Antibody-drug conjugates have moved from a promising concept to one of the most actively pursued modalities in oncology drug development. With over a dozen approved ADCs on the market and hundreds in clinical pipelines, the pressure on discovery teams to move efficiently from target selection to IND filing has never been greater. Yet the path from initial concept to a clinical-ready molecule is littered with decision points that can derail programs, wrong antibody format, suboptimal linker-payload chemistry, immunogenicity surprises, or IP entanglements that surface only at the worst possible moment.
Getting an ADC to IND requires more than assembling the right components. It demands an integrated strategy where antibody discovery, conjugation chemistry, and preclinical development are designed to work together from day one.
Selecting the Right Antibody Format for ADC Development
The antibody component of an ADC is not simply a delivery vehicle — it determines target specificity, tissue distribution, payload capacity, and ultimately the therapeutic window. Format selection at the discovery stage has downstream consequences that reach all the way to clinical dosing.
Conventional full-length IgG antibodies in the H2L2 format remain the backbone of most approved ADCs. Fully human H2L2 antibodies, such as those generated through the Harbour Mice® platform, offer a direct path to clinical translation by eliminating the humanization steps that add time, cost, and immunogenicity risk to programs built on murine or camelid-derived sequences. The Harbour Mice® platform generates fully human monoclonal antibodies in both the traditional H2L2 format and a heavy chain-only antibody (HCAb) format, giving development teams access to two structurally distinct starting points within a single discovery system.
The Case for Compact Binders in Next-Generation ADCs
The field is actively moving beyond conventional IgG-based ADCs. Three formats are drawing particular attention: bispecific ADCs, antibody fragment ADCs, and peptide fragment-derived ADCs. Each of these next-generation designs benefits from compact binders — specifically VH domains derived from HCAb technology.
Single-domain VH antibodies sourced from Harbour Mice® HCAbs combine the developability advantages of camelid VHH nanobodies with fully human sequences, removing the immunogenicity liability that comes with camelid-derived formats. For ADC applications, this matters because compact binders enable precise payload titration and, for molecules with a total molecular weight below approximately 40 kDa, can achieve renal clearance — a pharmacokinetic profile that is difficult to access with full-length IgG constructs. This size-dependent clearance pathway opens new possibilities for controlling systemic toxicity exposure.
Bispecific ADCs represent the most complex iteration of this trend. In these constructs, both arms must bind to distinct targets, and the payload is designed to become active only within the tumor microenvironment — for example, through pH-dependent release or click chemistry — thereby sparing healthy tissue. Developing these molecules requires an antibody discovery platform capable of generating binders with the right affinity, selectivity, and structural compatibility for downstream conjugation and bispecific assembly.
From Immunization to Lead Selection: Where Timelines Are Won or Lost
Speed-to-IND is a legitimate priority, but compressing the wrong steps creates problems that surface later at far greater cost. Immunization protocol is one area where shortcuts consistently backfire. A 3-week immunization protocol may appear to save time, but it produces unknown antibody titers and a weaker immune response, meaning the screening campaign starts with a lower-quality input. A 2-month immunization protocol, by contrast, ensures a robust immune response and a diverse, high-affinity antibody repertoire — the foundation for identifying leads that will survive the rigors of preclinical development.
Where legitimate acceleration is possible is in the screening and lead generation phase. Traditional hybridoma technology requires 2 to 3 months to generate stable cell lines for antibody production. Single B-cell (SBC) cloning compresses this to approximately one month while preserving the native antibody sequence and avoiding the somatic mutations that can occur during hybridoma fusion. For ADC programs where conjugation site engineering and developability assessment follow immediately after lead selection, this time saving is meaningful without introducing quality risk.
Screening Depth and Developability Assessment
ADC antibody components face a more demanding developability filter than conventional therapeutic antibodies. Beyond standard affinity and selectivity criteria, the antibody must tolerate conjugation chemistry without losing binding activity, maintain stability under the conditions used for linker attachment, and demonstrate acceptable pharmacokinetics in the conjugated form. Screening platforms that allow function-based assays — rather than binding-only selection — identify leads that are more likely to retain activity through conjugation and formulation.
