Considerations for the Design of Antibody-Based Therapeutics

Abstract

Keywords: antibody(s) antibody drug(s) antibody drug conjugate(s) (ADC) physicochemical properties pharmacokinetics monoclonal antibody(s) immunotherapy IgG antibody(s) drug design developability a b s t r a c t Antibody-based proteins have become an important class of biologic therapeutics, due in large part to the stability, specificity, and adaptability of the antibody framework. Indeed, antibodies not only have the inherent ability to bind both antigens and endogenous immune receptors but also have proven extremely amenable to protein engineering. Thus, several derivatives of the monoclonal antibody format, including bispecific antibodies, antibody-drug conjugates, and antibody fragments, have demonstrated efficacy for treating human disease, particularly in the fields of immunology and oncology. Reviewed here are considerations for the design of antibody-based therapeutics, including immunological context, therapeutic mechanisms, and engineering strategies. First, characteristics of antibodies are introduced, with emphasis on structural domains, functionally important receptors, isotypic and allotypic differences, and modifications such as glycosylation. Then, aspects of therapeutic antibody design are discussed, including identification of antigen-specific variable regions, choice of expression system, use of multispecific formats, and design of antibody derivatives based on fragmentation, oligomerization, or conjugation to other functional moieties. Finally, strategies to enhance antibody function through protein engineering are reviewed while highlighting the impact of fundamental biophysical properties on protein developability.

A rapid, sensitive, and reproducible in vivo PBMC humanized murine model for determining therapeutic‐related cytokine release syndrome

“…The advent of antibody-based immune therapies has revolutionized the treatment of several human disease states. 34,35 Over the past decade, a primary application of these immunotherapies has been the treatment of malignancies by targeting immune checkpoint molecules. 36 While antibody-based therapeutics are enjoying an unprecedented level of success in the clinic by targeting cells of the immune system, a number of clinical trials have reported adverse reactions, including CRS.…”

Predicting Antibody Developability Profiles Through Early Stage Discovery Screening

“…For the determination of self-interaction, the diffusion interaction parameter (kD) was determined by DLS. Highconcentration samples were diluted with the buffers of interest (20 mM sodium acetate pH 5.5 and 10 mM histidine hydrogen chloride pH 6.5) to obtain a concentration of 20 mg/mL, filtered through 0.22 µm filters, and diluted in filtered buffers (with desired pH and ionic strength) to obtain lower concentration samples (2,5,10,15, and 20 mg/mL), which were then added to the microplate. The kD was determined by a linear fit of the measured (mutual) diffusion coefficients as a function of concentration.…”

“…It is anticipated that mAbs will remain an important part of human health improvement for years to come. 2 Approximately nine out of every 10 drug candidates fail to win approval, i.e.,, 90% of drug candidates will fail during clinical development; possibly over 99% if preclinical stages of development are also included. 3 This failure rate has huge implications for the overall cost of drug development.…”

Designing Feature-Controlled Humanoid Antibody Discovery Libraries Using Generative Adversarial Networks

“…Antibodies are an important class of biologics-based therapeutics with clear advantages of specificity and efficacy. 1,2,3 The high cost and long development times, however, present key challenges in the accessibility of monoclonal antibody therapeutics. 4,5 To quickly respond to known and new pathogens and disease, and to provide affordable, high quality treatment to patients around the globe, a molecule must be designed for activity; but it must also be made developable and safe for patients.…”