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In addition to producing conventional tetrameric IgGs, camelids have the particularity of producing a functional homodimeric IgG type lacking L (light) chains and only made up of two H (heavy) chains. This nonconventional IgG type is characterized by variable and constant regions referred to as VHH and CHH, respectively, and which differ from conventional VH and CH counterparts. Although the structural properties of homodimeric IgGs have been well investigated, the genetic bases involved in their generation are still largely unknown. In this study, we characterized the organization of genes coding for the H chains of tetrameric and homodimeric IgGs by constructing an alpaca (Lama pacos) genomic cosmid library. We showed that a single IgH locus in alpaca chromosome 4 contains all of the genetic elements required for the generation of the two types of Igs. The alpaca IgH locus is composed of a V region that contains both VHH and VH genes followed by a unique DH-JH cluster and C region genes, which include both CHH and CH genes. Although this general gene organization greatly resembles that of other typical mammalian Vn-Dn-Jn-Cn translocon IgH loci, the intermixed gene organization within the alpaca V and C regions reveals a new type of translocon IgH locus. Furthermore, analyses of cDNA coding for the membrane forms of IgG and IgM present in alpaca peripheral blood B cells are most consistent with the notion that the development of a B cell bearing homodimeric IgG passes through an IgM+ stage, similar to the case for conventional IgG.

The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate with significant immune-related adverse events suboptimally limiting the doses of anti-CTLA4 mAb that can be used. MEDI5752 is a monovalent bispecific antibody designed to suppress the PD-1 pathway and provide modulated CTLA4 inhibition favoring enhanced blockade on PD-1+ activated T cells. We show that MEDI5752 preferentially saturates CTLA4 on PD-1+ T cells versus PD-1− T cells, reducing the dose required to elicit IL2 secretion. Unlike conventional PD-1/CTLA4 mAbs, MEDI5752 leads to the rapid internalization and degradation of PD-1. Moreover, we show that MEDI5752 preferentially localizes and accumulates in tumors providing enhanced activity when compared with a combination of mAbs targeting PD-1 and CTLA4 in vivo. Following treatment with MEDI5752, robust partial responses were observed in two patients with advanced solid tumors. MEDI5752 represents a novel immunotherapy engineered to preferentially inhibit CTLA4 on PD-1+ T cells. Significance: The unique characteristics of MEDI5752 represent a novel immunotherapy engineered to direct CTLA4 inhibition to PD-1+ T cells with the potential for differentiated activity when compared with current conventional mAb combination strategies targeting PD-1 and CTLA4. This molecule therefore represents a step forward in the rational design of cancer immunotherapy. See related commentary by Burton and Tawbi, p. 1008. This article is highlighted in the In This Issue feature, p. 995

ObjectiveApplying the science of networks to quantify the discriminatory impact of the ICD-9-CM to ICD-10-CM transition between clinical specialties.Materials and MethodsDatasets were the Center for Medicaid and Medicare Services ICD-9-CM to ICD-10-CM mapping files, general equivalence mappings, and statewide Medicaid emergency department billing. Diagnoses were represented as nodes and their mappings as directional relationships. The complex network was synthesized as an aggregate of simpler motifs and tabulation per clinical specialty.ResultsWe identified five mapping motif categories: identity, class-to-subclass, subclass-to-class, convoluted, and no mapping. Convoluted mappings indicate that multiple ICD-9-CM and ICD-10-CM codes share complex, entangled, and non-reciprocal mappings. The proportions of convoluted diagnoses mappings (36% overall) range from 5% (hematology) to 60% (obstetrics and injuries). In a case study of 24 008 patient visits in 217 emergency departments, 27% of the costs are associated with convoluted diagnoses, with ‘abdominal pain’ and ‘gastroenteritis’ accounting for approximately 3.5%.DiscussionPrevious qualitative studies report that administrators and clinicians are likely to be challenged in understanding and managing their practice because of the ICD-10-CM transition. We substantiate the complexity of this transition with a thorough quantitative summary per clinical specialty, a case study, and the tools to apply this methodology easily to any clinical practice in the form of a web portal and analytic tables.ConclusionsPost-transition, successful management of frequent diseases with convoluted mapping network patterns is critical. The http://lussierlab.org/transition-to-ICD10CM web portal provides insight in linking onerous diseases to the ICD-10 transition.