Red and blue represents mouse and human antibody sequence respectively. Since the first monoclonal antibody drug approval (OKT3) in 1986, over 60 antibody therapeutics have become marketed drugs to date [1]. The number of protein therapeutics entering clinical development, including antibodies, antibody fragments, bispecifics, Fc-fusion proteins, and antibody-drug conjugates is expected to grow due to robust pipelines and high success rates for treating various diseases [2,3]. With the advances and extensive N-Acetyl-L-aspartic acid experience in antibody engineering over the past decades [4], antibody therapeutics have evolved from murine (e.g., OKT3) to chimeric (e.g., Rituxan?) to fully human (e.g., Humira?) as depicted in Figure 1. Monoclonal antibody-based therapeutics have been built to deliver specific effector functions or as bispecifics and conjugates to achieve the desired pharmacological effects [5,6]. Antibody discovery was enabled by murine N-Acetyl-L-aspartic acid hybridoma technology [7] followed by humanization [8] to deliver therapeutic antibodies with lower risk of immunogenicity [9]. Display technologies and transgenic animals have pushed the boundaries to produce antibodies with fully human sequences [10]. Antibody conjugates have similarly taken advantage of the progress made in monoclonal antibody development and improvements in conjugation chemistries [11,12,13] to expand the druggable target space for antibody-based therapies. These advances in antibody development are crucial to the success of antibody conjugates. Open in a separate window 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 N-Acetyl-L-aspartic acid complementarity determining regions (CDRs) are shown as sticks. The new generation of antibody-drug-conjugates (ADCs) utilized humanized (c) and fully human antibodies (d). While chemotherapy and radiation have been the dominant treatments of cancer for decades, their lack of ability to distinguish between healthy and tumor cells has fueled the desire to create tumor specific delivery of cytotoxic payloads and radionuclides via antibody conjugates. Oncology antibody conjugates have successfully delivered potent chemotherapeutic and radioactive agents to kill tumor cells [12]. Currently, all of the FDA approved antibody-drug-conjugates (ADCs) are targeted cancer therapies (Table 1) [14], including the latest approval in June 2019 for Polivy? [15]. Herein, we review the progress made in oncology ADCs in terms of conjugate design and development, linker payload conjugation chemistries and highlight novel non-oncology conjugate innovations. Table 1 FDA approved antibody-drug-conjugates (ADCs). within host cells. Others have leveraged the internalization mechanism of antibodies to deliver immunosuppressive, cardiovascular or metabolic disorder small molecule drugs to specific cells using cell surface N-Acetyl-L-aspartic acid targets such as E-selectin [43], CD11a [44,45], CD25 [46], a3(IV)NC1 [47], CXCR4 [40,48], CD45 [49], CD70 [50], CD74 [51], and CD163 [52,53]. Examples of linker payloads as well as formulation and delivery challenges N-Acetyl-L-aspartic acid for non-oncology indications are discussed below. Additionally, genes of interest have been targeted in specific cell types to produce durable response using antibody-oligonucleotide conjugates [54,55]. Delivery of oligonucleotides have traditionally Rabbit Polyclonal to CHSY1 been challenging and various modifications have been employed to facilitate better cell penetration. This is explored in a later section. 2.2. Conjugation Methods Antibody conjugation methods (Figure 2) have been extensively reviewed [11,56,57,58]. To date, all the FDA approved ADCs have relied on coupling reactions using either the nucleophilic primary amino group of surface-exposed lysines or the thiol group of reduced structural disulfides. The resulting product is a controlled heterogeneous mixture of antibodies with average drug load. High DAR species leads to aggregate formation, lower tolerated dose, and faster systemic clearance while low DAR species suffer from low efficacy [59]. Although DAR profile can be controlled by conjugation process development and specific DAR can be purified, site-specific methods to produce more homogeneous.
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