Antibody Conjugates-Recent Advances and Future Innovations

Abstract

Monoclonal antibodies have evolved from research tools to powerful therapeutics in the past 30 years. Clinical success rates of antibodies have exceeded expectations, resulting in heavy investment in biologics discovery and development in addition to traditional small molecules across the industry. However, protein therapeutics cannot drug targets intracellularly and are limited to soluble and cell-surface antigens. Tremendous strides have been made in antibody discovery, protein engineering, formulation, and delivery devices. These advances continue to push the boundaries of biologics to enable antibody conjugates to take advantage of the target specificity and long half-life from an antibody, while delivering highly potent small molecule drugs. While the "magic bullet" concept produced the first wave of antibody conjugates, these entities were met with limited clinical success. This review summarizes the advances and challenges in the field to date with emphasis on antibody conjugation, linker-payload chemistry, novel payload classes, absorption, distribution, metabolism, and excretion (ADME), and product developability. We discuss lessons learned in the development of oncology antibody conjugates and look towards future innovations enabling other therapeutic indications.

Keywords: ADC; ADME; antibodies; antibody-drug conjugates; bioconjugates; developability; formulation; linkers; nucleic acids; payloads; site-specific conjugation.

Figure 1

The evolution of (a) murine, (b) chimeric, (c) humanized, and (d) fully human monoclonal antibodies through protein engineering. Red and blue represents mouse and human antibody sequence respectively. The antigen binding complementarity determining regions (CDRs) are shown as sticks. The new generation of antibody-drug-conjugates (ADCs) utilized humanized (c) and fully human antibodies (d).

Figure 2

Antibody conjugation methods include (a) cysteine-reactive, and (b) lysine-reactive chemistries which generate heterogeneous mixtures of drug-antibody-ratio (DAR), while (c) site specific conjugation methods deliver more homogeneous product with defined DAR using engineered residues, modified glycans, enzymatic ligations, and chemical cross-linkers. Schematic representation of antibody heavy chains and light chains are colored blue and green respectively. complementarity determining regions (CDRs) and conjugation sites are depicted as red bars and stars respectively. Approximate DAR distribution for stochastic cysteine and lysine conjugations are presented as bar charts.

Figure 3

Examples of ADC payloads used clinically include, monomethyl auristatin E (MMAE, a, emtansine (DM1, b), calicheamicin (c), pyrrolobenzodiazepine dimer (PBD, SGD-1882, d), and duocarmycin A (e).

Figure 4

Expanding payload space in oncology with DNA disrupting bis-intercalator depsipeptide (SW-163D, a), pyrrole-based kinesin spindle protein (KSP) inhibitor (b), topoisomerase I inhibitor (DXd, c), nicotinamide phosphoribosyltransferase (NAMPT) inhibitor (d), and MMP9 inhibitor (CGS27023A, e). Examples of non-oncology payloads include LXR agonist (f), PDE4 inhibitor (GSK256066, g), kinase inhibitor dasatinib (h), antimicrobial rifamycin analog (i), GR agonists dexamethasone (j), budesonide (k), and fluticasone propionate (l).

Figure 5

(a) stabilizing chemical modifications for siRNA, (b) oligo delivery conjugate moieties.

Figure 6

(a) Enzymatic cleavable linkers; (b) non-enzymatic cleavable linkers; (c) conjugation chemistry.

Figure 7

Low permeability linker-payload design.

Figure 8

Hydrophilic linker-payload design.