Engineering antibodies for imaging and therapy

doi:10.1016/S0958-1669(97)80067-5

Current Opinion in Biotechnology

Volume 8, Issue 4, August 1997, Pages 449-454

https://doi.org/10.1016/S0958-1669(97)80067-5 Get rights and content

Abstract

Several advances made during the past year will probably facilitate the development of therapeutic antibodies. Most notably, significant progress has been made in the rapid isolation of high affinity human antibodies from phage display libraries and by immunization of transgenic mice. The therapeutic potential of bispecific antibody fragments and Fc-containing proteins has been greatly enhanced by improved production methods. The utility of radiolabeled antibody fragments has been improved by the development of site-specific labeling methods and by the advent of the ‘minibody’, an engineered fragment that has proved to be highly successful for tumor imaging in mice.

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Interestingly, the HAMA response is less limiting in immunocompromised patients such as those with B-cell lymphoma or hematologic malignancies. This problem was largely eliminated by creating chimeric or humanized antibodies, which combine the variable region or the complimentary determining regions (CDRs), respectively, of murine antibodies with the constant regions of human antibodies [2]. Finally, large phage display libraries or humanized mice can be used to produce fully human antibodies, though the latter method permits only a limited variety of antibody production (Figure 1).
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Antibody is a very important protein in biotechnological and biomedical fields because of its high affinity and specificity to various antigens. Due to the rise of human antibody therapeutics, its cost-effective purification is an urgent issue for bio-industry. In this study, we made novel fusion proteins PAxPG with a flexible (DDAKK)n linker between the two Ig binding domains derived from Staphylococcus protein A and Streptococcus protein G. The fusion proteins bound human and mouse IgGs and their fragments with up to 58-times higher affinity and wider specificity than the parental binding domains. Interestingly, the optimal linker for human Fab fragment was n = 4, which was close to the modeled distance between the termini of domains bound to heavy chain, implying increased avidity as a possible mechanism. For binding to Fc, the longest n = 6 linker gave the highest affinity, implying longer interchain distance between the two binding sites. The novel fusion protein with optimized interdomain linker length will be a useful tool for the purification and detection of various IgGs including mouse IgG₁ that binds only weakly to natural protein A.
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The result is a polyclonal pool, which is then screened and sequenced for individual clones. Unique clones can then be engineered into immunoglobulin formats to test for therapeutic efficacy (Roovers et al., 2001; Carter and Merchant, 1997). Two recent studies have explored phage display technology against GSCs.
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in humans. It accounts for fifty-two percent of primary brain malignancies in the United States and twenty percent of all primary intracranial tumors. Despite the current standard therapies of maximal safe surgical resection followed by temozolomide and radiotherapy, the median patient survival is still less than 2 years due to inevitable tumor recurrence. Glioblastoma cancer stem cells (GSCs) are a subgroup of tumor cells that are radiation and chemotherapy resistant and likely contribute to rapid tumor recurrence. In order to gain a better understanding of the many GBM-associated mutations, analysis of the GBM cancer genome is on-going; however, innovative strategies to target GSCs and overcome tumor resistance are needed to improve patient survival. Cancer stem cell biology studies reveal basic understandings of GSC resistance patterns and therapeutic responses. Membrane proteomics using phage and yeast display libraries provides a method to identify novel antibodies and surface antigens to better recognize, isolate, and target GSCs. Altogether, basic GBM and GSC genetics and proteomics studies combined with strategies to discover GSC-targeting agents could lead to novel treatments that significantly improve patient survival and quality of life.
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Using a nonsuppressing host HB2151, we could actually produce a soluble Fab fragment in the culture supernatant, which enables rapid production and evaluation of chimeric Fab protein. Nowadays humanized and human antibodies are of particular interest, since they are considered to be valuable for diagnostic and therapeutic applications [21], avoiding the HAMA (human anti-mouse antibody) response frequently observed with rodent antibodies. OS-ELISA with a full-length Fab fragment with the C-terminal cysteine of the kappa chain on phage was not very successful.
Previously, immunological detection of small haptens or peptides was only possible in a competitive format, which needed competitor antigen either labeled by a reporter or attached to a carrier protein. Beside this, open-sandwich immunoassay (OS-IA) is a simple but powerful immunoassay that can noncompetitively determine monovalent antigen concentration by measuring the antigen-dependent increase in V_H/V_L interaction of an antibody. However, the procedure to obtain suitable assay reagents for OS-IA for a target antigen has not been straightforward because of the lack of easy-to-use antibody selection/manipulation methods. Here we devise a new Fab antibody phage display system that is useful for rapidly evaluating and selecting suitable antibody Fv fragments to OS-IA. The system is based on a phagemid vector in which two identical restriction sites were incorporated into both ends of a human constant region domain. After selection of the M13 phage displaying a Fab fragment, the vector can be easily converted to the vector that can simultaneously produce the V_H-displaying phage and the light chain in the culture supernatant, which can be directly used for OS-ELISA. The successful results of model selection as well as conversion to OS format show the potential in developing various OS-IA for clinically and environmentally important targets.
A broad range of Fab stabilities within a host of therapeutic IgGs
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Although the functional properties of IgGs are well known, little has been published concerning the stability of whole IgG molecules. Stability is, however, a requirement for the development of antibodies for therapeutic or diagnostic applications. The hypervariable antigen-binding region (Fv) is responsible for stability variations between IgGs of identical subclass. To determine the range of stabilities that may be expected for human(ized) antibodies, differential scanning calorimetry was performed on 17 human(ized) antibodies from various in-house programs. The antigen-binding fragments (Fabs) of these antibodies exhibited thermal unfolding transitions with midpoints (T_Ms) varying from 57 to 82 °C. Antibodies with very low Fab stabilities were found to aggregate and express poorly. Fab instability was often associated with high levels of uncommonly observed amino acids or CDR loop lengths particularly within the variable heavy chain domain. Overall, the study provides a thermostability range for IgGs and suggests possible stability guidelines for developing antibody diagnostics or therapeutics.

