Among the most studied macromolecular structures within structural biology are those of monoclonal antibodies. The number of entries in the Structural Antibody Database (SabDab) is exponentially growing and has currently (July 2023) reached a total of 7471 antibody structures and 7151 structures of antibody-antigen complexes. Thanks to the efforts of many research groups, structural biology, primarily with the help of X-ray crystallography, has provided a detailed description of the basic principles of antibody structure and dynamics, providing valuable insights into antibody structure-function relationships.

The three-dimensional structures of monoclonal antibodies and antibody-antigen complexes have revealed detailed information on the paratope (the antibody residues contacting the antigen) and epitope (the antigen residues involved in stabilizing the antibody-antigen complex), domain organization and dynamics, including flexibility of the different parts of the structure. They have also clearly delineated the parts of the antibody structure responsible for antigen binding, the complementarity determining region loops (CDRs), and the supporting framework regions (FRs), which often participate directly in antigen binding.

The development of new drugs of biological origin, the majority of which are monoclonal antibodies, is a major focus of modern-day drug design. The information on antibody three-dimensional structure, in combination with antibody engineering, plays a central role in this process and has opened the way for the rapidly growing field of monoclonal antibody therapeutics.  As of June 2023, the Antibody Therapies Database ( contains information on over 9400 monoclonal antibodies targeting over 2400 human disorders ranging from cancer and rheumatoid arthritis to osteoporosis and asthma. Antibodies are considered attractive therapeutic molecules due to their specificity, long half-life in vivo (two to four weeks), and lack of immunogenicity for fully humanized antibodies.

Designing new monoclonal antibody variants suitable for therapeutic and diagnostic purposes (such as immunofluorescence, Western blotting, and enzyme-linked immunosorbent assay (ELISA) analysis) normally requires extensive studies and modification of naturally occurring antibodies. As in the case of small-molecule drug discovery, structural biology, and structure-based antibody engineering play a crucial role, both at the early stages of design and development and at the later stages of clinical studies. Structural information, combined with monoclonal antibody engineering, can help optimize the chemical properties of antibodies, like selectivity, solubility, efficacy, and can even help overcoming drug-resistant mutations. Structural information can also be important in patent applications and intellectual property protection. Structure-guided design of new mutations in developing new therapeutic monoclonal antibodies may also improve their stability and resistance against degradation and aggregation in blood and during production, storage, and transportation.


Developing new monoclonal antibodies against human targets often starts with non-human antibodies from rodents, chicken, or rabbits. These antibodies require humanization. The availability of the three-dimensional structure of the antibody-antigen complex or even just the antibody greatly facilitates the definition of the CDR and framework regions, revealing the residues involved in complex stabilization. Humanization proceeds in several steps, first defining the CDRs of the non-human antibody, after which the human sequence to be utilized as the donor of the rest of the antibody needs to be selected. Some residues of the framework region and the CDRs must be replaced to reduce immunogenicity while maintaining the engineered molecule's activity. The three-dimensional structure helps design these replacements by so-called back mutations (replacing non-human amino acids) and “resurfacing”.

The three-dimensional structure of the antibody-antigen complex can also be used to design bispecific monoclonal antibodies. In a recent publication by Beckmann et al., the development of a platform of dual targeting Fab (DutaFab) molecules, which comprise two spatially separated and independent binding sites within the human antibody CDR loops, was reported. The CDRs were separated into the H-side paratope containing loops HCDR1, HCDR3, and LCDR2 and the L-side paratope containing loops LCDR1, LCDR3, and HCDR2. The SARomics Biostructures team crystallized the complex with the antigens and determined the X-ray structures (shown in the image above). The structures showed that DutaFabs indeed can simultaneously bind two target molecules at the same Fv region comprising a VH-VL heterodimer of the Fab.

The SARomics team has gathered extensive experience in monoclonal antibody and antibody-antigen crystallization and structure determination and has produced a large number of structures. Several disclosable structures in collaboration with SARomics have been published by the project authors.

This is our first post dedicated to antibody therapeutics. The second post will be focused on the exciting area of biosimilars, the design of which is also helped by structural information. Follow us on LinkedIn to ensure you don’t miss our future posts. You may also visit our antibody structure services page or download a PDF with a short company presentation and antibody-related case studies


Beckmann R, Jensen K, Fenn S, Speck J, Krause K, Meier A, Röth M, Fauser S, Kimbung R, Logan DT, Steegmaier M & Kettenberger H (2021). DutaFabs: A novel platform of bispecific therapeutic Fab fragments that simultaneously bind two targets with high affinity. Nature Communications 12, 708.

 For additional information on the subject, please see the excellent review below:

Chiu ML, Goulet DR, Teplyakov A, and Gilliland GL (2019). Antibody structure and function: the basis for engineering therapeutics. Antibodies, 8(4), 55;