Bringing the Heavy Chain to Light: Creating a Symmetric, Bivalent IgG-Like Bispecific.

Bispecific molecules are biologically significant, yet their complex structures pose important manufacturing and pharmacokinetic challenges. Nevertheless, owing to similarities with monoclonal antibodies (mAbs), IgG-like bispecifics conceptually align well with conventional expression and manufacturing platforms and often exhibit potentially favorable drug metabolism and pharmacokinetic (DMPK) properties. However, IgG-like bispecifics do not possess target bivalency and current designs often require tedious engineering and purification to ensure appropriate chain pairing. Here, we present a near-native IgG antibody format, the 2xVH, which can create bivalency for each target or epitope and requires no engineering for cognate chain pairing. In this modality, two different variable heavy (VH) domains with distinct binding specificities are grafted onto the first constant heavy (CH1) and constant light (CL) domains, conferring the molecule with dual specificity. To determine the versatility of this format, we characterized the expression, binding, and stability of several previously identified soluble human VH domains. By grafting these domains onto an IgG scaffold, we generated several prototype 2xVH IgG and Fab molecules that display similar properties to mAbs. These molecules avoided the post-expression purification necessary for engineered bispecifics while maintaining a capacity for simultaneous dual binding. Hence, the 2xVH format represents a bivalent, bispecific design that addresses limitations of manufacturing IgG-like bispecifics while promoting biologically-relevant dual target engagement.

Impact of oral vitamin E supplementation on oxidative stress & lipid peroxidation in patients with polymorphous light eruption.

BACKGROUND & OBJECTIVES: Polymorphous light eruption (PMLE) is a photo-induced disease which clinically manifests in the form of pruritic eruptions on sun/light exposed parts. Little is known about lipid peroxidation and free radical scavengers in patients during PMLE. The present study was therefore undertaken to evaluate oxidative stress and levels of antioxidant enzymes in patients of PMLE. METHODS: The PMLE was diagnosed clinically by a consultant dermatologist and validated independently by another and through histopathologic findings. Blood samples were collected on day 1 and patients were given oral vitamin E supplementation (400 mg OD) along with topical sunscreen and advice for photo-protection. Samples were collected again after one week. The blood samples were evaluated for lipid peroxidation, oxygen free radical (OFR) scavenging enzymes, glutathione (GSH) and related enzymes such as glutathione reductase (GR), glutathione peroxidase (GPx), gamma glutamyl transpeptidase (GGT) and glutathione- S-transferase (GST) in erythrocytes and compared with healthy controls. RESULTS: The serum malondialdehyde (MDA) level was higher and GSH level was lower in PMLE cases as compared to controls. There was a significant decrease in superoxide dismutase (SOD) activity while activities of catalase (CAT) and glutathione related enzymes were increased in PMLE cases. Administration of oral vitamin E for one week, along with photoprotection resulted in a significant decrease in MDA levels and activities of all others enzymes except SOD. The GSH was replenished and returned to normal. INTERPRETATION & CONCLUSION: Oxidative stress and differential modulation of antioxidant enzymes in PMLE might play a pathogenic role in humans, which supports the incorporation of antioxidant drugs in the treatment protocol of the disease.

Cytology of testicular changes in leprosy.

OBJECTIVE: To study the changes in testicular aspirates and semen of patients with leprosy. STUDY DESIGN: A prospective study of 56 patients in the reproductive-age group, with no record of treatment for leprosy. Both Ridley-Jopling and WHO classification systems were used. Skin and/or nerve biopsies were performed for documentation of the diagnosis. Semen analysis and fine needle aspirates of the testes were performed. Smears from the testicular aspirates were stained with May-Grünwald-Giemsa and Ziehl-Neelsen stain. RESULTS: Five patients were unable to produce an ejaculate. Abnormal semen analysis and/or testicular aspirates were seen in 24 (42.8%) patients. Eleven had oligospermia and eight azoospermia. Abnormalities in testicular aspirates ranged from hypospermatogenesis (4) through maturation arrest (1) and atrophy (11). Two patients had hydrocoele, and two had associated microfilariae. Three patients with multibacillary leprosy had type 2 reaction. Mycobacterium lepre was demonstrable in testicular aspirates from all patients with multibacillary and in three with paucibacillary leprosy. CONCLUSION: Abnormal semen analysis and/or testicular aspirates occur in a very high percentage of patients with leprosy. While this is expected for multibacillary disease, the high incidence in the paucibacillary form was surprising. With the rapid elimination of leprosy, fertility-related disability might emerge as a major problem in these people.