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View full text

Engineering antibodies for imaging and therapy

Abstract

Curr Opin Struct Biol

Curr Opin Immunol

Curr Opin Biotechnol

Curr Opin Immunol

Biochemistry

Cancer Res

Nat Struct Biol

Engineering therapeutic antibodies

Progress with humanized antibodies — an update

Exp Opin Invest Drugs

Making antibodies by phage display technology

Ann Rev Immunol

Mice perform a human repertoire

Nature

Toward the production of bispecific antibody fragments for clinical applications

J Hematotherapy

Monoclonal antibody-based therapy

Curr Opin Oncol

Engineering antibody Fv fragments for cancer detection and therapy: disulfide-stabilized Fv fragments

Nat Biotech

Antibody-enzyme conjugates for cancer therapy

J Natl Cancer Inst

Antibody-directed enzyme prodrug therapy: a review

Drug Dev Res

Producing antibodies in Escherichia coli: from PCR to fermentation

Novel genetic immunotoxins and intracelular antibodies for cancer therapy

Semin Oncol

Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer

J Clin Oncol

Isolation of high affinity human antibodies directly from large synthetic repertoires

EMBO J

Human antibodies with sub-nanomolar affinities isolated from a large non-immunized phage display library

Nat Biotechnol

High avidity human IgGκ monoclonal antibodies from a novel strain of minilocus transgenic mice

Nat Biotechnol

Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice

Nat Genet

CDR walking mutagenesis for the affinity maturation of a potent human anti-HIV-1 antibody into the picomolar range

J Mol Biol

Isolation of picomolar affinity anti-c-erbB-2 single-chain Fv by molecular evolution of the complementarity determining regions in the center of the antibody binding site

J Mol Biol

Treatment of advanced solid tumors with immunotoxin LMB-1: an antibody linked to Pseudomonas exotoxin

Nat Med

Humanization of immunotoxins

Proc Natl Acad Sci USA

Phase II study of weekly intravenous recombinant humanized anti-p185^HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer