Avidity and variable domain spacing strongly influence the therapeutic potency of bispecific antibodies against Crimean-Congo hemorrhagic fever virus
ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) is an enveloped, negative-sense RNA virus that is spread by ticks across Europe, Africa, and Asia and causes a lethal disease in humans (~30%–40% case fatality). There are currently no approved vaccines or therapeutics. Antibody-based therapeuti...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2025-05-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03202-24 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849322097320394752 |
|---|---|
| author | Albert Wang Stephanie R. Monticelli Ariel S. Wirchnianski Dafna M. Abelson Ana I. Kuehne Russell R. Bakken Marissa Middlecamp Michael Weingart Olivia Vergnolle Zachary A. Bornholdt Crystal L. Moyer Jacob L. Berrigan Brandyn R. West J. Maximilian Fels Larry Zeitlin Andrew S. Herbert Kartik Chandran Chowdhury Raihan Bikash Jonathan R. Lai |
| author_facet | Albert Wang Stephanie R. Monticelli Ariel S. Wirchnianski Dafna M. Abelson Ana I. Kuehne Russell R. Bakken Marissa Middlecamp Michael Weingart Olivia Vergnolle Zachary A. Bornholdt Crystal L. Moyer Jacob L. Berrigan Brandyn R. West J. Maximilian Fels Larry Zeitlin Andrew S. Herbert Kartik Chandran Chowdhury Raihan Bikash Jonathan R. Lai |
| author_sort | Albert Wang |
| collection | DOAJ |
| description | ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) is an enveloped, negative-sense RNA virus that is spread by ticks across Europe, Africa, and Asia and causes a lethal disease in humans (~30%–40% case fatality). There are currently no approved vaccines or therapeutics. Antibody-based therapeutics targeting the CCHFV surface glycoproteins Gn and Gc, which are responsible for viral attachment and fusion during entry, are a promising therapeutic approach. We previously isolated three broadly neutralizing Gc-targeting human monoclonal antibodies (mAbs) and showed certain cocktails of these mAbs demonstrated synergistic virus neutralization. Furthermore, physical linkage of two of these mAbs into a dual variable domain (DVD) bispecific antibody (bsAb) DVD-121-801 resulted in improved neutralization and therapeutic protection against a lethal CCHFV challenge in mice. However, the molecular requirements for the activity of DVD-121-801, and why it is augmented over monospecific parental mAbs, remain the topic of investigation. Here, we generated a new panel of bsAb variants of DVD-121-801 to explore the spacing and avidity requirements and further optimize its protective efficacy against divergent CCHFV isolates. We evaluated these variants for neutralization, fusion inhibition, and protection with virus-like particles, authentic viruses, and in vivo challenge studies. We found that neutralization potency was relatively unaffected by spacing or identity of variable domains within the bsAb, but that one next-generation design employing longer and more flexible linkers between variable domains (DVD-121-801GS) had a greater breadth of therapeutic protection. Our efforts highlight the importance of antibody avidity and lead to an improved bsAb variant of DVD-121-801 for further therapeutic development.IMPORTANCECrimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus endemic to Europe, Africa, and Asia that causes severe disease in humans (30%–40% case fatality). There are currently no approved vaccines or therapeutics. In prior work, physical linkage of two Gc-specific monoclonal antibodies (mAbs) targeting distinct epitopes into a dual variable domain (DVD) bispecific antibody (bsAb), termed DVD-121-801, resulted in potent neutralization in vitro and therapeutic protection in vivo. Here, a panel of variants of this bsAb was developed and evaluated for neutralization potency, fusion inhibition, and therapeutic efficacy, and our work shows this panel to be effective against multiple isolates of CCHFV. Furthermore, incorporating longer, more flexible linkers between variable domains resulted in a lead candidate with improved activity and therapeutic potential compared to the parental bsAb. Utilizing this panel, we also explored the contribution of antibody avidity in antibody-mediated protection against CCHFV infection. |
| format | Article |
| id | doaj-art-f4b5950fdb5f45b2b6dc46e079a79752 |
| institution | Kabale University |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj-art-f4b5950fdb5f45b2b6dc46e079a797522025-08-20T03:49:32ZengAmerican Society for MicrobiologymBio2150-75112025-05-0116510.1128/mbio.03202-24Avidity and variable domain spacing strongly influence the therapeutic potency of bispecific antibodies against Crimean-Congo hemorrhagic fever virusAlbert Wang0Stephanie R. Monticelli1Ariel S. Wirchnianski2Dafna M. Abelson3Ana I. Kuehne4Russell R. Bakken5Marissa Middlecamp6Michael Weingart7Olivia Vergnolle8Zachary A. Bornholdt9Crystal L. Moyer10Jacob L. Berrigan11Brandyn R. West12J. Maximilian Fels13Larry Zeitlin14Andrew S. Herbert15Kartik Chandran16Chowdhury Raihan Bikash17Jonathan R. Lai18Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USAVirology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USADepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USAMapp Biopharmaceutical, Inc., San Diego, California, USAVirology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USAVirology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USAMapp Biopharmaceutical, Inc., San Diego, California, USAMapp Biopharmaceutical, Inc., San Diego, California, USADepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USAMapp Biopharmaceutical, Inc., San Diego, California, USAMapp Biopharmaceutical, Inc., San Diego, California, USADepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USAMapp Biopharmaceutical, Inc., San Diego, California, USADepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USAMapp Biopharmaceutical, Inc., San Diego, California, USAVirology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USADepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USADepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USADepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USAABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) is an enveloped, negative-sense RNA virus that is spread by ticks across Europe, Africa, and Asia and causes a lethal disease in humans (~30%–40% case fatality). There are currently no approved vaccines or therapeutics. Antibody-based therapeutics targeting the CCHFV surface glycoproteins Gn and Gc, which are responsible for viral attachment and fusion during entry, are a promising therapeutic approach. We previously isolated three broadly neutralizing Gc-targeting human monoclonal antibodies (mAbs) and showed certain cocktails of these mAbs demonstrated synergistic virus neutralization. Furthermore, physical linkage of two of these mAbs into a dual variable domain (DVD) bispecific antibody (bsAb) DVD-121-801 resulted in improved neutralization and therapeutic protection against a lethal CCHFV challenge in mice. However, the molecular requirements for the activity of DVD-121-801, and why it is augmented over monospecific parental mAbs, remain the topic of investigation. Here, we generated a new panel of bsAb variants of DVD-121-801 to explore the spacing and avidity requirements and further optimize its protective efficacy against divergent CCHFV isolates. We evaluated these variants for neutralization, fusion inhibition, and protection with virus-like particles, authentic viruses, and in vivo challenge studies. We found that neutralization potency was relatively unaffected by spacing or identity of variable domains within the bsAb, but that one next-generation design employing longer and more flexible linkers between variable domains (DVD-121-801GS) had a greater breadth of therapeutic protection. Our efforts highlight the importance of antibody avidity and lead to an improved bsAb variant of DVD-121-801 for further therapeutic development.IMPORTANCECrimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus endemic to Europe, Africa, and Asia that causes severe disease in humans (30%–40% case fatality). There are currently no approved vaccines or therapeutics. In prior work, physical linkage of two Gc-specific monoclonal antibodies (mAbs) targeting distinct epitopes into a dual variable domain (DVD) bispecific antibody (bsAb), termed DVD-121-801, resulted in potent neutralization in vitro and therapeutic protection in vivo. Here, a panel of variants of this bsAb was developed and evaluated for neutralization potency, fusion inhibition, and therapeutic efficacy, and our work shows this panel to be effective against multiple isolates of CCHFV. Furthermore, incorporating longer, more flexible linkers between variable domains resulted in a lead candidate with improved activity and therapeutic potential compared to the parental bsAb. Utilizing this panel, we also explored the contribution of antibody avidity in antibody-mediated protection against CCHFV infection.https://journals.asm.org/doi/10.1128/mbio.03202-24Crimean-Congo hemorrhagic fever virusmonoclonal antibodybispecific antibodyimmunotherapy |
| spellingShingle | Albert Wang Stephanie R. Monticelli Ariel S. Wirchnianski Dafna M. Abelson Ana I. Kuehne Russell R. Bakken Marissa Middlecamp Michael Weingart Olivia Vergnolle Zachary A. Bornholdt Crystal L. Moyer Jacob L. Berrigan Brandyn R. West J. Maximilian Fels Larry Zeitlin Andrew S. Herbert Kartik Chandran Chowdhury Raihan Bikash Jonathan R. Lai Avidity and variable domain spacing strongly influence the therapeutic potency of bispecific antibodies against Crimean-Congo hemorrhagic fever virus mBio Crimean-Congo hemorrhagic fever virus monoclonal antibody bispecific antibody immunotherapy |
| title | Avidity and variable domain spacing strongly influence the therapeutic potency of bispecific antibodies against Crimean-Congo hemorrhagic fever virus |
| title_full | Avidity and variable domain spacing strongly influence the therapeutic potency of bispecific antibodies against Crimean-Congo hemorrhagic fever virus |
| title_fullStr | Avidity and variable domain spacing strongly influence the therapeutic potency of bispecific antibodies against Crimean-Congo hemorrhagic fever virus |
| title_full_unstemmed | Avidity and variable domain spacing strongly influence the therapeutic potency of bispecific antibodies against Crimean-Congo hemorrhagic fever virus |
| title_short | Avidity and variable domain spacing strongly influence the therapeutic potency of bispecific antibodies against Crimean-Congo hemorrhagic fever virus |
| title_sort | avidity and variable domain spacing strongly influence the therapeutic potency of bispecific antibodies against crimean congo hemorrhagic fever virus |
| topic | Crimean-Congo hemorrhagic fever virus monoclonal antibody bispecific antibody immunotherapy |
| url | https://journals.asm.org/doi/10.1128/mbio.03202-24 |
| work_keys_str_mv | AT albertwang avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT stephaniermonticelli avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT arielswirchnianski avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT dafnamabelson avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT anaikuehne avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT russellrbakken avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT marissamiddlecamp avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT michaelweingart avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT oliviavergnolle avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT zacharyabornholdt avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT crystallmoyer avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT jacoblberrigan avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT brandynrwest avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT jmaximilianfels avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT larryzeitlin avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT andrewsherbert avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT kartikchandran avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT chowdhuryraihanbikash avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus AT jonathanrlai avidityandvariabledomainspacingstronglyinfluencethetherapeuticpotencyofbispecificantibodiesagainstcrimeancongohemorrhagicfevervirus |