Abstract
Monoclonal antibodies (mAbs) for therapeutic applications should be as similar to native human antibodies as possible to minimize their immunogenicity in patients. Several transgenic animal platforms are available for the generation of fully human mAbs. Attributes such as specificity, efficacy and Chemistry, Manufacturing and Controls (CMC) developability of antibodies against a specific target are typically established for antibodies obtained from one platform only. In this study, monoclonal antibodies (mAbs) cross-reactive against human and cynomolgus LAMP1 were derived from the human immunoglobulin transgenic TRIANNI mouse and OmniChicken® platforms and assessed for their specificity, sequence diversity, ability to bind to and internalize into tumor cells, expected immunogenicity and CMC developability. Our results show that the two platforms were complementary at providing a large diversity of mAbs with respect to epitope coverage and antibody sequence diversity. Furthermore, most antibodies originating from either platform exhibited good manufacturability characteristics.
Highlights
Lysosome-associated membrane protein 1 (LAMP1) is a type I transmembrane protein composed of a large highly glycosylated luminal domain with 18 potential N-glycosylation sites and 6 O-linked oligosaccharides, a transmembrane domain, and a small cytoplasmic tail [1]
Antibodies generated in each platform were screened for their binding to recombinant human and cynomolgus LAMP1 and 37 Monoclonal antibodies (mAbs) were assessed head-to-head for their reactivity with human and cynomolgus LAMP1 on different supports, their propensity to be internalized into LAMP1-expressing cells, and their human germinality
OmniChickens were immunized with the extracellular domain of LAMP1 produced in HEK293 cells and single B cells from spleens were screened with the Gel Encapsulated Microenvironment (GEM) assay [14] using beads coated with either human or cynomolgus LAMP1 protein
Summary
Lysosome-associated membrane protein 1 (LAMP1) is a type I transmembrane protein composed of a large highly glycosylated luminal domain with 18 potential N-glycosylation sites and 6 O-linked oligosaccharides, a transmembrane domain, and a small cytoplasmic tail [1]. Developability is a key aspect of mAb therapeutics as their development entails challenges associated with CMC development such as aggregation, viscosity, susceptibility to chemical degradation and insufficient product stability Such development risks are often associated with the intrinsic properties of the antibody candidates [15] and may vary depending on the transgenic platform used to generate the mAbs. Here we report a comparative study of anti-LAMP1 mAbs generated in human immunoglobulin transgenic mouse (TRIANNI [16]) and chicken (OmniChicken1 [14]) platforms. Antibodies generated in each platform were screened for their binding to recombinant human and cynomolgus LAMP1 and 37 mAbs were assessed head-to-head for their reactivity with human and cynomolgus LAMP1 on different supports, their propensity to be internalized into LAMP1-expressing cells, and their human germinality. Comparison of two transgenic animal platforms for human therapeutic antibody discovery characteristics, 15 mAbs were further evaluated for their manufacturability and stability in a developability study
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