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AAPS J (2021) 23:115 Vol.:(0123456789) https://doi.org/10.1208/s12248-021-00642-5 Review Article Theme: Compendium of Immunogenicity Risk Assessments: an Industry Guidance Built on Experience and Published Work Guest Editor: Johanna Mora. 1 2 3 4 5,6 Mark A. Kroenke · Mark N. Milton · Seema Kumar · Eris Bame · Joleen T. White Received: 21 May 2021 / Accepted: 23 August 2021 Abstract. The objective of this manuscript is to provide the reader with a hypothetical case study to present an immunogenicity risk assessment for a multi-specific therapeutic as part of Investigational New Drug (IND) application. In order to provide context for the bioanalytical strategies used to support the multi-specific therapeutic presented herein, the introduction focuses on known immunogenicity risk factors. The subsequent hypothetical case study applies these principles to a specific example HC-12, based loosely on anti-TNFα and anti-IL-17A bispecific molecules previously in development, structured as an example immunogenicity risk assessment for submission to health authorities. The risk of higher incidence and safety impact of anti-drug antibodies (ADA) due to large protein complexes is explored in the context of multi-specificity and multi-valency of the therapeutic in com- bination with the oligomeric forms of the targets. KEY WORDS: Anti-drug antibody · Bispecific therapeutic · Immunogenicity risk assessment · Multi-specific therapeutic · Oligomeric target response and risk of clinical consequences if an immune INTRODUCTION response is generated. The latter is particularly critical to the overall benefit risk assessment and likely to inform the Immunogenicity risk assessment is an important compo- nent of biotherapeutic drug development, and part of the acceptable level of immunogenicity risk. The potential clinical applications of multi-specific therapeu- overall benefit risk assessment. A robust immunogenicity risk assessment process ensures that the most appropriate tics are demonstrated by 3 approved products (Table I and II) and a breadth of molecules currently under investigation (1, 2). These candidate molecules advance into the clinic, and that clini- cal immunogenicity is appropriately monitored. Risk assess- include obligate concepts where having both specificities in the same molecule is critical (Table II), and combinatorial concepts ment for multi-specific therapeutics can be especially chal- lenging given that many molecules in this family can bind where the two specificities do not necessarily need to be in the same molecule but may provide additional efficacy benefit over immune cells, trigger T cell activation, or bring together dis- parate molecules in a non-native way. Immunogenicity risk combination therapy (Table III). Of the 92 multi-specific thera- peutics in clinical development as of March 2019 (2 ), 78 are for assessments include both the risk of generating an immune cancer and 14 in other indications such as autoimmune disorders, infectious diseases, hemophilia, diabetes, and ophthalmology. Guest Editor: Johanna Mora. There are additional concepts that are no longer in development Amgen Inc, Thousand Oaks, California, USA not represented in these tables, such as the anti-TNFα and anti- Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, IL-17A bispecific hypothetical case study presented herein (3 –7), USA and new concepts introduced since the source article was written EMD Serono Research & Development Institute, Inc, Billerica, in 2019 (2), such as the Ang-2 and VEGF bispecific faricimab ( 8). Massachusetts, USA Biogen, Cambridge, Massachusetts, USA As there are no formatting requirements around authoring Bill & Melinda Gates Medical Research Institute, One Kendall Square, an immunogenicity risk assessment, this article is part of a Building 600, Suite 6-301, Cambridge, Massachusetts 02139, USA series designed to provide examples for consideration. The To whom correspondence should be addressed. (e–mail: document structure of the immunogenicity risk assessment Joleen.white@gatesmri.org) Vol.:(0123456789) Vol.:(0123456789) AAPS J (2021) 23:115 Table I FDA or EMA approved multi-specific therapeutics as of April 2021 including immunogenicity incidence reported on the label Name Company Molecule description Indication(s) Immuno- Approval year genicity (% Incidence) Malignant ascites HAMA 94% EMA 2009–2017 Removab® (9) Fresenius Biotech and Rat-mouse hybrid IgG2 EpCAM, which is found (catumaxomab) Trion Pharma Neovii in high levels on some Biotech GmbH types of cancer cells CD3, which is found on T cells < 2% FDA 2014 Blincyto® (10, 11) Amgen CD19/CD3 Relapsed or refractory (blinatumomab) B cell precursor acute lymphoblastic leuke- mia (ALL) Acute lymphoblastic leu- kemia (ALL) who are in remission but still have minimal residual disease (MRD) Hemlibra® (12, 13) Chugai and Roche FIXa x FX Routine prophylaxis of 3.5% ADA FDA 2017 (emicizumab) patients with hemo- < 1% nAb philia A with and with- out FVIII inhibitors Removab (catumaxomab) was previously approved by EMA with the subsequent removal at the request of the license holder presented here is a result of input from the authors and their bispecific killer engager (BiKE), trispecific killer engager view of a fit for purpose risk assessment that may be sub- (TriKE), multi-specific antibody-based therapeutics by mitted to health authorities. It does not reflect a structure cognate heterodimerization (MATCH), nanobody, diabody, endorsed by health authorities nor the experiences of any diabody-Ig, etc. to bring together specific recombinant particular sponsor. This content is generally consistent with domains in a non-native