Dataset Information

Engineered SIRP? variants as immunotherapeutic adjuvants to anticancer antibodies.

ABSTRACT: CD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. Here, we modified the binding domain of human SIRP?, the receptor for CD47, for use as a CD47 antagonist. We engineered high-affinity SIRP? variants with about a 50,000-fold increased affinity for human CD47 relative to wild-type SIRP?. As high-affinity SIRP? monomers, they potently antagonized CD47 on cancer cells but did not induce macrophage phagocytosis on their own. Instead, they exhibited remarkable synergy with all tumor-specific monoclonal antibodies tested by increasing phagocytosis in vitro and enhancing antitumor responses in vivo. This "one-two punch" directs immune responses against tumor cells while lowering the threshold for macrophage activation, thereby providing a universal method for augmenting the efficacy of therapeutic anticancer antibodies.

SUBMITTER: Weiskopf K

PROVIDER: S-EPMC3810306 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies.

Weiskopf Kipp K Ring Aaron M AM Ho Chia Chi M CC Volkmer Jens-Peter JP Levin Aron M AM Volkmer Anne Kathrin AK Ozkan Engin E Fernhoff Nathaniel B NB van de Rijn Matt M Weissman Irving L IL Garcia K Christopher KC

Science (New York, N.Y.) 20130530 6141

CD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. Here, we modified the binding domain of human SIRPα, the receptor for CD47, for use as a CD47 antagonist. We engineered high-affinity SIRPα variants with about a 50,000-fold increased affinity for human CD47 relative to wild-type SIRPα. As high-affinity SIRPα monomers, they potently antagonized CD47 on cancer cells but did not induce macrophage phagocytosis on their own. Instead, they exhibited ...[more]

PMID: 23722425

Similar Datasets

Project description:Targeting the CD47-signal-regulatory protein ? (SIRP?) pathway represents a novel therapeutic approach to enhance anti-cancer immunity by promoting both innate and adaptive immune responses. Unlike CD47, which is expressed ubiquitously, SIRP? expression is mainly restricted to myeloid cells and neurons. Therefore, compared to CD47-targeted therapies, targeting SIRP? may result in differential safety and efficacy profiles, potentially enabling lower effective doses and improved pharmacokinetics and pharmacodynamics. The development of effective SIRP? antagonists is restricted by polymorphisms within the CD47-binding domain of SIRP?, necessitating pan-allele reactive anti-SIRP? antibodies for therapeutic intervention in diverse patient populations. We immunized wild-type and human antibody transgenic chickens with a multi-allele and multi-species SIRP? regimen in order to discover pan-allelic and pan-mammalian reactive anti-SIRP? antibodies suitable for clinical translation. A total of 200 antibodies were isolated and screened for SIRP? reactivity from which approximately 70 antibodies with diverse SIRP? binding profiles, sequence families, and epitopes were selected for further characterization. A subset of anti-SIRP? antibodies bound to both human SIRP? v1 and v2 alleles with high affinity ranging from low nanomolar to picomolar, potently antagonized the CD47/SIRP? interaction, and potentiated macrophage-mediated antibody-dependent cellular phagocytosis in vitro. X-ray crystal structures of five anti-SIRP? antigen-binding fragments, each with unique epitopes, in complex with SIRP? (PDB codes 6NMV, 6NMU, 6NMT, 6NMS, and 6NMR) are reported. Furthermore, some of the anti-SIRP? antibodies cross-react with cynomolgus SIRP? and various mouse SIRP? alleles (BALB/c, NOD, BL/6), which can facilitate preclinical to clinical development. These properties provide an attractive rationale to advance the development of these anti-SIRP? antibodies as a novel therapy for advanced malignancies. Abbreviations: ADCC: antibody-dependent cellular cytotoxicity; ADCP: antibody-dependent cellular phagocytosis; CFSE: carboxyfluorescein succinimidyl ester; Fab: fragment antigen binding; Fc: fragment crystallizable; Fc?R: Fc? receptor; Ig: immunoglobulin; IND: investigational new drug; MDM?: monocyte-derived macrophage; NOD: non-obese diabetic; scFv: single chain fragment variable; SCID: severe combined immunodeficiency; SIRP: signal-regulatory protein.

Project description:BackgroundWith the increase in production and use of engineered nanoparticles (NP; ? 100 nm), safety concerns have risen about the potential health effects of occupational or environmental NP exposure. Results of animal toxicology studies suggest that inhalation of NP may cause pulmonary injury with subsequent acute or chronic inflammation. People with chronic respiratory diseases like asthma or allergic rhinitis may be even more susceptible to toxic effects of inhaled NP. Few studies, however, have investigated adverse effects of inhaled NP that may enhance the development of allergic airway disease.MethodsWe investigated the potential of polyethylene glycol coated amorphous silica NP (SNP; 90 nm diameter) to promote allergic airway disease when co-exposed during sensitization with an allergen. BALB/c mice were sensitized by intranasal instillation with 0.02% ovalbumin (OVA; allergen) or saline (control), and co-exposed to 0, 10, 100, or 400 ?g of SNP. OVA-sensitized mice were then challenged intranasally with 0.5% OVA 14 and 15 days after sensitization, and all animals were sacrificed a day after the last OVA challenge. Blood and bronchoalveolar lavage fluid (BALF) were collected, and pulmonary tissue was processed for histopathology and biochemical and molecular analyses.ResultsCo-exposure to SNP during OVA sensitization caused a dose-dependent enhancement of allergic airway disease upon challenge with OVA alone. This adjuvant-like effect was manifested by significantly greater OVA-specific serum IgE, airway eosinophil infiltration, mucous cell metaplasia, and Th2 and Th17 cytokine gene and protein expression, as compared to mice that were sensitized to OVA without SNP. In saline controls, SNP exposure did cause a moderate increase in airway neutrophils at the highest doses.ConclusionsThese results suggest that airway exposure to engineered SNP could enhance allergen sensitization and foster greater manifestation of allergic airway disease upon secondary allergen exposures. Whereas SNP caused innate immune responses at high doses in non-allergic mice, the adjuvant effects of SNP were found at lower doses in allergic mice and were Th2/Th17 related. In conclusion, these findings in mice suggest that individuals exposed to SNP might be more prone to manifest allergic airway disease, due to adjuvant-like properties of SNP.

Dataset Information

Engineered SIRP? variants as immunotherapeutic adjuvants to anticancer antibodies.

Publications

Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets