Surrogate Antibodies & Therapeutic Monoclonals: Humans Mimicking Animals


By definition, a surrogate is a substitute.


Something or someone that can be used instead of something or someone else. In Latin, the term comes from the alliance of “rogare”, meaning “to ask” and “super”, meaning “over”. The superrogare was the person who had been elected as a replacement for a political function, the one the crowd expected a lot from.


Regarding the field of antibodies, a surrogate antibody is an immunoglobulin with equivalent functionality as the therapeutic antibody, but directed against the orthologous antigen. This antibody is generated from a certain species and detect an auto-antigen of the same selected species.


“But to what end?” will you say.


When a biotechnology or pharmaceutical entity intends to develop a therapeutic monoclonal antibody - and despite the considerable success and incredible evolution of in-vitro assays developed by CRO suppliers - the company is obligated to perform a series of proof-of-concept studies to attest the in-vivo functionality of this new drug candidate in animal efficacy models, before entering into humans (1-8).


The most important factor in conducting successful preclinical evaluation of a therapeutic monoclonal antibody is the choice of the most relevant animal species (Tabrizi et al. 2007, Martin et al. 2009), so offering comparative data of:

  • Antibody binding affinity,
  • Antibody avidity for the antigen,
  • Target tissue distribution profile,
  • Mechanism of action of the antibody,
  • Safety of the antibody via the absence of both immunogenicity and on-target toxicity.

In fact, the need of a judicious animal model for safety evaluation is so critical to the overall success of the monoclonal development program that species cross-reactivity should be included as part of the selection criteria when screening antibodies during lead candidates selection.


Developing directly the human version of the therapeutic antibody, biotech drug developers take the risk to trigger an anti-drug antibody (ADA) response in the animals. In fact, many antibodies, even chimeric or humanized, are immunogenic in animals.


A first potential option to circumvent this issue is the use of transgenic animal models, engineered to express the human target antigen. This solution is unfortunately very expensive and it is highly likely that pharmacokinetic properties of the antibody will be very different in the transgenic rodent compared to humans.


Another cost-effective option is the custom generation of a surrogate antibody, as proposed by SYnabs with its access to the different immune repertoires of mouse and rat. Of course, the disadvantage of this approach is that the monoclonal used in preclinical experiments won’t be the one entering into the clinics, potentially demonstrating some immunological differences (9).


Nevertheless, this approach has been successful in evaluating Infliximab (Remicade®), an chimeric IgG1 developed by Centocor (Johnson & Johnson), and Efalizumab (Raptiva®), mouse humanized antibody developed by Genentech / Merck Serono to treat auto-immune diseases.


More recently, in November 2019, Surface Oncology demonstrated that combination of a murine surrogate of SRF617 (enzymatic inhibitor of CD39) with anti-PD-1 inhibition significantly increases survival in a preclinical mouse tumor model (10).


One month later, BioInvent and Transgene announced compelling results from in-vivo preclinical studies with BT-001 murine surrogate, a multifunctional oncolytic virus (OV) expressing an anti-CTLA4 antibody and the cytokine GM-CSF (11).


In June 2020, Jounce Therapeutics explained that a surrogate mouse antibody showed synergistic combination activity with PD-1 inhibitors in anti-PD-1 resistant murine tumor models. Based on these preclinical data, JTX-1811, a high affinity CCR8-specific humanized monoclonal antibody with enhanced ADCC activity, is being developed for the selective depletion of TITR cells (12).


At the same moment, Agenus demonstrated the potential of mouse surrogate approach for the development of therapeutic AGEN1181 Fc Enhanced Anti-CTLA-4 immune checkpoint inhibitor (13).




(1)   ICH S6: Note for guidance on preclinical safety evaluation of biotechnology-derived pharmaceuticals (CPMP/ICH/302/95)


(2)   ICH S8: Note for guidance on immunotoxicity studies for human pharmaceuticals (CHMP/167235/2004)


(3)   ICH S9: Note for guidance on nonclinical evaluation for anticancer pharmaceuticals (EMEA/CHMP/ICH/646107/2008)


(4)   ICH S5a: Note for guidance on the detection of toxicity to reproduction for medicinal products including toxicity to male fertility (CPMP/ICH/386/95)


(5)   Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use (CDER/FDA 2007)


(6)   Guideline on development, production, characterization and specification for monoclonal antibodies and related products (EMEA/CHMP/BWP/157653/2007)


(7)   Concept paper on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use (EMEA/CHMP/BMWP/114720/2009)


(8)   Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins (EMEA/CHMP/BMWP/14327/2006)


(9)   Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol. 2004 Mar 1;172(5):2731-8. doi: 10.4049/jimmunol.172.5.2731. PMID: 14978070.


(10)  Warren M.C., Das S.G. Dulak A, Zaidi T., Devereaux E. The fully human antibody SRF617 is a potent enzymatic inhibitor of CD39 with strong immunomodulatory activity


(11)    https://www.bioinvent.com/media/press-releases/releases?id=0F9CF9B9D7828643


(12) https://www.globenewswire.com/fr/news-release/2020/06/22/2051269/0/en/Jounce-Therapeutics-Presents-First-Preclinical-Data-on-Anti-CCR8-Antibody-JTX-1811-and-Vopratelimab-Translational-Data-at-The-American-Association-for-Cancer-Research-Virtual-Annua.html


(13)   Tanne A, Vincent S, Paltrinieri E, Pawaria S. Expanding the Therapeutic Potential of anti-PD-1 and anti-CTLA-4 Therapy with Innovative Fc Engineering and Rationale Combinations for the Treatment of Solid Tumors