way for simultaneous multi-target a truncated version of the integrated summary of immuno- recognition (2, 18–25). The extensive protein engineering genicity structure option proposed by health authorities (14, required to design and optimize such novel multi-specific 15), with removal of sections not pertinent depending on the therapeutics with mono- or multi-valency could inadvert- development stage of the biotherapeutic program. ently increase the product attribute-related immunogenic risk for these recombinant molecules. Sequence Considerations Critical Quality Attributes As with all protein therapeutics, one of the main drivers of risk of developing an immune response for a multi-specific thera- Product critical quality attribute (CQA)-related risk is another peutic is the primary amino acid sequence and T cell epitope driver that is typically considered in protein therapeutic content (16). Any protein that has been engineered to change immunogenicity risk assessment (14, 26–28), and multi- the amino acid sequence, has linker regions that introduce new specific therapeutics are no exception. The CQA risk factors linear epitopes that are not present in either parent, or that has such as protein aggregates, posttranslational modifications, non-natural or modified amino acids may have an elevated risk host cell- and process-related impurities (such as host- of developing an immune response. Most multi-specific thera- cell proteins and DNA, endotoxin, chromatography resin, peutics contain these elements, and consequently, these novel contaminants, and degradants, etc.), formulation excipients sequences should be evaluated for immunogenic risk using and container closure, etc. are also relevant to multi-specific available tools such as in silico prediction, in vitro T cell assays, therapeutics. MHC binding assays, or ex vivo models (17). Given the non-native arrangement of disparate functional Additionally, multi-specific therapeutics employ diverse domains in multi-specific molecules, there is potentially a protein engineering techniques such as quadroma, knobs-in- higher immunogenicity risk related to aggregation. For all holes (KIH), CrossMAb, Triomab, strand-exchange engi- other CQAs, the potential for an impact on immunogenic- neered domain (SEED), cross-over dual variable (CODV), ity risk is similar for mono-specific and multi-specific DART® (Dual-affinity Retargeting), TRIDENT®, dock- molecules. and-lock (DNL), BiTE® (Bispecific T cell Engager), AAPS J (2021) 23:115 Vol.:(0123456789) Table II Obligate concept multi-specific therapeutics in clinical development as of March 2019 Mechanism of action Targets Indication Bridging cells (in-trans): T cell redirection and/or activation CD3 x B7-H3 Solid malignancies CD3 x BCMA Hematological malignancies CD3 x CD123 Hematological malignancies CD3 x CD19 Hematological malignancies CD3 x CD20 Hematological malignancies CD3 x CD33 Hematological malignancies CD3 x CD38 Hematological malignancies CD3 x CEA Solid malignancies CD3 x CLEC12A Hematological malignancies CD3 x DLL3 Solid malignancies CD3 x EGFRvIII Solid malignancies (EGFRvIII + glioblastoma) CD3 x EpCAM Solid malignancies CD3 x FcRH5 (CD307) Hematological malignancies CD3 x FLT3 Hematological malignancies CD3 x GPC3 Solid malignancies CD3 x gpA33 Solid malignancies CD3 x GPRC5D Hematological malignancies CD3 x HER2 Solid malignancies (HER2 +) CD3 x MUC16 Solid malignancies CD3 x P-cadherin Solid malignancies CD3 x PSMA Solid malignancies (prostrate) CD3 x SSTR2 Solid malignancies CD3 x HIV-1 Env HIV-1 infection Bridging cells (in-trans): NK cell redirection and/or activation CD16A x CD30 Hematological malignancies CD16 x CD33 Hematological malignancies Bridging cells (in-trans): immune cell redirection and/or activation CD40 x MSLN Solid malignancies PD-L1 × 4-1BB Hematological and solid malignancies Bridging receptors (in-cis) HER2 x HER3 Solid malignancies (breast cancer) EGFR x MET Solid malignancies PD-1 × ICOS Solid malignancies CD32b x CD79b Immune-mediated disorders FGFR1 x KLB Diabetes Cofactor mimetic FIXa x FX and/or FXa Hemophilia A Piggyback Psl x PcrV Pneumonia in mechanically ventilated subjects Piggyback (bispecific molecules for half-life extension) IL-6R x HSA SLE and rheumatoid arthritis TNFα x HSA Rheumatoid arthritis Adapted from (2) Mechanism of Action—Immune Modulation antibodies (ADA), to be assessed during the clinical pro- gram. Data from combination studies with nivolumab and As the industry gains experience with immunomodulatory ipilimumab have clearly demonstrated this concept. When multi-specific therapeutics, pharmacological or mechanism used as a monotherapy, nivolumab had a reported incidence of action (MoA)-based immunogenic risk factors are emerg- of anti-nivolumab antibodies of 11.2%. As a combination ing as a crucial factor impacting the immune response to the therapy with ipilimumab, however, the incidence jumped to drug. For instance, does the protein involve antagonism of 37.8%, presumably based on the same antibody assay (29, more than one immune checkpoints, does it bind B cells, and/ 30). A similar finding was observed with durvalumab and or does it agonize a costimulatory molecule? If the answer tremelimumab (31). Multi-specific therapeutics that combine is yes to one or more of these possibilities, the molecule multiple immune stimulatory domains into the same mol- may have a higher than average risk of eliciting anti-drug ecule will carry this enhanced immunogenic risk. Vol.:(0123456789) AAPS J (2021) 23:115 Table III Combinatorial concept multi-specific therapeutics in clinical development as of March 2019 Mechanism of action Targets Indication Targeting tumor heterogeneity CD19 x