it helps to explain the emergence of integrated mobile-sedentist societies in the first millennium AD in Central Asia as a result of agricultural change. It also provides cultural and historical context to the spread of millet cultivation in the first millennium BC, suggesting that this phenomenon had significantly different implications for societies across Eurasia.

A mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model was used for preclinical to clinical translation of inotuzumab ozogamicin, a CD22-targeting antibody-drug conjugate (ADC) for B cell malignancies including non-Hodgkin's lymphoma (NHL) and acute lymphocytic leukemia (ALL). Preclinical data was integrated in a PK/PD model which included (1) a plasma PK model characterizing disposition and clearance of inotuzumab ozogamicin and its released payload N-Ac-γ-calicheamicin DMH, (2) a tumor disposition model describing ADC diffusion into the tumor extracellular environment, (3) a cellular model describing inotuzumab ozogamicin binding to CD22, internalization, intracellular N-Ac-γ-calicheamicin DMH release, binding to DNA, or efflux from the tumor cell, and (4) tumor growth and inhibition in mouse xenograft models. The preclinical model was translated to the clinic by incorporating human PK for inotuzumab ozogamicin and clinically relevant tumor volumes, tumor growth rates, and values for CD22 expression in the relevant patient populations. The resulting stochastic models predicted progression-free survival (PFS) rates for inotuzumab ozogamicin in patients comparable to the observed clinical results. The model suggested that a fractionated dosing regimen is superior to a conventional dosing regimen for ALL but not for NHL. Simulations indicated that tumor growth is a highly sensitive parameter and predictive of successful outcome. Inotuzumab ozogamicin PK and N-Ac-γ-calicheamicin DMH efflux are also sensitive parameters and would be considered more useful predictors of outcome than CD22 receptor expression. In summary, a multiscale, mechanism-based model has been developed for inotuzumab ozogamicin, which can integrate preclinical biomeasures and PK/PD data to predict clinical response.

Purpose: T cell-engaging bispecific molecules (TCEs) are protein therapeutics that can bind to both T cells, via CD3 interactions, and target cells through target specific/overexpressed molecules. The TCEs bring cytolytic T cells to kill tumor cells through the formation of the trimolecular complex (CD3:TCE:Target). While it offers a potentially very potent approach to treat cancer, it also has a complex relationship between binding potency, exposure, and efficacy. These complex relationships bring challenges to drug discovery and development such as identifying optimal Kds for the drug candidate, predicting efficacious dose, and selecting dosing regimen in clinical study. Methods: A quantitative systems pharmacology model was developed for solitomab, a bispecific T-cell engager binding to CD3 and EpCAM. The model includes solitomab binding to both CD3 and EpCAM in both tumor and normal tissue, different E:T ratios for tumor and normal tissue, turnover of CD3 and EpCAM proteins, as well as pharmacokinetics (PK) and tissue distribution of the drug. Literature data such as binding Kds, in vitro cell killing, and PK were used to inform model development. Results: Using the calibrated QSP model, we demonstrated that the trimolecular complex per T cells required for in vitro T-cell killing are ~200 molecules, which is similar to the number predicted at the maximal tolerated dose observed in the clinical study despite many differences between in vivo and in vitro conditions such as E:T ratios. The therapeutic index (TI) for solitomab was predicted to be close to 1 based on the trimolecular complex per T cells in tumor and in normal tissue. This result is consistent with clinical observation. Using the developed model, we explored the effects of varying binding Kds to EpCAM and CD3, varying half-life of the drug, and varying target expression levels on TI. Conclusion: Current work demonstrated the possibility of using a QSP model integrating in vitro data, human PK, and target biology to predict efficacious dose and TI for treating cancer. The model also demonstrated the complex relationship between Kds, target expression level, drug half-life, and TI for TCEs. This model can be used to guide future drug candidate selection and clinical study design. Citation Format: Lin Lin, Lucia Wille, Alison Betts, Fei Hua, David Hagen, Jennifer Park, Josh Apgar, John Burke. Bridging nonclinical studies to clinical design using quantitative systems pharmacology model of T cell-engaging bispecifics [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A70.

The linear pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs) can be considered a class property with values that are similar to endogenous IgG. Knowledge of these parameters across species could be used to avoid unnecessary in vivo PK studies and to enable early PK predictions and pharmacokinetic/pharmacodynamic (PK/PD) simulations. In this work, population-pharmacokinetic (popPK) modeling was used to determine a single set of 'typical' popPK parameters describing the linear PK of mAbs in human, cynomolgus monkey and transgenic mice expressing the human neonatal Fc receptor (hFcRn Tg32), using a rich dataset of 27 mAbs. Non-linear PK was excluded from the datasets and a 2-compartment model was applied to describe mAb disposition. Typical human popPK estimates compared well with data from comparator mAbs with linear PK in the clinic. Outliers with higher than typical clearance were found to have non-specific interactions in an affinity-capture self-interaction nanoparticle spectroscopy assay, offering a potential tool to screen out these mAbs at an early stage. Translational strategies were investigated for prediction of human linear PK of mAbs, including use of typical human popPK parameters and allometric exponents from cynomolgus monkey and Tg32 mouse. Each method gave good prediction of human PK with parameters predicted within 2-fold. These strategies offer alternative options to the use of cynomolgus monkeys for human PK predictions of linear mAbs, based on in silico methods (typical human popPK parameters) or using a rodent species (Tg32 mouse), and call into question the value of completing extensive in vivo preclinical PK to inform linear mAb PK.

Excavations at Akchakhan-kala in Uzbekistan, a region known in antiquity as Chorasmia, recovered a large, elaborately carved and heavily burned cylinder of some very solid material. Its poor condition made identification of the raw material difficult. Here we used neutron tomography to examine the internal structure in a non-destructive way, and X-ray Diffraction to determine the main chemical composition of the material which confirmed it as ivory. This was followed by preparation for stable isotope and radiocarbon analysis. The stable isotope analysis suggests a tropical or subtropical grassland source for the ivory, which is unlikely to be from Uzbekistan. The dating shows the ivory to be much earlier than the context in which it was found. Whatever its origin, the ivory travelled far to reach Chorasmia, perhaps in its raw state, and perhaps also for some time in its carved form.