Justin A Caravella

Biogen Idec, Weston, Massachusetts, United States

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Publications (4)15.04 Total impact

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    ABSTRACT: The ability to generate and design antibodies recognizing specific targets has revolutionized the pharmaceutical industry and medical imaging. Engineering antibody therapeutics in some cases requires modifying their constant domains to enable new and altered interactions. Engineering novel specificities into antibody constant domains has proved challenging due to the complexity of inter-domain interactions. Covarying networks of residues that tend to cluster on the protein surface and near binding sites have been identified in some proteins. However, the underlying role these networks play in the protein resulting in their conservation remains unclear in most cases. Resolving their role is crucial, because residues in these networks are not viable design targets if their role is to maintain the fold of the protein. Conversely, these networks of residues are ideal candidates for manipulating specificityif they are primarily involved in binding, such as the myriad inter-domain interactions maintained within antibodies.Here, we identify networks of evolutionarily-related residues in C-class antibody domains by evaluating covariation, a measure of propensity with which residue pairs vary dependently during evolution. We computationally test whether mutation of residues in these networks affects stability of the folded antibody domain, determining their viability as design candidates. We find that members of covarying networks cluster at domain-domain interfaces, and that mutations to these residues are diverse and frequent during evolution, precluding their importance to domain stability. These results indicate that networks of covarying residues exist in antibody domains for functional reasonsunrelated to thermodynamic stability, making them ideal targets for antibody design. Proteins 2012. © 2012 Wiley Periodicals, Inc.
    No preview · Article · May 2013 · Proteins Structure Function and Bioinformatics
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    ABSTRACT: Engineered antibodies are emerging as a promising class of therapeutic biomolecules, as well as having applications in medical research. Knowledge of conserved functional and structural regions within antibody domains is imperative in order to rationally design stable and specific antibodies. Of particular interest for the design of therapeutics are antibody variable and constant domains, which are responsible for antigen binding and immune response. These antibody domains are part of the larger immunoglobulin (Ig) V-class and C-class families, respectively. We find that, although both classes belong to the Ig-fold superfamily, the sets of conserved residue positions and identities differ between these classes. We exploit these evolutionary differences to derive a metric based on sequence positional entropy that distinguishes C-class from V-class sequences utilizing only sequence information. By distinguishing different domain families using sequence information alone, we enable the application of domain-specific design strategies without the need for secondary or tertiary structural information.
    No preview · Article · Dec 2012 · Journal of Molecular Biology
  • Justin Caravella · Alexey Lugovskoy
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    ABSTRACT: Since the first protein therapeutics were approved two decades ago, the field has seen a transition from the development of naturally occurring proteins to design of molecules engineered for optimal target recognition, pharmacokinetics, biodistribution, and therapeutic function. Many modified antibodies and monovalent or multispecific antibody-like molecules with custom profiles are in different stages of drug development. In addition, several non-antibody protein scaffolds that interrogate a broad range of targets are being pursued. As protein engineering efforts have expanded and diversified, it has become increasingly important to understand the biophysical and biochemical properties of proteins and to translate this knowledge into design of optimized pharmaceutical agents.
    No preview · Article · Aug 2010 · Current opinion in chemical biology
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    Justin A Caravella · Deping Wang · Scott M Glaser · Alexey Lugovskoy
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    ABSTRACT: Monoclonal antibodies capable of recognizing antigens with high affinity and specificity represent a well established class of biological agents. Since the development of hybridoma technology in 1975, advances in recombinant DNA technologies and computational and biophysical methods have allowed us to develop a better understanding of the relationships between antibody sequence, structure, and function. These advances enable us to manipulate antibody sequences with the goal of improving upon, or creating new biological or biophysical properties. In this review we will focus on recent successes in using structure-guided computational methods to design antibodies and antibody-like molecules with optimized affinity and specificity to antigen and for enhancing protein stability.
    Preview · Article · Apr 2010 · Current Computer - Aided Drug Design