CD22 Hematological malignancies EGFR x MET Solid malignancies EGFR x LGR5 Solid malignancies Targeting ligand redundancy ANG2 x VEGF Solid malignancies DLL4 x VEGF Solid malignancies BAFF x B7RP1 SLE and rheumatoid arthritis BAFF x IL-17A Sjögren syndrome IL-17 × IL-13 Asthma IL-23 × CGRP Autoimmune diseases IL-4 × IL-13 Diffuse cutaneous systemic sclerosis NGF x TGF Painful osteoarthritis of the knee and painful diabetic neuropa- thy VEGFA x ANG2 Neovascular wet age-related macular degeneration and diabetic macular oedema Targeting multiple checkpoints PD-1 × CTLA-4 Solid malignancies PD-1 × LAG3 Hematological and solid malignancies PD-1 × TIM3 Solid malignancies PD-L1 x CTLA-4 Hematological and solid malignancies PD-L1 x LAG3 Solid malignancies PD-L1 x TIM3 Solid malignancies Targeting checkpoint and tumor antigens PD-1 × undisclosed TAA Solid malignancies CD47 x CD19 Hematological malignancies Increasing avidity: biparatopic bispecific antibodies HER2 x HER2 Solid malignancies (HER2 +) HER2 x HER2 ADC Solid malignancies (HER2 +) Adapted from (2) When assessing MoA-based immunogenicity risk fac- increase linkage of T cells to B cells that recognize the tors, direct binding to B cells of at least one domain of the other domain(s) of the multi-specific therapeutic, poten- multi-specific therapeutic must be considered. For exam- tially enhancing the likelihood of drug-specific B cell ple, a multi-specific therapeutic may be intended to deliver clones receiving T cell help. a signal to a specific subset of cells expressing target X On the other hand, the MoA of some biotherapeutics may via linkage of the signaling domain to an anti-target X also mitigate the risk of generating an immune response. antibody. In this scenario, B cell clones that recognize One potential example of this is blinatumomab, which the antibody may also efficiently receive the signal. If the depletes CD19 + B cells. Even though it is composed of 2 signaling domain has the ability to modulate B cell biol- murine single chain antibodies, the clinical immunogenic- ogy, then the antibody response to the therapeutic could ity incidence remains less than 2% (10, 11). Other multi- be either enhanced or diminished. specific therapeutics may mitigate the immune response via Evidence also suggests that inclusion of a CD3 bind- other mechanisms, such as expanding regulatory T cells. ing domain into a multi-specific therapeutic may be an immunogenicity risk factor. In general, molecules that Mechanism of Action—Complex Formation bind CD3, such as otelixizumab or teplizumab, appear to be prone to ADA responses (32, 33) and this may hold Another MoA-based immunogenicity risk factor is the true for T cell engagers as well, with AMG 211 eliciting ability of the therapeutic to form large complexes with antibodies in all subjects treated at > 3.2 mg in a phase 1 the target(s). This means targets that are oligomeric (as study (34). There are several plausible hypotheses for this mentioned earlier) and either soluble or shed at significant finding depending on whether the mechanism is T cell levels pose the highest risk of large complex formation. engagement or T cell binding. For mechanisms engaging Large complexes have long been hypothesized to be T cells, ADA responses may be more likely in the presence immunogenic (35, 36). of wide-spread T cell activation. For T cell binders that are While there are no definitive examples of mechanisti- not intended to activate T cells, anti-CD3 domains may cally proven, large complex-mediated immunogenicity to a AAPS J (2021) 23:115 Vol.:(0123456789) therapeutic, strong correlative data exist. Adalimumab and can be used to inform risk of positive seroconversion, it infliximab both bind trimeric TNFα and form complexes of must be assessed in the clinic. SC administration may have 4,000 kDa and 14,000 kDa, respectively; both are immu- an increased risk of protein aggregation due to dosing high nogenic in clinical studies, while etanercept does not form concentrations in small volume (47). The aggregates and large complexes and is relatively non-immunogenic (37, other antigenic attributes may cause an increase in the thera- 38). Multi-specific therapeutics can further enhance this peutic protein uptake, processing and presentation by APCs complex forming ability since there are multiple targets. resulting in immune responses (48). High therapeutic doses For instance, ABT-122 and JNJ-61178104 are both built in some cases have been shown to saturate neutralizing Ab on an adalimumab backbone and involve the addition of responses and restore therapeutic binding to its intended an IL-17A binding domain (39, 40). In healthy volunteer target. High doses may also induce long-term immune tol- studies, ABT-122 and JNJ-61178104 have a reported ADA erance (49). incidence of 99% and 100%, respectively, presumably due Longer treatment duration may also increase the risk of to enhanced ability to form large complexes (3, 41). In order an immune response for protein therapeutics. The clinical to assess this risk, complex formation should be evaluated immunogenicity incidence of IFNβ-1a-Rebif increased preclinically so that the ratio in which the therapeutic can- with a more frequent dosing regimen and subcutane- didate binds the target is well understood. Any downstream ous administration relative to IFNβ-1a-Avonex (50, 51), effector function driven by the drug Fc domains should also with the caveat that this increase could be due to dif- be explored. ferent study populations, immunogenicity assay formats, In addition to soluble complexes, multimeric membrane etc. While the highly potent immune-stimulatory multi- bound targets can mediate complex formation on the