Antibody-Drug Conjugates: Design, Formulation and Physicochemical Stability

Abstract

The convergence of advanced understanding of biology with chemistry has led to a resurgence in the development of antibody-drug conjugates (ADCs), especially with two recent product approvals. Design and development of ADCs requires the synergistic combination of the monoclonal antibody, the linker and the payload. Advances in antibody science has enabled identification and generation of high affinity, highly selective, humanized or human antibodies for a given target. Novel linker technologies have been synthesized and highly potent cytotoxic drug payloads have been created. As the first generation of ADCs utilizing lysine and cysteine chemistries moves through the clinic and into commercialization, second generation ADCs involving site specific conjugation technologies are being evaluated and tested. The latter aim to be better characterized and controlled, with wider therapeutic indices as well as improved pharmacokinetic-pharmacodynamic (PK-PD) profiles. ADCs offer some interesting physicochemical properties, due to conjugation itself, and to the (often) hydrophobic payloads that must be considered during their CMC development. New analytical methodologies are required for the ADCs, supplementing those used for the antibody itself. Regulatory filings will be a combination of small molecule and biologics. The regulators have put forth some broad principles but this landscape is still evolving.

High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer

“…We also noted that the scFvD2 antibody formats did not present any detectable agonist activity at the concentration tested. In the context of the potential therapeutic application the Fc-fusion format shows several advantages, including higher tumor uptake due to prolonged circulation half-life, Fc-mediated effector functions (47) and convenient drug conjugation possibilities (30).…”

“…This should lead to a beneficial therapeutic effect meaning a higher efficacy with minimized side effects (30). The approvals of brentuximab vedotin (Adcetris) and trastuzumab emtansine (Kadcyla) have validated the strategy of ADCs for both hematologic malignancies and solid tumors (30,31).…”

“…This should lead to a beneficial therapeutic effect meaning a higher efficacy with minimized side effects (30). The approvals of brentuximab vedotin (Adcetris) and trastuzumab emtansine (Kadcyla) have validated the strategy of ADCs for both hematologic malignancies and solid tumors (30,31). Recently, the ADC rovalpituzumab tesirine (Rova-T; SC16LD6.5) targeting DLL3 (Delta-like 3 protein) antigen overexpressed in patients with SCLC showed encouraging results in preclinical and phase I studies (NCT01901653; ref.…”

Antibody drug conjugates

“…ADC payloads approved or under development are for the most part cytotoxic agents with picomolar or sub-picomolar potencies (e.g., 100-2000 fold more potent than doxorubicin, vinca alkaloids, or taxanes). The mechanisms-of-action of these payloads are often either interference with the tumor cell mitotic cycle by inhibition of tubulin polymerization, yielding G2/M phase cell cycle arrest or disruption of DNA by alkylation, cleavage (Lambert 2012;Singh et al 2015). Some of these payloads, mainly natural products, such as monomethyl auristatin E are extremely toxic (potency *10 -11 -10 -9 M) to healthy cells and cannot be administered as mono-therapy to cancer patients.…”

“…Thus, multiple chromatographic steps, ultrafiltration, and diafiltration are used to remove any unconjugated cytotoxin by [99.5 %. A recent excellent review on ADCs formulation, physicochemical stability, and characterization discusses some of the above challenges in more detail (Singh et al 2015).…”