Trends in industrialization of biotherapeutics: a survey of product characteristics of 89 antibody-based biotherapeutics

Abstract

There is considerable interest in the pharmaceutical industry toward development of antibody-based biotherapeutics because they can selectively bind diverse receptors and often possess desirable pharmacology. Here, we studied product characteristics of 89 marketed antibody-based biotherapeutics that were approved from 1986 to mid-2020 by gathering publicly available information. Our analyses revealed major trends in their emergence as the best-selling class of pharmaceuticals. Early on, most therapeutic monoclonal antibodies were developed to treat cancer, with CD20 being the most common target. Thanks to industrialization of antibody manufacturing technologies, their use has now blossomed to include 15 different therapeutic areas and nearly 60 targets, and the field is still growing! Drug manufacturers are solidifying their choices regarding types of antibodies and their molecular formats. IgG1 kappa continues to be the most common molecular format among marketed antibody-based biotherapeutics. Most antibody-based biotherapeutics approved since 2015 are either humanized or fully human, but the data we collected do not show a direct correlation between humanness and reported incidence of anti-drug antibodies. Furthermore, there have also been improvements in terms of drug product stability and high concentration liquid formulations suitable for subcutaneous route of administration, which are being approved more often in recent years. These improvements, however, have not been uniformly adopted across all therapeutic areas, suggesting that multiple options for drug product development are being used to serve diverse therapeutic purposes. Insights gained from this analysis may help us devise better end-to-end antibody-based biotherapeutic drug discovery and development strategies.

Keywords: Antibody; biotherapeutics; developability; drug; formulation; pharmacology.

Figure 1.

(a) Marketed antibody-based biotherapeutics by year. By June 2022, 111 antibody-based biotherapeutic drug products have been approved by the FDA (shown in orange) and 106 have been approved by the EC (shown in green). 19 total antibody-based biotherapeutic drugs have been approved by India (3), Cuba (2), Russia (4), China (9), and Japan (1), but not by the FDA or EC (shown in gray). The total number of unique marketed antibody-based biotherapeutics as of June 2022 is 136 shown in blue with right y-axis showing growth over time. (b) Molecular formats of marketed antibody-based biotherapeutics. Gray regions represent constant regions. Green regions are variable regions. Red regions are a second variable region in the bispecific therapeutics. The purple circles are examples of where a small molecule drug could attach to an antibody and form antibody-drug conjugates (ADCs).

Figure 2.

(a) Light chain isotypes of marketed antibody-based biotherapeutics over time. Kappa isotypes are much more common than lambda isotypes. (b) Heavy chain isotypes of marketed antibody-based biotherapeutics over time. IgG1 is the most common heavy isotype, while IgG2 and IgG4 are equally common. (c) Types of marketed antibody-based biotherapeutics over time. Murine and chimeric were common early on, but nearly all approved marketed antibody-based biotherapeutics are now either human or humanized. (d) Heavy chain variable region (V_H) percent humanness over time. V_H humanness is commonly between 70 and 90%. (e) Light chain variable region (V_L) percent humanness over time. V_L humanness is commonly between 80 and 90%. (f) Reported percent anti-drug antibodies (% ADAs) over time. In recent years it is much more common to see a reported % ADAs below 5%. (g) Comparison of % Humanness and % ADAs. There is no statistically significant correlation between % Humanness and % ADAs reported for the marketed antibody-based biotherapeutics. (h) % ADAs by antibody type. In general, % ADAs decrease from murine to human, however a direct comparison of % ADAs across the products should be interpreted with caution (see results).

Figure 3.

Product information. (a) Product presentation of marketed antibody-based biotherapeutics over time. Current trends show a preference of lyophilized and pre-filled syringe or pen over vial. (b) Route of administration of marketed antibody-based biotherapeutics over time. Intravenous is the most used route of administration, but recently, subcutaneous has seen a similar number of approvals as intravenous. Other routes of administration are intradermal, intramuscular, and intravitreal. (c) Regular maintenance dose frequency for marketed antibody-based biotherapeutics over time. QW stands for once weekly, Q2W stands for once every two weeks, and so on. There are 79 regular dosing regiments. In general, Q2W and Q4W are the most used maintenance dosing regimens.

Figure 4.

Pharmacokinetic (PK) data over time. (a) Elimination half-life. This varies for all antibody-based biotherapeutics, but most marketed products are eliminated between 15 and 25 days. (b) Clearance. This varies too, but most antibody-based biotherapeutics have a clearance between 5 and 15 mL/hour. (c) Volume of distribution. Values fall mainly between 3 and 9 liters with values between 3 and 6 liters being the most common. (d) Bioavailability. Recent marketed drugs with a subcutaneous route of administration commonly have 90% or more bioavailability. (e) Clearance versus dosing frequency. In general, a higher clearance should result in more frequent dosing, but the median values do not reflect this. (f) Elimination half-life versus dosing frequency. A trend of longer elimination half-lives enabling less frequent dosing is observed.

Figure 5.

Four of the main inactive ingredient categories for marketed antibody-based biotherapeutics over time (see Table S1 for all). (a) Buffers. Histidine is the most common, included in 36 marketed antibody-based biotherapeutic formulations. (b) Stabilizing agents. No stabilizing agents is the most common, but if one is used, sucrose is the most common. (c) Tonicity modifiers. No tonicity modifier is the most common, but if one is used, NaCl is the most common. (d) Surfactants. Polysorbate 80 is included in 52 formulations. (e) Buffering agent usage versus heavy chain isotype. The four most common buffers are seen in all isotypes, but histidine is much more common in IgG1. (f) Stabilizing agent usage. Sucrose is the most common in all isotypes, but trehalose is not used in IgG2 or IgG4 products. (g) Tonicity modifiers. Sodium chloride and no tonicity modifier have similar representation across all isotypes. (h) Surfactant. Polysorbate 20 is paired mostly with IgG1 formulations while polysorbate 80 is paired with IgG2 and IgG4.

Figure 6.

API concentration and formulation pH. (a) API concentration over time. The most common API concentration is between 10 and 50 mg/mL, however, API concentrations≥100 mg/mL are becoming more common in recent years. (b) Formulation pH over time. In recent years, drug products are being more frequently formulated under acidic formulations (≤6.0). (c) API concentration and formulation pH comparison. Antibody-based biotherapeutics with high concentration formulations are often formulated in mildly acidic conditions.