sur- specific therapeutics may not require long treatment dura- face of cells. When these targets are expressed in antigen- tion, the immune-suppressive multi-specific therapeutics presenting cells (APCs), it can facilitate complex uptake and may benefit from their pharmacological activity, irrespec- increase the T cell mediated adaptive immune response (42). tive of treatment duration. The concomitant medications (e.g., antihistamines, corticosteroids, methotrexate, inter- ferons) and standard of care may also augment or reduce Treatment‑Related Risk Factors—Patient and Regimen the antigen-processing of multi-specifics through their immunomodulatory effects. As with all proteins, the intended patient population could also contribute to the immunogenic risk of multi-specific therapeutics. Important considerations include immune sta- Potential Clinical Consequences tus of the patient population and prior exposure to related therapeutics. In an example for prior exposure, subjects with The risk of consequences from an immune response needs prior exposure to adalimumab have an increased immuno- to be considered in addition to the risk of generating an genic risk for a multi-specific therapeutic built on an adali- immune response. mumab backbone. Immune status may be on a population For multi-specifics that contain non-antibody compo- level, such as autoimmune disease, or on an individual level, nents, a key aspect for multi-specific therapeutics is if one such as immunosuppressive methotrexate therapy. or more components resembles an endogenous counterpart, Treatment-related immunogenicity risk factors such as the potential consequences of cross-reactivity of ADA are administration route, dose, dosing frequency, treatment determined by the function and uniqueness of that endog- duration and concomitant immunomodulators (14, 27, 43, enous counterpart (52). Since the multi-specific therapeu- 44) are also critical elements in the immunogenicity risk tic may be more immunogenic than the native protein, any assessment for multi-specific proteins. The extent of immune increased incidence may adversely impact patient safety to a response due to treatment-related risk factors is dependent greater extent than occurs for the mono-specific compound. on the complex interplay between product-related intrinsic While non-clinical studies are not predictive of factors and patient-related extrinsic factors. the clinical incidence (16, 53, 54), they can provide Historically, subcutaneous administration (SC) has been valuable information on potential clinical consequences considered more likely to produce an immune response of an immune response if generated. For example, compared to intramuscular (IM) and intravenous (IV) if a multi-specific therapeutic antibody, which was routes; however, this has not been observed consistently for engineered to include an immunostimulatory cytokine, products with both SC and IV routes approved (45, 46). drives an enhanced immune response in cynomolgus An analysis of clinical data for 27 non-oncology immu- macaques relative to the parent antibody alone, that nomodulatory antibodies showed no clinically meaningful enhancement may be clinically relevant if the cytokine difference in immunogenicity incidence between IV and SC biology is conserved across species. An important administration routes (31). While the route of administration caveat to this nonclinical risk assessment approach is Vol.:(0123456789) AAPS J (2021) 23:115 that immunogenicity driven by foreign sequence (in IMMUNOGENICITY RISK ASSESSMENT this case the human sequence) cannot be differentiated from MoA-driven immunogenicity with any degree of Planned Administration certainty and this must be acknowledged in the integrated immunogenicity risk assessment. The planned administration is dosing SC every 3 weeks (q3w) for life-long treatment. With long-term exposure, seroconversion may occur at any point during treatment, so understanding the kinetics of ADA seroconversion during HYPOTHETICAL CASE STUDY HC‑12 clinical trials will inform the cumulative risk of seroconver- sion for individual patients. This will help determine if there In this hypothetical case study, HC-12 is based on a con- is a time period after which incidence has plateaued and cept of an anti-TNFα monoclonal antibody (adalimumab) patients who have not seroconverted are unlikely to do so. with anti-IL-17A domains fused to the C-terminus of the For patients with autoimmune diseases on immunosup- heavy chains (Fig. 1). Of the various TNFα and IL-17A pressants, there would be gaps in treatment during life-long bispecifics previously in development, it is closest to use. Patients are recommended to stop anti-TNFα immu- COVA-322/JNJ-63823539. Please note that none of the nomodulatory therapies for surgeries, during infections, and authors have worked on COVA-322/JNJ-63823539, and sometimes when receiving vaccinations (55, 56). If there are therefore, the contents of the actual immunogenicity risk opportunities during the clinical development to evaluate assessment are unknown. rechallenge after these types of drug holidays, that could be As illustrated below, the risk factors requiring the most helpful for prescribers to understand the potential impact of attention vary depending on the molecule and intended drug holidays on immunogenicity incidence of their patients. use. The three areas of greatest attention for HC-12 were If opportunities arise during clinical development, such as planned administration, primary sequence, and mechanism gaps between a blinded study and an open-label extension or of action. temporary cessation of treatment during rescreening for con- tinued eligibility, immunogenicity