Developability assessment should be integrated into the lead generation workflow rather than treated as a downstream checkpoint. Aggregation propensity, thermal stability, and expression yield in the intended production system are all parameters that, if assessed early, prevent the costly experience of advancing a lead through conjugation chemistry only to discover a manufacturing liability. Nona’s Hu-mAtrIX platform enables early developability prediction to be built into the screening workflow, flagging liabilities before they become program-stopping surprises.
Linker-Payload Selection and the Path to IND-Enabling Studies
Antibody selection and conjugation chemistry are interdependent decisions. The choice of linker and payload affects not only efficacy but also the conjugation strategy, which in turn influences which antibody formats and conjugation sites are viable. Prospects evaluating ADC development partners consistently ask detailed questions about linker chemistry, payload options, and conjugation methods — and for good reason. These decisions lock in the molecule’s core pharmacology.
Current approved ADCs rely heavily on a small number of payload classes, including topoisomerase I inhibitors (Topo1i) and tubulin-targeting agents like MMAE. Resistance to these payloads is an emerging clinical problem, and the field is actively seeking novel linker-payload combinations that can overcome resistance mechanisms and improve overall toxicology profiles. For discovery teams, this means payload selection should be evaluated not only against the current competitive landscape but also with an eye toward differentiation and patient populations where existing ADC payloads have failed. Nona’s recent blog on evolving ADCs through emerging payloads and linkers covers this landscape in depth.
IP ownership across the linker-payload space is complex. Some of the most widely used chemistries carry licensing requirements that, if not assessed early, can create freedom-to-operate problems during IND-enabling studies or at commercialization. Platform selection — including the antibody discovery platform — should be evaluated alongside linker-payload IP to ensure the full molecule has a clear path to the clinic. Nona’s model grants clients complete IP ownership and freedom to operate, which removes one of the most common late-stage deal complications in ADC development.
Preclinical Package Requirements for ADC INDs
The IND-enabling package for an ADC is more complex than for a conventional monoclonal antibody. Regulators require characterization of the drug-antibody ratio (DAR) distribution, linker stability data, payload release kinetics, and species-appropriate toxicology studies that account for both the antibody and the payload. CMC timelines and costs are a consistent area of concern for development teams, and clarity on whether these activities are conducted in-house or through partner CROs affects both timeline predictability and risk management.
Oncology remains the dominant indication for ADC development, accounting for approximately 50% of industry spending in this space. However, the engineering principles driving next-generation ADCs — conditional activation, tumor microenvironment-dependent payload release, compact binder formats — are beginning to find application in autoimmune and neurological indications, where off-target toxicity constraints are equally demanding.
Building an ADC Program That Reaches the Clinic
The ADC programs most likely to reach IND on schedule are those where antibody format, conjugation chemistry, and preclinical strategy are aligned from the earliest discovery decisions. Retrofitting an antibody lead that was selected without ADC-specific developability criteria, or discovering IP conflicts in the linker chemistry after lead optimization is complete, are avoidable failures that consistently delay programs by months.
Nona’s integrated Idea-to-IND® model — spanning target validation, antigen preparation, immunization, antibody screening, lead engineering, developability assessment, and preclinical pharmacology — is designed to keep these decisions connected throughout the program. The combination of Harbour Mice® H2L2 and HCAb platforms within a single discovery system means teams developing conventional IgG ADCs and those exploring next-generation fragment or bispecific ADC formats can access the right antibody format without switching platforms or partners mid-program.
If you are evaluating antibody discovery partners for an ADC program, the right conversation starts with format strategy and IP — not just timelines and pricing. Connect with Nona’s scientific team to discuss how the I to I® platform maps to your specific ADC development objectives.
