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Antibody fragment-drug conjugates (FDCs) use smaller antibody fragments (single-chain scFv) to replace larger antibody molecules. It is generally believed that antibody fragments are relatively easy to discover and bioengineering techniques can be used to achieve higher DAR. BOC Sciences is a leading provider of antibody fragment drug conjugate development services, offering comprehensive solutions to support the discovery and optimization of novel FDCs for a variety of therapeutic indications. With expertise in antibody engineering, protein conjugation and drug development, BOC Sciences is well-positioned to help biopharmaceutical companies accelerate the development of next-generation antibody fragment drug conjugates to improve efficacy and reduce toxicity.
Antibody fragments are a good choice when considering smaller format ADCs. Antibody fragments may be structurally more stable, especially fragments that do not contain a thermally labile CH2 domain. Fragment antibodies (Fabs) can have remnants of the IgG hinge region, leaving native thiol/disulfide conjugation points. However, the C-terminal cysteine is often specifically designed, following trends in IgG site-specific conjugation strategies. Thiol or disulfide rebridging techniques for conjugation are well established and widely used elsewhere. Next-generation maleimide linkers address thioether bond instability issues in earlier ADCs. Glycan conjugation is generally not followed due to the prokaryotic manufacturing systems used primarily for antibody fragments, but non-natural amino acid incorporation and enzymatic conjugation methods are still very suitable.
Fig. 1. Schematic representation of antibody fragments (Antibodies (Basel). 2018, 7(2): 16).
BOC Sciences offers a range of antibody fragment formats for drug conjugation, including single chain variable fragments (scFv), Fab fragments and Nanobodies. These antibody fragments can be designed to target a variety of antigens, including cell surface receptors, tumor-associated antigens, and immune checkpoint proteins. By leveraging our expertise in antibody engineering and protein conjugation, BOC Sciences can design and optimize antibody fragment drug conjugates to enhance specificity and potency for a variety of therapeutic applications. We offer a comprehensive suite of custom antibody fragment drug conjugate development services to support biopharmaceutical companies in the discovery and optimization of novel FDCs.
BOC Sciences' fragment drug conjugate development services offer a range of options for targeted drug delivery and therapeutics, utilizing a variety of antibody fragments for specific antigen binding and drug delivery. Our expertise in this field can help develop novel and effective treatments for a variety of diseases. Our fragment-drug conjugate development capabilities include Fab-drug conjugates, scFv-drug conjugates, diabody-drug conjugates, SIP-drug conjugates and domain antibody-drug conjugates.
Fab-drug conjugates utilize antigen-binding fragments (Fabs) of antibodies to target specific antigens on cancer cells. Fab fragments contain the constant and variable domains of IgG, linked by a single disulfide bond present at the C-terminus. They are the most clinically explored fragment form (~50 KD) and are well suited for drug conjugation via dialkylation conjugation because they possess a single, solvent-accessible interchain disulfide bond. By conjugating cytotoxic drugs to Fab fragments, ADCs can selectively deliver drugs to target cells, thereby increasing efficacy and reducing off-target toxicity.
Single chain Fv (ScFv) is composed of a flexible linker peptide (linker) connecting the antibody variable region heavy chain (VH) and light chain (VL) (~27 KD). It is the smallest functional structural unit that possesses the full antigen-binding specificity of the parent antibody. It has attracted much attention due to its small molecular weight (only 1/6 of a complete antibody), strong penetrating power, short half-life in vivo, low immunogenicity, expression in prokaryotic cell systems, and ease of genetic engineering. By conjugating cytotoxic drugs to scFv fragments, ADCs can selectively deliver drugs to target cells, resulting in potent antitumor activity. scFv-drug conjugates have shown great promise in preclinical studies and are currently being evaluated in clinical trials for the treatment of solid tumors and hematological malignancies.
Diabody refers to the bispecific antibody format (~60 KD). Diabodies are designed to have two antigen-binding sites, thereby increasing binding affinity and improving tumor penetration. By combining a cytotoxic drug with a diabody, ADCs can effectively target and kill cancer cells while minimizing damage to healthy tissue. At present, studies have shown that the new diabody can successfully target RAS and P53 mutations, and can significantly inhibit tumor growth by acting on the RAS-HLA complex or P53-HLA complex.
Small immune proteins (SIPs) (~80 KD) contain scFv fragments fused to Ig-derived constant regions. The presence of these constant regions promotes noncovalent dimerization of the two monomers. Chemical conjugation to SIP is typically accomplished by site-specific incorporation of cysteine residues into the constant domain of the monomer. SIP-drug conjugates utilize stabilized immunoglobulins as targeting moieties. By combining cytotoxic drugs with immunoglobulins, ADCs can effectively target cancer cells while maintaining stability and specificity.
Domain antibody-drug conjugates utilize small antibody fragments called domain antibodies (~12 KD) to target specific antigens on cancer cells. By combining cytotoxic drugs with domain antibodies, ADCs can effectively target and kill cancer cells while minimizing off-target toxicity.
BOC Sciences has a proven track record of success in developing antibody fragment drug conjugates for a variety of therapeutic indications. We designed a high-affinity scFv targeting the HER2 receptor and conjugated it to a potent cytotoxic drug using a cleavable linker. The resulting FDC demonstrated potent antitumor activity in preclinical models of breast cancer, with superior efficacy and lower toxicity compared with standard chemotherapy.
Additionally, BOC Sciences designed a bispecific scFv targeting two different antigens expressed on tumor cells, conjugated to a dual-acting cytotoxic drug with synergistic antitumor activity. Bispecific FDC demonstrated potent tumor cell killing and enhanced tumor penetration in preclinical models of solid tumors, highlighting the potential of this novel therapeutic approach.
Antibody fragments are smaller antibody fragments derived from the antigen-binding region of an antibody molecule. They retain the ability to specifically bind antigen but lack the effector functions of full-length antibodies. Antibody fragments are often used in research, diagnosis and therapy because their smaller size allows them to better penetrate tissue and be cleared from the body more quickly. Examples of antibody fragments include Fab fragments, F(ab')2 fragments, and single chain variable fragments (scFv).
The scFv fragment is composed of the variable regions of the heavy and light chains of the antibody, which are connected by a short peptide (15-20 amino acids). The Fab fragment consists of a complete light chain and a partial heavy chain structure (variable region and the first constant region). The Fab antibody has a CH1 and CL region, which are linked by a disulfide bond and do not require short peptides. The scFv fragment lacks this region, and the heavy chain variable region (V) and the light chain variable region (L) need to be connected together by a short peptide.
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