samples will be acquired using the frequency at initial startup to evaluate potential accelerated kinetics of seroconversion. While gaps in treat- ment for immunosuppresants are hypothesized to potentially increase the risk of positive seroconversion versus continu- ous administration, there is a dearth of clinical data to test this hypothesis. Sequence‑Based Risk An-TNFα When bispecifics are generated, they may use fragments of IgG antibodies that are joined by a linker. The use of antibody fragments and the linker molecule may result in the generation of neo-epitopes that were not present in the full-length parental antibodies or uncover hidden (cryptic) Fc scaffold epitopes that were buried in the 3D structure of the paren- tal antibodies. Such epitopes may increase the immuno- genicity risk for the bispecific compared to the parental antibodies. To assess the sequence-based risk of HC-12, in silico analysis of MHC class II binding peptides (agretopes) was An-IL-17A carried out using the Immune Epitope Database (free access at http:// www. iedb. org, paid licenses for local installation behind a firewall). In silico analysis focused on the novel sequences from the candidate IL-17A binding domains and associated linkers which had not previously been adminis- HC-12 structure tered to humans. An in silico score was calculated for each candidate molecule taking into account the strength and Fig. 1 Structure of HC-12 AAPS J (2021) 23:115 Vol.:(0123456789) breadth of the predicted agretopes, and the IL-17A binding complexes can also trigger T-dependent antibody produc- domain with the lowest in silico score was selected. tion (35) and the formation of antigen–antibody immune In silico analysis does not take into account TCR recog- complexes is often used as a vaccination strategy. nition; therefore, sequence-based risk was further assessed HC-12 has 2 binding domains for each target, raising the using an in vitro T cell assay (such as an ELISpot or flow possibility of significant protein complex formation (Fig. 2). cytometry assay). The parent monoclonal antibody adali- In order to assess this risk, HC-12 was mixed at various mumab was compared to the full HC-12 molecule to assess ratios with TNFα and IL-17A and immune complex forma- the additional risk posed by the IL-17A binding domains and tion was assessed using SEC-MALS. At high drug to tar - linker sequence. Both adalimumab and HC-12 elicited simi- get ratios, immune complex formation was limited. When lar T cell responses in a panel of 50 donors, indicating that HC-12 and targets were present at roughly equimolar con- the addition of the IL-17A binding domains did not enhance centrations, large immune complexes of up to 6,000 kDa sequence-based risk in naïve subjects. were observed. While concerning, a similar phenomenon is observed Mechanism of Action‑Based Risk with the HC-12 parent monoclonal antibody, adalimumab. Complexes of up to 4,000 kDa of adalimumab and TNFα Antagonism of two pro-inflammatory molecules, TNFα were observed in vitro (38). The introduction of a second oligomeric target binding sequence into HC-12 could further and IL-17A, is not expected to enhance immunogenicity and may cause a slight mitigation of immunogenicity by enhance immunogenic risk relative to adalimumab, and the potential for immune complex formation contributes signifi - inhibiting inflammation. Consequently, there is a low risk of immunogenicity based on downstream target biology. cantly to the immunogenic risk of HC-12. However, both targets are oligomeric and soluble. TNFα is a homo-trimeric cytokine and IL-17A can exist in solution Attribute‑Related Risk as a homo-dimer or a hetero-dimer with IL-17F. Although TNFα is usually considered to be a soluble pro- HC-12 drug product attributes may impact immunogenic tein, it exists in a transmembrane form. It has been proposed risk. The primary risks are formation of HC-12 aggregates that the high incidence of immunogenicity observed with and complementarity determining region tryptophan anti-TNFα antibodies may be partially explained by trans- oxidation. Levels of these attributes in HC-12 drug membrane TNFα-mediated therapeutic uptake and antigen substance are low and within target ranges, indicating that presentation on professional APCs (42). the attribute-related risk of immunogenicity is low. Aggregates with highly repetitive structures can elicit ADA responses by directly activating B cells by the T cell Excipient‑Related Risk independent mechanism (57). Both B1 and MZ B cells pro- duce a rapid response that does not involve affinity matura- The level of formulation excipients such as polysorbate 80 tion or the development of memory resulting in short-lived, and sucrose in HC-12 are within target ranges and comply low affinity and broad specificity. Furthermore, immune with United States Pharmacopeia-National Formulary, Fig. 2 Potential quaternary structure of HC-12, TNFα, and IL-17A HC-12 IL-17A dimer TNFα trimer Vol.:(0123456789) AAPS J (2021) 23:115 European Pharmacopoeia, and Japanese Pharmacopeia Pharmacokinetic Assays guidelines. Formulation components are not expected to impact immunogenic risk. For the case study of HC-12, measuring the clinically rel- evant therapeutic concentrations by means of a free PK assay format is recommended (58). A free assay format is Patient‑Related Risk designed to measure the drug that is unbound to targets and therefore available for binding. Due to the design, it is also HC-12 will be administered subcutaneously to subjects with autoimmune disease. In the absence of any immunosuppres- the most sensitive to interference by antibodies binding the active sites, and therefore can suggest neutralizing activity sive concomitant medications, the risk of immunogenicity in this population and with this route of administration is of an ADA response when available PD and ADA data are integrated together (i.e. association of reduced PK and PD generally thought to be higher relative to administering a therapeutic intravenously to immunosuppressed oncology with ADA positivity) (58). The bispecific nature of HC-12 and circulating concentrations of oligomeric TNFα and IL- patients (45). 17A, make it an intricate process to select the most suitable free PK assay format (59). With a cellularly expressed target Summary TNFα, it is not possible to do a total assay in serum since a proportion of antibody will be bound to the cellular portion. The primary driver of immunogenic risk for HC-12 is phar- Please note that all free assay formats will underestimate macological immunogenic risk; specifically, the formation the total protein concentration since intentionally measur- of large protein complexes with target, particularly for this ing the portion that has binding arm(s) available. In addi- format with four binding moeities. Secondary to this risk is tion, the free concentration will increase during the assay patient-related immunogenic risk due to the target popula- process as both dilution and exposure to reagents will alter tion and route of administration. The clinical study will be the equilibrium. designed with these risks in mind, and a dosing scheme has A ligand-binding assay utilizing an anti-idiotype antibody been selected which will maintain a high ratio of HC-12 to to adalimumab, or immobilized TNFα, may be one approach target in patient serum in order to reduce immune complex to capture free HC-12 in the collected patient samples. Once formation as much as possible. Based on this immunogenic- HC-12 is captured, it can then be detected in the assay via ity risk assessment, immunogenicity incidence will be care- an anti-human antibody conjugated to HRP or a reagent that fully monitored in the first in human study, and a robust binds anti-IL-17A. The former approach, however, will not bioanalytical strategy has been devised. distinguish whether IL-17A is bound, or not, to the IL-17A selective domains fused to the C-terminus of the antibody’s heavy chains. Instead, our recommendation is to pursue a PK assay format utilizing the unoccupied IL-17A selec- BIOANALYTICAL STRATEGY FOR HC‑12 tive domains as means of detecting the anti-adalimumab- captured HC-12 as the primary PK assay. To accomplish Successful implementation of the bioanalytical strategy this, IL-17A or an antibody specific to the domains, which ensures that scientific, data-driven decisions are made also blocks their binding to IL-17A, may be used. When towards the clinical advancement of the therapeutic drug using anti-idiotype reagents, binding surfaces may mimic and in the context of the immunogenicity risk assessment. conformational epitopes of targets. Therefore, target inter- The strategy primarily involves the appropriate selection ference will be evaluated during reagent selection and assay and development of bioanalytical assays measuring development. therapeutic drug concentrations and detection of ADA Please note that this intact free assay format can only which may have developed during treatment. However, detect molecules that have both an unoccupied anti-TNFα considering pharmacodynamic (PD) assessments as part of and an unoccupied anti-IL-17A. Since HC-12 is not an the bioanalytical strategy is also highly encouraged, as the obligate bispecific concept, additional assays measuring utility of integrating pharmacokinetic (PK), ADA, and PD free adalimumab and free anti-IL-17A may also be needed data may prove beneficial in understanding clinical impact pairing the anti-idiotype reagents with anti-human immu- of immunogenicity. As it pertains to the selection and noglobulin framework, with the understanding that there development of the bioanalytical assays, it is important to is overlap between the species detected in the three assays apply scientific and strategic judgement, considering aspects (59). In addition, a total serum assay may be needed to char- related to assay format, pre-analytics of sample collection, acterize the risk for complex formation, acknowledging that as well as understanding the underlying biology of the target it is not a true total assay because the cell-bound portion is and the therapeutic. not detected. AAPS J (2021) 23:115 Vol.:(0123456789) Immunogenicity assay, coupled with a loss or reduction in signal, would provide valuable insight on the characterization of ADA against HC-12. Similar to the multi-domain biotherapeutic-specific considera- tions for PK bioanalytical strategies, drug development-phase Neutralizing Antibodies appropriate scientific and strategic considerations must be applied to the selection and development of immunogenicity While it is important to assess neutralizing anti-drug anti- assays for multi-specific therapeutics. For the case study of bodies (nAb) throughout clinical development of HC-12, HC-12, a bridging assay format where study samples are incu- we propose to not develop a dedicated neutralizing antibody bated with therapeutic drug labeled with either capture (i.e., assay. Instead, we propose a data integration approach uti- biotin) or detection (i.e., digoxin, ruthenium) molecules, was lizing the available data from assays such as pharmacoki- selected for detecting the presence of both low and high affin- netic (free PK format), PD and ADA, as more informative ity antibodies against HC-12. Though this bridging assay for- than the use of a stand-alone nAb assay (63). For HC-12, mat captures ADA of multiple binding affinities and isotypes, a reduction of free drug concentration in ADA-positive it does require that drug tolerance of the assay is appropriate samples would indicate reduced biological activity either for the anticipated samples to be tested, ensuring meaningful directly via neutralizing antibodies, indirectly via clearing ADA detection even in those samples expected to contain high antibodies, or even partially bound species. With no endog- trough concentration (C ) levels of therapeutic drug. enous counterparts to the two HC-12 moieties, there is not trough Related to the mechanism of action of HC-12, which tar- a mechanistic safety risk for nAb, so it may not be critical gets the neutralization of TNFα and IL-17A cytokines, it is of to differentiate between the possibilities. For a therapeutic great relevance to know that both TNFα and IL-17A exist as with an antagonistic mechanism of action which is deemed trimeric and dimeric proteins, respectively (60, 61). Due to low immunogenic risk, based on considerations such as the oligomeric nature of these targets, the presence of circulat- the target, sequence homology to endogenous molecules ing TNFα and/or IL-17A in study samples could facilitate the and other factors discussed throughout, data from a stan- target-mediated bridging between the labeled drugs intended dalone nAb assay would not provide additional insight into to detect presence of ADA in the assay, therefore yielding a clinically meaningful neutralizing activity. Moreover, and false positive result. Hence, during development of the ADA where appropriate, recent guidance from FDA recognizes assay, it is important to understand if certain concentrations of the potential of the data integration approach as a means of oligomeric TNFα and/or IL-17A cytokines will allow bridg- informing on the neutralizing activity of an anti-drug anti- ing of the labeled drugs. This can be assessed by spiking in body response (64). titrating concentrations of IL-17A and TNFα cytokines in the Lastly, the bioanalytical strategy of a therapeutic is ADA assay, starting at 1,000-fold over the expected circulat- predominantly comprised of the strategic selection and ing endogenous concentration of each cytokine for the rel- development of assays informing on therapeutic concen- evant disease indication. This excess is used to reflect possible trations as well as presence of anti-therapeutic antibodies. increases in total target in the presence of binding antibodies Even though PD biomarkers are mainly driven by program (3, 58). Various pretreatment steps could be explored such and study specific aims, the apparent value of integrat- as stripping excess target, longer incubation times in reagent ing PD data along with PK and ADA supports that when excess, or switching to a sandwich format with anti-idiotype appropriate, PD assessments should also be taken into detection. At least one adalimumab biosimilar was able to suc- consideration as part of the overall bioanalytical strategy. cessfully implement a bridging format even with the trimeric Thus, biomarker and bioanalytical scientific leads need TNFα target (62). to work closely together and leverage synergies during Upon the successful testing of study samples, there may be the course of program’s development. For the purposes of incremental value to characterize if the ADA against HC-12 is the HC-12 case study, appropriate PD assessments, based targeted towards the therapeutics’ IL-17A selective domain or the on the therapeutics’ proposed mechanism of action, may adalimumab domain. One quick approach which may provide include the quantification of circulating free TNFα and insight, would be to separately incubate confirmed ADA posi- IL-17A cytokines as well as autoimmune disease markers. tive study samples with excess adalimumab lacking the IL-17A Though more challenging and complex, other PD assess- selective domain or with the IL-17A selective domain fused to ments may include TNFα and/or IL-17A pathway-specific another antibody of a similar isotype to adalimumab. To ensure cellular responses on the cellular subset(s) of clinical ADA specificity is to the IL-17A selective domain for the latter, interest for the indication. Ultimately, based on hypoth- it would also be recommended to incubate study samples with esis, such PD biomarkers should track well with drug con- the isotype control to adalimumab antibody lacking the IL-17A centration levels and be sensitive enough to detect nAb selective domain moiety. Testing these conditions in the ADA responses. Vol.:(0123456789) AAPS J (2021) 23:115 Sampling Schedule IL-17A) while both ABT-122 and JNJ61178104 both bind only one TNFα and IL-17A molecule each (66, 67). In the Since the totality of data needs to be incorporated into the FIH study for COVA322 (68), patients with stable chronic interpretation of the immunogenicity impact, sampling time moderate-to-severe plaque psoriasis received ascending points also impact interpretation. For HC-12, a more fre - single-doses of COVA322 or placebo as a constant-rate IV quent sampling schedule is recommended for the evalua- infusion followed by 12 weeks of evaluation. The immuno- tion of ADA with matched PK and PD analysis. To evaluate genicity and pharmacokinetics have been published, and an the kinetics of seroconversion in the phase 1 and phase 2 immune response against either the adalimumab or fynomer studies, sampling is recommended prior to dosing at day 1, moieties was observed with the ADA leading to an acceler- at C prior to subsequent doses every 3 weeks through ated clearance of COVA322 compared to the parental mol- trough month 6, and at C prior to subsequent doses every ecules and ADA incidence of 93.3% (6, 69). The clinical trough 12 weeks thereafter. It is anticipated that more PK and PD trial was terminated in 2016 based upon the observed safety samples will be needed for other development questions. profile of COVA322 (68). While the safety results of this In patient studies, monitoring is recommended for at least clinical trial have not been published as of writing this arti- 24 months assuming that patients will be given the option cle, the safety findings were presumably not observed in the to enroll in an open-label extension. Batch testing is rec- cynomolgus model with a NOAEL of 100 mg/kg/week, the ommended every 1–3 months as samples accumulate. The highest dose tested (40). The ADA incidence was also high time points and testing frequency can be decreased for the for JNJ61178104 (100%) and ABT-122 (99% healthy vol- phase 3 study pending seroconversion kinetics and inci- unteers, 34% across autoimmune patients on stable metho- dence. While a transient peak of IgM development may trexate immunosuppression) (3, 41). For JNJ61178104, be missed at 1–2 weeks, the 3-week interval aligned with the immunogenicity was significantly higher than the two trough concentrations increases the likelihood of detecting parent monospecific molecules golimumab (1.3%) and early seroconversion. JNJ54160444 (0%), which presumably used comparable assays (3). These data, taken together, show a high risk of developing ADA for bispecific anti-TNFα/IL-17A antibod- ies. Both JNJ61178104 and ABT-122 were well-tolerated, with no significant safety findings (3 , 41). ABT-122 was DISCUSSION discontinued due to no efficacy improvement over the mono- specific anti-TNFα (70). In the absence of published safety The presented hypothetical case study illustrates the impor- tance of understanding the potential quaternary structure of findings for COVA322, we hypothesize that larger immune complexes formed with the multivalent molecule could the drug and target that may lead to large structures. These structures can increase immunogenicity incidence by pre- have been the differentiating factor between the bispecifics, all of which exhibited high immunogenicity. This further senting as large immune complexes. In particular, the known immunogenic risk for adalimumab, hypothesized as a con- illustrates the importance of distinguishing between the risk of seroconversion and the risk of consequences from sequence of large complexes from multi-valency combined with oligomeric target, may have been further exacerbated seroconversion. by adding multi-valency to another oligomeric target in the multi-specific HC-12. While comparing immunogenicity incidence rates between molecules is fraught with assump- tions, this comparison generates a viable hypothesis that CONCLUSIONS should be considered in immunogenicity risk assessments of other multi-specific therapeutics. For visual scientists, draw- The vast majority of multi-specific therapeutics in the clinic ing the potential complexes can be a useful tool (as shown are based on an immunoglobulin framework. As novel in Fig. 2), understanding that there would be a distribution modalities emerge in the mono-specific space, it is reason- of sizes for any complex formation. If ADA are developed able to expect these to expand further into the multi-specific against the drug, these complexes can grow even larger lead- therapeutic space. The diverse immunogenicity risk assess- ing the risk of safety sequelae related to immune complex ments for those modalities may reveal additional risk factors deposition including glomerulonephritis (65). impacting multi-specific therapeutics that are less prevalent Data from past clinical trials of TNFα and IL-17A multi- on immunoglobulin scaffolds. specific therapeutics illustrate how the risk assessment could The valency of multi-specific therapeutics and targets can have informed candidate selection and clinical development. lead to large immune complexes in vivo per the presented As discussed above, the HC-12 matches the stoichiometry hypothetical case study and published literature. The of COVA322/JNJ-63823539 (bivalent for both TNFα and use of monovalent bispecific therapeutics may provide AAPS J (2021) 23:115 Vol.:(0123456789) opportunities to target oligomeric targets with reduced References immunogenic risk. Gathering additional information 1. Deshaies RJ. 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Nnane I, Schlereth B, Locher M, Shankar G, Davis H, Xu Z. the acquisition, analysis, or interpretation of data for the work; drafting Influence of immunogenicity on the pharmacokinetics of the work or revising it critically for important intellectual content; final JNJ63823539, a novel tumor necrosis factor alpha and interleu- approval of the version to be published; and agreement to be account- kin17a bispecific antibody, in healthy subjects. Clin Pharmacol able for all aspects of the work in ensuring that questions related to Ther. 2017;101(S1):S81. the accuracy or integrity of any part of the work are appropriately 7. Othman AA, Khatri A, Loebbert R, Peloso PM. Pharmacokinet- investigated and resolved. ics, safety, and tolerability of the dual inhibitor of tumor necrosis factor-alpha and interleukin 17A, ABBV-257, in healthy volun- teers and patients with rheumatoid arthritis. Clin Pharmacol Drug Dev. 2019;8(4):492–502. https:// doi. org/ 10. 1002/ cpdd. 611. 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"The AAPS Journal" – Springer Journals
Published: Nov 5, 2021
Keywords: Anti-drug antibody; Bispecific therapeutic; Immunogenicity risk assessment; Multi-specific therapeutic; Oligomeric target
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